A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) Plus Pembrolizumab (MK-3475) in Previously Treated Subjects With Selected Solid Tumors (LEAP-005)
Phase: PHASE2
Conditions: Advanced Solid Tumors, Triple Negative Breast Cancer, Ovarian Cancer, Gastric Cancer, Colorectal Cancer, Glioblastoma, Biliary Tract Cancers, Pancreatic Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:                NCT03797326
Document Date:            18-Jan-2024
A Multicenter, Open-label Phase 2 Study of Lenvatinib 
(E7080/MK-7902) Plus Pembrolizumab (MK-3475) in 
Previously Treated Subjects with Selected Solid 
Tumors (LEAP-005)

PRODUCT: MK-7902 
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PROTOCOL/AMENDMENT NO.: MK-7902-005-06 (E7080-G000-224)
MK-7902-005-06 FINAL PROTOCOL
18-JAN-2024
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) 
Plus Pembrolizumab (MK-3475) in Previously Treated Subjects with Selected Solid Tumors 
(LEAP-005)
Protocol Number: MK-7902-005-06 (E7080-G000-224)
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 cofunded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
140,509
Eudra CT Number
2018-003747-37
Approval Date: 18 January 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 6
18-JAN-2024
This change provides an option for participants to 
continue in an extension study
Amendment 5
14-OCT-2022
Sponsor underwent an entity name change and 
update to the address
Amendment 4
11-JUN-2021
Amended to indicate that the triple-negative breast 
cancer (TNBC) and the ovarian cancer cohort will 
not enroll participants in the expansion phase and 
to correct minor errors
Amendment 3
10-DEC-2020
Amended to add lenvatinib monotherapy arms to 
the ovarian and colorectal cancer (CRC) cohorts to 
obtain contribution of component data and to add 
a pancreatic cancer cohort
Amendment 2
17-JUN-2020
Amended to update and clarify language for
progression of the study to the expansion phase
and to correct minor errors
Amendment 1
12-JUN-2019
Amended to incorporate changes requested by 
Health Authorities and correct minor errors
Original protocol
25-OCT-2018
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendment:
This change provides an option for participants to continue in an extension study.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 6.7, 
Intervention After 
the End of the 
Study
Updated language to provide guidance for 
eligible participants to continue in an extension 
study, if available.
This change provides an option for participants 
to continue in an extension study.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1.1, 
Synopsis
Estimated Duration of Study:
Updated the number of months.
To align with the revised estimate for study 
duration.
Section 1.1, 
Synopsis
Duration of Participation:
Updated language to include participation in an 
extension study.
The language updates align with the enrollment 
of eligible participants to an extension study.
4.4, Beginning 
and End of Study 
Definition
The language was updated to include 
participation in an extension study.
Refer to Section 1.1 duration of participation 
rationale.
Section 8.4.1, 
Time Period and 
Frequency for 
Collecting AE, 
SAE, and Other 
Reportable Safety 
Event 
Information
Updated language specific to participants who 
enter the extension study.
To provide safety reporting directions for 
participants who enter the extension study. 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................22
2
INTRODUCTION..........................................................................................................41
2.1
Background ..........................................................................................................41
2.1.1
Pharmaceutical and Therapeutic Background .............................................41
2.1.1.1
Lenvatinib ..........................................................................................41
2.1.1.2
Pembrolizumab ..................................................................................42
2.1.1.3
Scientific Rationale for the Combination of Lenvatinib with 
Pembrolizumab ..................................................................................43
2.1.2
Preclinical and Clinical Studies ...................................................................44
2.1.3
Ongoing Clinical Studies.............................................................................44
2.2
Benefit/Risk Assessment......................................................................................44
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................44
4
STUDY DESIGN............................................................................................................48
4.1
Overall Design......................................................................................................48
4.1.1
Cohort Expansion (Cohorts A-F).................................................................50
4.1.2
Cohort G (Pancreatic Cancer)......................................................................50
4.1.3
Early Termination of Cohort(s) and/or Discontinuation of Cohort 
Enrollment....................................................................................................51
4.2
Scientific Rationale for Study Design.................................................................51
4.2.1
Cohorts A-F .................................................................................................51
4.2.2
Cohort G (Pancreatic Cancer)......................................................................51
4.2.3
Rationale for Endpoints ...............................................................................52
4.2.3.1
Efficacy Endpoints.............................................................................52
4.2.3.1.1
RECIST 1.1..............................................................................52
4.2.3.1.2
Modified RECIST 1.1 for Immune-based Therapeutics 
(iRECIST)................................................................................53
4.2.3.1.3
Response Assessment in Neuro-Oncology (RANO)...............53
4.2.3.2
Safety Endpoints................................................................................54
4.2.3.3
Patient-reported Outcomes.................................................................54
4.2.3.3.1
EORTC QLQ-C30 ...................................................................54
4.2.3.3.2
EQ-5D-5L ................................................................................55
4.2.3.3.3
Cohort-Specific Patient-reported Outcomes............................55
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4.2.3.3.3.1
EORTC QLQ-BR23.......................................................55
4.2.3.3.3.2
EORTC QLQ-OV28 ......................................................56
4.2.3.3.3.3
EORTC QLQ-STO22 ....................................................56
4.2.3.3.3.4
EORTC QLQ-CR29.......................................................56
4.2.3.3.3.5
EORTC QLQ-BN20 ......................................................56
4.2.3.3.3.6
EORTC QLQ-BIL21 .....................................................56
4.2.3.3.3.7
EORTC QLQ-PAN26....................................................56
4.2.3.4
Pharmacokinetic Endpoints ...............................................................57
4.2.3.5
Pharmacodynamic Endpoints.............................................................57
4.2.3.6
Planned Exploratory Biomarker Research.........................................57
4.3
Justification for Dose...........................................................................................59
4.3.1
Starting Dose for This Study........................................................................59
4.3.1.1
Lenvatinib ..........................................................................................59
4.3.1.2
Pembrolizumab ..................................................................................60
4.3.2
Maximum Dose/Exposure for This Study ...................................................61
4.4
Beginning and End of Study Definition .............................................................61
4.4.1
Clinical Criteria for Early Study Termination .............................................61
5
STUDY POPULATION ................................................................................................61
5.1
Inclusion Criteria.................................................................................................62
5.1.1
Triple-Negative Breast Cancer-Specific Inclusion Criteria.........................66
5.1.2
Ovarian Cancer-Specific Inclusion Criteria.................................................66
5.1.3
Gastric Cancer-Specific Inclusion Criteria..................................................67
5.1.4
Colorectal Cancer-Specific Inclusion Criteria.............................................68
5.1.5
GBM Specific Inclusion Criteria .................................................................69
5.1.6
Biliary Tract Cancer-Specific Inclusion Criteria .........................................70
5.1.7
Pancreatic Cancer-Specific Inclusion Criteria.............................................71
5.2
Exclusion Criteria................................................................................................72
5.2.1
GBM Specific Exclusion Criteria................................................................75
5.3
Lifestyle Considerations......................................................................................76
5.3.1
Contraception...............................................................................................76
5.3.2
Pregnancy.....................................................................................................76
5.3.3
Use in Nursing Women................................................................................76
5.4
Screen Failures.....................................................................................................76
5.5
Participant Replacement Strategy......................................................................76
6
STUDY INTERVENTION............................................................................................77
6.1
Study Intervention(s) Administered...................................................................77
6.1.1
Medical Devices...........................................................................................79
6.2
Preparation/Handling/Storage/Accountability .................................................79
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6.2.1
Dose Preparation..........................................................................................79
6.2.2
Handling, Storage, and Accountability........................................................79
6.3
Measures to Minimize Bias: Randomization and Blinding..............................80
6.3.1
Intervention Assignment..............................................................................80
6.3.2
Stratification.................................................................................................80
6.3.3
Blinding........................................................................................................80
6.4
Study Intervention Compliance..........................................................................80
6.5
Concomitant Therapy..........................................................................................80
6.5.1
Allowed Concomitant Medication(s)...........................................................81
6.5.2
Prohibited Concomitant Medication(s)........................................................82
6.5.3
Drug Interactions .........................................................................................83
6.5.4
Rescue Medications and Supportive Care ...................................................83
6.6
Dose Modification (Escalation/Titration/Other)...............................................84
6.6.1
Pembrolizumab ............................................................................................84
6.6.1.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................84
6.6.1.2
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Pembrolizumab................................................88
6.6.1.3
Other Allowed Dose Interruption for Pembrolizumab ......................91
6.6.2
Lenvatinib ....................................................................................................91
6.6.2.1
Management of Hypertension............................................................93
6.6.2.2
Management of Proteinuria................................................................95
6.6.2.3
Management of Diarrhea ...................................................................96
6.6.2.4
Management of Hepatotoxicity..........................................................96
6.6.2.5
Management of Thromboembolic Events..........................................96
6.6.2.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .......................................96
6.6.2.7
Management of Hypocalcemia ..........................................................97
6.6.2.8
Management of Hemorrhage .............................................................97
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation ...97
6.6.2.10
Management of QT Prolongation ......................................................97
6.6.2.11
Management of Osteonecrosis of the Jaw .........................................97
6.6.3
Dose Modifications for Overlapping Toxicities ..........................................98
6.6.4
Other Allowed Dose Interruptions...............................................................99
6.7
Intervention After the End of the Study............................................................99
6.8
Clinical Supplies Disclosure................................................................................99
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................99
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7.1
Discontinuation of Study Intervention...............................................................99
7.2
Participant Withdrawal From the Study.........................................................102
7.3
Lost to Follow-up ...............................................................................................102
8
STUDY ASSESSMENTS AND PROCEDURES......................................................103
8.1
Administrative and General Procedures .........................................................103
8.1.1
Informed Consent.......................................................................................103
8.1.1.1
General Informed Consent...............................................................104
8.1.2
Inclusion/Exclusion Criteria ......................................................................104
8.1.3
Participant Identification Card...................................................................104
8.1.4
Medical History .........................................................................................105
8.1.5
Disease-specific Biomarker Data Collection.............................................105
8.1.6
Prior and Concomitant Medications Review.............................................106
8.1.6.1
Prior Medications.............................................................................106
8.1.6.2
Concomitant Medications................................................................106
8.1.7
Assignment of Screening Number.............................................................106
8.1.8
Assignment of Treatment/Randomization Number...................................106
8.1.9
Study Intervention Administration ............................................................106
8.1.9.1
Timing of Dose Administration.......................................................106
8.1.9.1.1
Lenvatinib ..............................................................................106
8.1.9.1.2
Pembrolizumab ......................................................................107
8.1.9.2
Compliance ......................................................................................107
8.1.10
Discontinuation and Withdrawal ...............................................................107
8.1.11
Participant Blinding/Unblinding................................................................107
8.1.12
Calibration of Equipment...........................................................................107
8.1.13
Antineoplastic Treatment...........................................................................108
8.2
Efficacy/Immunogenicity Assessments ............................................................108
8.2.1
Tumor Imaging and Assessment of Disease..............................................108
8.2.1.1
Initial Tumor Imaging......................................................................109
8.2.1.2
Tumor Imaging During the Study....................................................109
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging..........................110
8.2.1.4
RECIST 1.1 Assessment of Disease (Non-GBM Cohorts) .............110
8.2.1.5
iRECIST Assessment of Disease.....................................................110
8.2.1.6
Response Assessment in Neuro-Oncology (RANO).......................113
8.2.2
Patient-reported Outcomes.........................................................................114
8.3
Safety Assessments.............................................................................................115
8.3.1
Physical Examinations...............................................................................115
8.3.1.1
Full Physical Examination...............................................................115
8.3.1.2
Symptom-Directed Physical Examination.......................................116
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8.3.2
Vital Signs..................................................................................................116
8.3.3
Electrocardiograms ....................................................................................116
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan...............................117
8.3.5
Child-Pugh Score.......................................................................................117
8.3.6
Clinical Safety Laboratory Assessments ...................................................117
8.3.6.1
Laboratory Safety Assessments.......................................................118
8.3.6.2
Urine Dipstick..................................................................................118
8.3.7
Eastern Cooperative Oncology Group Performance Status.......................118
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................119
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................119
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....122
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.122
8.4.4
Regulatory Reporting Requirements for SAE ...........................................122
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................122
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................123
8.4.7
Events of Clinical Interest (ECIs)..............................................................123
8.5
Treatment of Overdose......................................................................................124
8.6
Pharmacokinetics...............................................................................................124
8.7
Pharmacodynamics............................................................................................124
8.8
Biomarkers .........................................................................................................125
8.8.1
Planned Genetic Analysis Sample Collection............................................125
8.9
Health Economics Medical Resource Utilization and Health Economics.....125
8.10
Visit Requirements.............................................................................................125
8.10.1
Screening....................................................................................................126
8.10.2
Rescreening................................................................................................126
8.10.3
Treatment Period........................................................................................126
8.10.3.1
Phone Contact Visit .........................................................................126
8.10.4
Post treatment Visit....................................................................................127
8.10.4.1
Safety Follow-up Visit.....................................................................127
8.10.4.2
Efficacy Follow-up Visits................................................................127
8.10.4.3
Survival Follow-up Assessments.....................................................127
8.10.5
Survival Status ...........................................................................................128
9
STATISTICAL ANALYSIS PLAN ...........................................................................128
9.1
Statistical Analysis Plan Summary...................................................................128
9.2
Responsibility for Analyses/In-house Blinding ...............................................129
9.3
Hypotheses/Estimation ......................................................................................130
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9.4
Analysis Endpoints.............................................................................................130
9.4.1
Efficacy Endpoints.....................................................................................130
9.4.2
Safety Endpoints........................................................................................130
9.4.3
Patient-reported Outcome Endpoints.........................................................131
9.5
Analysis Populations..........................................................................................131
9.5.1
Efficacy Analysis Populations...................................................................131
9.5.2
Safety Analysis Populations ......................................................................132
9.5.3
PRO Analysis Population ..........................................................................132
9.6
Statistical Methods.............................................................................................132
.................................................132
9.6.2
Statistical Methods for Safety Analyses ....................................................135
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................135
................................................................................................135
9.8
Multiplicity .........................................................................................................137
9.9
Sample Size and Power Calculations ...............................................................137
9.10
Subgroup Analyses.............................................................................................141
9.11
Compliance (Medication Adherence)...............................................................141
9.12
Extent of Exposure.............................................................................................141
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................142
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......142
10.1.1
Code of Conduct for Clinical Trials...........................................................142
10.1.2
Financial Disclosure...................................................................................144
10.1.3
Data Protection...........................................................................................144
10.1.3.1
Confidentiality of Data ....................................................................145
10.1.3.2
Confidentiality of Participant Records.............................................145
10.1.3.3
Confidentiality of IRB/IEC Information..........................................145
10.1.4
Committees Structure.................................................................................145
10.1.4.1
Scientific Advisory Committee (SAC)............................................145
10.1.5
Publication Policy......................................................................................145
10.1.6
Compliance with Study Registration and Results Posting Requirements .146
10.1.7
Compliance with Law, Audit, and Debarment ..........................................146
10.1.8
Data Quality Assurance .............................................................................147
10.1.9
Source Documents .....................................................................................148
10.1.10
Study and Site Closure...............................................................................148
10.2
Appendix 2: Clinical Laboratory Tests............................................................149
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................151
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10.3.1
Definitions of Medication Error, Misuse, and Abuse................................151
10.3.2
Definition of AE ........................................................................................151
10.3.3
Definition of SAE ......................................................................................152
10.3.4
Additional Events Reported in the Same Manner as SAE.........................153
10.3.5
Recording AE and SAE .............................................................................154
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................155
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................156
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................157
10.5.1
Definitions..................................................................................................157
10.5.2
Contraception Requirements......................................................................158
10.5.3
Pregnancy Testing......................................................................................159
10.6
Appendix 6: NYHA Criteria.............................................................................160
10.7
Appendix 7: Country-specific Requirements..................................................161
10.7.1
France.........................................................................................................161
10.7.2
Germany.....................................................................................................162
10.7.3
United Kingdom.........................................................................................162
10.7.4
Canada........................................................................................................163
10.7.5
Argentina....................................................................................................163
10.8
Appendix 8: Clinical Studies Evaluating Drug-Drug Interactions With 
Lenvatinib...........................................................................................................164
10.9
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................165
10.10 Appendix 10: Response Assessment in Neuro-Oncology (RANO) 
Response Criteria...............................................................................................169
10.11 Appendix 11: Abbreviations .............................................................................174
11
REFERENCES.............................................................................................................178
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values................................................65
Table 2
Study Interventions.........................................................................................78
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations..............................................................85
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.......................................................................................................89
Table 5
Dose Modification Guidelines for Lenvatinib-Related Adverse Events........92
Table 6
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease..........................................................................................................112
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events .............................................................................121
..................................................133
.............................................134
 
..................................................136
 
.......................................................................................138
 
.................................................................................139
 
....................................................................................................140
 
..........................................................................140
Table 15
Protocol-required Safety Laboratory Assessments ......................................150
Table 16
Target Lesion Response ...............................................................................170
Table 17
Lesion Response for Enhancing Nontarget Lesions.....................................170
Table 18
Radiographic Response ................................................................................171
Table 19
Overall Response..........................................................................................173
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LIST OF FIGURES
Figure 1
Study Diagram................................................................................................20
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator...................................................................................................113
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) 
Plus Pembrolizumab (MK-3475) in Previously Treated Subjects with Selected Solid Tumors 
(LEAP-005)
Short Title: Pembrolizumab plus lenvatinib as second-line plus intervention for select solid 
tumors
Acronym: Protocol 005
Hypotheses, Objectives, and Endpoints:
In participants with triple-negative breast cancer (TNBC, Cohort A), ovarian cancer 
(Cohort B), gastric cancer (Cohort C), colorectal cancer (CRC, Cohort D), glioblastoma 
(GBM, Cohort E), biliary tract cancers (BTC, Cohort F), or pancreatic cancer (Cohort G), the 
objectives and endpoints outlined below will be evaluated.
Efficacy analyses will be performed by cohort/tumor type and Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1, modified to follow a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ (Section 4.2.3.1), will be used for all tumor cohorts 
except GBM, which will use Response Assessment in Neuro-Oncology (RANO) Criteria 
(Section 4.2.3.1.3).
For Cohorts A-F, RECIST 1.1 (RANO for GBM) by investigator assessments will be used in 
the initial 30 enrolled participants. RECIST 1.1 (RANO for GBM) by blinded independent 
central review (BICR) will be used in cohorts that expand to combine the initial 30 enrolled 
participants with the additional 70 to 100 expansion participants. For Cohort G, which will 
enroll 100 participants, RECIST 1.1 by BICR will be used.
For participants receiving pembrolizumab (Arm 1 only), modified RECIST 1.1 for immune-
based therapeutics (iRECIST) will be used by investigators to assess tumor response and 
progression, and make treatment decisions, as well as for exploratory efficacy analyses 
(Section 4.2.3.1.2).
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Primary Objectives
Primary Endpoints
Objective: To evaluate objective response 
rate (ORR) of pembrolizumab in 
combination with lenvatinib per tumor 
cohort based on RECIST 1.1 by investigator 
assessments in initial cohorts and BICR in 
cohorts that expand combining the initial 
and expansion cohorts (Cohorts A-F). In 
Cohort G, RECIST 1.1 by BICR will be 
utilized in all participants.
(For participants with GBM, response will 
be assessed based on Response Assessment 
in Neuro-Oncology [RANO] criteria; all 
further references to RECIST 1.1 
assessment apply to all cohorts except 
GBM.)
Objective response (OR), complete 
response (CR), or partial response (PR)
Objective: To assess safety and tolerability 
of treatment with pembrolizumab in 
combination with lenvatinib per tumor 
cohort assessed by the proportion of adverse 
events (AEs).
AEs
Discontinuation due to AEs
Objective: To assess safety and tolerability 
of treatment with lenvatinib monotherapy 
assessed by the proportion of AEs.
AEs
Discontinuation due to AEs
Secondary Objectives
Secondary Endpoints
Objective: To evaluate disease control rate 
(DCR), duration of response (DOR), and 
progression-free survival (PFS) of 
pembrolizumab in combination with 
lenvatinib per tumor cohort based on 
RECIST 1.1 (RANO for GBM) by 
investigator assessments in initial cohorts 
and BICR in cohorts that expand combining 
the initial and expansion cohorts 
(Cohorts A-F). In Cohort G, RECIST 1.1 by 
BICR will be utilized in all participants.
Disease control, defined as best overall 
response of CR, PR, or SD
DOR, determined by disease assessment 
defined as the time from the earliest date of 
qualifying response until the earliest date of 
disease progression or death from any 
cause, whichever comes first.
PFS, defined as the time from the first day 
of study intervention to the day of the first 
documentation of disease progression or 
death from any cause, whichever occurs 
first.
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Objective: To evaluate overall survival (OS) 
of pembrolizumab in combination with 
lenvatinib per tumor cohort.
OS, defined as the time from the first day of 
study intervention to day of death from any 
cause.
Objective: To evaluate ORR, DCR, DOR, 
PFS, and OS of lenvatinib monotherapy 
based on RECIST 1.1 by BICR.
OR
DCR
DOR
PFS
OS
Objective: To characterize the population 
pharmacokinetics (PK) of lenvatinib when 
co-administered with pembrolizumab in 
participants per tumor cohort (Cohorts A-F 
only).
Plasma concentration of lenvatinib.
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Treatment of participants with relapsed/refractory TNBC, 
ovarian cancer, gastric cancer, CRC, GBM, BTC, or 
pancreatic cancer
Population
Participants with TNBC, ovarian cancer, gastric cancer, 
CRC, GBM, BTC, or pancreatic cancer
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
None
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 70 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.
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Number of Participants:
Initially, approximately 180 participants (30 per cohort in Cohorts A-F) will be stratified by 
tumor cohort and enrolled in the study as described in Section 4.1.
Expansion portion of the study: an interim analysis, based on investigator assessments of 
efficacy, will be conducted for each tumor-specific cohort when the last of the initial 
30 participants have been followed up for approximately 6 months from study entry. Since 
enrollment rates will be variable for each cohort, separate interim analyses may be needed for 
individual or groups of cohorts. In the event of slow enrollment, IAs may take place when the 
majority of participants have been followed up for 6 months from study entry. After Sponsor 
review of the results of each IA, recommendations for expansion will be given. Cohorts A 
and B will not enroll participants in the expansion phase. Cohorts C, E, and F will each 
include 100 participants: the initial 30 participants enrolled into each cohort, plus the 
additional 70 participants enrolled in the expansion phase. Cohort D will include 130 
participants: the initial 30 participants enrolled, plus an additional 100 participants enrolled 
in the expansion phase, with the last approximately 60 participants randomized 1:1 to receive 
pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 2). Additionally, 
Cohort G will enroll 100 participants. The potential total number of participants in the study 
will be 590.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Intervention
Dose 
Strength
Dose 
Frequency
Route of 
Admini-
stration
Regimen/ 
Treatment 
Period
Use
Arm 1
Lenvatinib
20 mg
qd
Orally
Daily
Test 
product
Arm 1
Pembrolizumab
200 mg
q3w
IV 
infusion
Day 1 of 
each 21-
day cycle
Test 
product
Arm 2a
Lenvatinib
24 mg
qd
Orally
Daily
Test 
product
IV = intravenous; q3w = once every 3 weeks; qd = once per day
a Cohort D (CRC) only.
Total 
Number
2 arms
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Duration of 
Participation
After a screening phase of up to 28 days, each eligible participant will be 
assigned to receive study intervention with pembrolizumab + lenvatinib
(Arm 1, Cohorts A-G) or lenvatinib monotherapy (Arm 2, Cohort D only).
Participants will continue on study intervention until disease progression is 
radiographically documented per RECIST 1.1 or RANO criteria for 
participants with GBM, unacceptable toxicity, withdrawal of consent, 
initiation of new anticancer treatment, intercurrent illness that prevents 
further administration of treatment, investigator’s decision to discontinue 
the participant, pregnancy, administrative reasons requiring cessation of 
treatment or death. Pembrolizumab treatment will be discontinued once the 
participant has received 35 administrations of pembrolizumab 
(approximately 2 years). Participants in Arm 1 and Arm 2 may continue 
treatment with lenvatinib beyond 2 years if they experience clinical benefit 
according to the PI, with Sponsor consultation. In addition, discontinuation 
of study treatment with pembrolizumab and lenvatinib may be considered 
for participants who have attained a confirmed CR per RECIST 1.1 (or per 
RANO for GBM cohort) and have been treated for at least 24 weeks, 
receiving at least 2 additional doses of pembrolizumab beyond the date 
when the initial CR is declared.
Participants will be permitted to continue treatment beyond RECIST 1.1- or 
RANO-defined progression (Arm 1 only) as long as investigator-assessed 
clinical stability is observed, the participant is tolerating study intervention
(Section 8.2.1.5 or Section 8.2.1.6) and after obtaining documented 
informed consent addendum. Treatment beyond confirmed progressive 
disease (PD) per iRECIST or RANO may be permitted on Sponsor 
consultation.
After the end of treatment (EOT), each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4.
Participants who discontinue study intervention without documented 
disease progression will have posttreatment follow-up imaging for disease 
status until the start of a new anticancer treatment, disease progression, 
pregnancy, death, withdrawal of consent, or the end of the study, whichever 
occurs first.
All participants will be contacted (by telephone or visit) approximately 
every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first (unless this 
information is not allowed to be provided due to confidentiality).
The end of the study will be the date when the last participant completes the 
last study-related telephone call or visit, withdraws from the study, is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator), 
or is planned to be enrolled in an extension study.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 11.
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1.2
Schema
Figure 1
Study Diagram
FU = follow-up; GBM = glioblastoma; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-Based Therapeutics; ORR = objective response rate; 
q3w = once every 3 weeks; q24w = once every 24 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RANO = Response Assessment in Neuro-Oncology; 
TNBC = triple-negative breast cancer.
Note: For all cohorts (except GBM), tumor imaging should be performed every 9 weeks (63 days ±7 days) or more frequently if clinically indicated. After 54 weeks (378 days 
±7 days), participants who remain on treatment will have imaging performed every 12 weeks (84 days ±7 days) or sooner if clinically indicated, until Week 102. After Week 
102, imaging should be performed q24w or sooner if clinically indicated. For participants with GBM, imaging will be performed at 6 weeks (42 days to 49 days) from the
date of treatment initiation. Subsequent tumor imaging should be performed every 6 weeks (42 days ±7 days) until Week 18 and then every 9 weeks thereafter or more 
frequently if clinically indicated. After 54 weeks (378 days ±7 days), participants who remain on treatment will have imaging performed every 12 weeks (84 days ±7 days) or 
sooner if clinically indicated until Week 102. After Week 102, imaging should be performed q24w or sooner if clinically indicated.
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Note: Specific cohort(s) may be terminated early and/or further enrollment stopped as noted in Section 4.1.3
a
Evaluation of response by RECIST 1.1; RANO (GBM only); or iRECIST (Arm 1 only)
b
Initial allocation; if adequate ORR determined, cohort expansion to 100 participants (Cohorts C, E, and F) or 130 participants (Cohort D)
c
Expansion phase
d
Total allocation (Cohort G)
e
The last 60 participants will be randomized 1:1.
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Administrative and General Procedures
Informed Consent
X
Consent form can be 
documented at any time before
any protocol-specific screening 
procedures are performed. If the 
investigator plans to treat beyond 
disease progression, additional 
consent is required.
Inclusion/Exclusion 
Criteria
X
Participant Identification 
Card
X
Demographics
X
Staging
X
At initial diagnosis and at study 
entry
Medical/Surgical History
X
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
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.
Subsequent antineoplastic 
treatment
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 via telephone or email.
Allocation/randomization
via IRT
X
Participants will be 
allocated/randomized on C1D1 
(-3d) after confirmation of 
eligibility.
All procedures and assessments 
on C1D1 should be performed 
after allocation/randomization.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Phone contact visit
X
Telephone contact or visit on 
C1D8 will assess participants for 
BP and development of early 
toxicity.
BP will be taken, for example, at 
home or at a local pharmacy, and 
will be reviewed with the 
investigator or designee (See 
Sec. 8.3.2).
The investigator or medically 
qualified designee (consistent 
with local requirements) will 
assess participants for 
development of early toxicity. 
An unscheduled visit can occur 
before C1D15 if necessary for 
safety.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Survival Status
Participants who experience 
confirmed PD or start a new 
anticancer therapy, will be 
contacted (by telephone or visit) 
approximately every 12 weeks to 
assess for survival status until 
death, withdrawal of consent or 
the end of the study, whichever 
occurs first (unless this 
information is not allowed to be 
provided due to confidentiality).
All subsequent anticancer 
therapy will be recorded.
Updated survival status may be 
requested by the Sponsor at any 
time during the course of the 
study. See Section 8.10.5.
 
 
 
CCI
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
 
 
 
 
 
 
 
 
CCI
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Administration of Study Treatment
Pembrolizumab + 
lenvatinib (Arm 1) and 
lenvatinib monotherapy 
(Arm 2) 
Administration/Dispensing
X
X
X
X
Pembrolizumab 200 mg 
q3w/lenvatinib 20 mg qd (Arm 
1, all cohorts); lenvatinib 24 mg 
qd (Arm 2, CRC cohort only); 
21-day cycle.
Lenvatinib will be administered 
0 to 4 hours after completion of 
pembrolizumab administration 
on C1D1, C1D15, and C2D1 
(Arm 1 only).
Efficacy Procedures
Tumor Assessment -
(CT/MRI)c
X
X
X
All imaging visits have a 
scheduling window of ±7 days.
Imaging at EOT is not required if 
the previous tumor imaging 
assessment was within 4 weeks 
before the EOT Visit.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Brain MRId
X
X
X
All imaging visits have a 
scheduling window of ±7 days.
For participants with GBM, brain 
MRI is required at baseline and 
every imaging visit thereafter.
For non-GBM cohorts, 
participants with previously 
treated brain metastases are 
required to have a brain MRI at 
screening and at all subsequent 
tumor assessment time points. A 
brain MRI is also required for all 
participants when clinically 
indicated.
Imaging at EOT is not required if 
the previous tumor imaging 
assessment was within 4 weeks 
before the EOT Visit.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Bone Scan
X
X
X
For breast cancer cohort, bone
scan is required at screening.
If bone metastases are present, 
bone scans are required every 27 
weeks, or more often if clinically 
indicated.
If CR is suspected based on 
anatomic imaging, a bone scan is 
required to confirm clearance of 
bone metastases either within the 
same imaging visit as the 
anatomic imaging, or on the next 
anatomic scan.
Imaging at EOT is not required if 
the previous tumor imaging 
assessment was within 4 weeks 
before the EOT Visit.
Clinical Procedures or Assessments
Full physical examination
X
To be performed within 7 days 
before the start of study 
treatment. Includes oral 
examination.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Directed Physical 
Examination
X
X
X
X
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. Includes oral 
examination.
Vital Signs (resting BP, 
HR, RR, and temperature), 
height and weight
X
X
X
X
X
X
X
X
BP and HR will be measured 
after the participant has been 
resting for 5 minutes.
Height measured at screening 
only.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
12-lead ECG
X
X
X
X
X
X
ECG at screening, C1D1, C2D1, 
D1 of every 4th cycle (12 weeks) 
thereafter (eg, C6, C10, C14, 
etc.), EOT, and safety follow-up.
On C1D1 and C2D1: A predose 
ECG and a repeat ECG 
(approximately 2 hours after
lenvatinib dosing) must be 
performed.
For high-risk participants (as 
defined in Section 8.3.3), 
conduct ECG monitoring every 
cycle.
If lenvatinib is discontinued, 
ECGs are only required at the 
EOT and Safety Follow-up 
visits.
MUGA or ECHO for 
LVEF assessment
X
X
Additional assessments as 
clinically indicated.
Assessments should use the same 
method (MUGA or ECHO)
throughout the study.
NYHA
X
See Appendix 6
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
ECOG performance status
X
X
X
X
To be assessed within 3 days 
before allocation/randomization.
Should be assessed before dosing 
at treatment visits.
Child-Pugh Score
X
For BTC cohort only:
To be assessed within 7 days of 
treatment initiation.
Child-Pugh Score must be 5-6
(Class A) for participant 
eligibility.
AE monitoring
X
X
X
X
X
X
X
X
X
AEs monitored up to 30 days 
after last dose.
SAEs monitored up to 90 days
and pregnancy monitored up to 
120 days after last dose, or
30 days after last dose if 
participant starts a new 
anticancer therapy, whichever is 
sooner.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Local Laboratory Procedures and Assessmentse
Hematology and chemistry 
laboratory assessment
X
X
X
X
X
X
Performed locally within 7 days
before start of treatment. Every
effort should be made to collect 
samples at the same time of day.
LDH is only required at 
screening.
Urine dipstick testing
X
X
X
X
X
X
X
Performed locally within 7 days
before the start of treatment.
Urinalysis may be used if the use 
of urine dipsticks is not feasible.
Participants with >1+ (30 
mg/dL) 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.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
PT or INR, aPTT and 
Fibrinogen
X
Screening samples collected 
within 7 days of treatment 
initiation.
Additional testing to be 
conducted as clinically indicated 
for participants taking 
anticoagulant therapy.
T3, FT4, TSH
X
X
X
X
At Screening, C2D1, then every 
2 cycles thereafter.
Screening samples to be 
collected within 7 days of 
treatment initiation.
Free T3 is acceptable where T3
cannot be determined.
Pregnancy test (WOCBP 
only)
X
X
X
X
X
X
WOCBP require a negative test 
before randomization and within 
24 hours before to the first dose 
of study intervention. If less than 
24 hours have elapsed between 
the randomization test and the 
first dose of study intervention, 
another pregnancy test is not 
required.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
HIV, HBsAg, HCV
X
Testing is not required unless 
mandated by local health 
authority.
Pharmacokinetics/Biomarkers
Pembrolizumab PK
X
X
X*
*Predose C1D1, C2D1, and 
C8D1 only; Cohorts A-F only.
Pembrolizumab antidrug 
antibodies
X
X
X*
*Predose C1D1, C2D1, and 
C8D1 only; Cohort A-F only.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Lenvatinib PK
X
X
X
C1D1: 0.5-4 h and 6-10 h after
dosing
Note: no predose sampling on 
C1D1
C1D15: predose and 2-12 h 
postdose
C2D1: predose, 0.5-4 h and 6-10 
h postdose
Note: All predose samples 
should be collected within 2 
hours of lenvatinib dosing.
Note: Postdose samples not 
needed if lenvatinib 
administration is skipped.
Cohorts A-F only
Note: does not apply to Arm 2.
Blood for serum 
biomarker
X
X
X
X
X
Collect predose. Collect C1D1, 
C1D15, C2D1, C3D1, C5D1 and 
at EOT.
Blood for RNA Analysis
X
X
X
X
Collect predose on C1D1, C2D1, 
C3D1, C5D1, and at EOT.
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Blood for circulating 
tumor nucleic acids
X
X
X
X
Collect predose. C1D1, C2D1, 
C3D1, C5D1, and then D1 every 
3 cycles, and at EOT.
Blood for plasma 
biomarkers
X
X
X
X
Collect predose. C1D1, C2D1, 
C3D1, C5D1 and then D1 every 
3 cycles, and at EOT.
Blood for genetic analysis
X
Collect predose
Tumor blocks or slides
X
Collected during screening
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Study Period
Screening
Intervention Period
21-Day Cycles
EOT
Post Intervention Visits
Notes
Cycle Number/Day
Cycle 1
Cycle 2
Cycle 3 
Onward
Safety FUa
Efficacy FU
Survival 
FU
1
8
15
1
15
1
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
At DC
30 Days After 
Last Dose 
(+ 7 d)
q9wb (± 7 d)
q12w
(± 7 d)
Patient-Reported Outcomes

EORTC QLQ-C30

EORTC QLQ-
disease-specific:

Breast (QLQ-
BR23)

Ovarian (QLQ-
OV28)

Gastric (QLQ-
STO22)

Colorectal (QLQ-
CR29)

GBM (QLQ-BN20)

Biliary (QLQ-
BIL21)

Pancreatic (QLQ-
PAN26)

EuroQol (EQ)-5D-5L
X
X
X
X
X
PRO assessments will be 
collected at baseline, every cycle 
through Cycle 13, Cycle 17, 
Cycle 21, EOT, and at the 30-
day Safety FU visit.
ePROs will also be obtained at 
the treatment discontinuation 
visit and the 30-day Safety 
Follow-up Visit.
If the treatment discontinuation 
visit occurs 30 days from the last 
dose of study treatment, at the 
time of the mandatory Safety 
Follow-up Visit, ePROs do not 
need to be repeated.
See additional details in Section 
8.2.2.
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AE = adverse event; aPTT = activated partial thromboplastin time; BICR = blinded independent central review; BP = blood pressure; BRCA = breast cancer susceptibility gene; 
BTC = biliary tract cancer; C1 = Cycle 1; C2 = Cycle 2; CR = complete response; CT = computed tomography; CV = cardiovascular; D1 = Day 1; D8 = Day 8; D15 = Day 
15; DC = discontinuation; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; 
EORTC = European Organisation for the Research and Treatment of Cancer; EOT = end of treatment; ePRO = electronic patient-reported outcome; EQ-5D-5L = European 
Quality of Life 5-dimension 5-level; ER = estrogen receptor; FT4 = free thyroxine; FU = follow-up; GBM = glioblastoma; HBsAg = Hepatitis B surface antigen; HCV =
Hepatitis C virus; HER-2 = human epidermal growth factor receptor; HIV = human immunodeficiency virus; HR = heart rate; iCRO = imaging contract research 
organization; IDH 1/2 = isocitrate dehydrogenase 1/2; INR = International normalized ratio; IRT = interactive response technology; LDH = lactic dehydrogenase; LVEF =
left ventricular ejection fraction; MGMT = O6-methylguanine-DNA methyltransferase; MMR = mismatch repair; MRI = magnetic resonance imaging; MSI = microsatellite 
instability; MUGA = multigated acquisition; NYHA = New York Heart Association; PD = progressive disease; PD-L1 = programmed cell death ligand 1; PE = physical 
examination; PK = pharmacokinetics; PRO = patient-reported outcome; PT = prothrombin time; q3w = once every 3 weeks; q6w = once every 6 weeks; q9w = once every 9
weeks; q12w = once every 12 weeks; q24w = once every 24 weeks; qd = once daily; QLQ = quality of life questionnaire; qw = once per week; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors version 1.1; RNA = ribonucleic acid; RR = respiratory rate; SAE = serious adverse event; SIM = site imaging manual; T3 =
triiodothyronine; TMB = tumor mutational burden; TNBC = triple-negative breast cancer; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
Note: See Section 10.7 (Appendix 7) for country-specific requirements.
a
If EOT Visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required. In this situation, all procedures required at both the EOT Visit and 
the Safety Follow-up Visit should be performed at the EOT Visit. End of treatment will be defined as the date when the participant discontinues all study treatments.
b
During the Efficacy Follow-up Phase, tumor assessments should be performed according to the same imaging schedule used while receiving study intervention. Calculated 
from the date of first dose, imaging non-GBM cohorts should be performed q9w (63 days ±7 days) until Week 54 of study intervention (or sooner if clinically indicated) and 
q12w (84 days ±7 days) until Week 102. After Week 102, imaging should be performed q24w (168 days ±7 days) or sooner if clinically indicated. Imaging timing should 
follow calendar days. For the GBM cohort, imaging to be performed at 6 weeks (42 days to 49 days) from the date of treatment initiation. Subsequent tumor imaging should 
be performed q6w (42 days ±7 days) until Week 18 and then q9w thereafter or more frequently if clinically indicated. After 54 weeks (378 days ±7 days), participants who 
remain on treatment will have imaging performed q12w (84 days ±7 days) or sooner if clinically indicated until Week 102. After Week 102, imaging should be performed 
q24w, or sooner if clinically indicated.
c
For non-GBM cohorts, tumor assessments will be based on chest, abdomen and pelvis CT or MRI. Historical scans performed within the screening period but before 
providing documented informed consent may be used if consistent with protocol requirements per SIM. All imaging visits have a scheduling window of ±7 days.
Confirmation of baseline measurable disease per RECIST 1.1 by BICR is required before participant allocation/randomization. Imaging will be performed at 9 weeks 
(63 days ±7 days) from the date of treatment initiation. Subsequent tumor imaging should be performed q9w (63 days ±7 days) or more frequently if clinically indicated. 
After 54 weeks (378 days ±7 days), participants who remain on treatment will have imaging performed q12w (84 days ±7 days) or sooner if clinically indicated until Week 
102. After Week 102, imaging should be performed q24w or sooner if clinically indicated (details to be provided in the SIM). For participants discontinuing for reasons other 
than PD, imaging should be performed q9w (until Week 54) and q12w thereafter. After Week 102 of FU, imaging should be performed q24w. Imaging at EOT is not required 
if the previous tumor imaging assessment was within 4 weeks before the EOT Visit. Imaging of any anatomy that shows disease either at screening or in subsequent 
evaluations will be required and should be submitted to the iCRO.
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d
For the GBM cohort, tumor assessments will be based on MRI of the brain. Historical scans performed within the screening period but before providing documented 
informed consent may be used if consistent with protocol requirements per SIM. Confirmation of baseline measurable disease per RANO by BICR is required before
participant allocation. Imaging will be performed at 6 weeks (42 days to 49 days) from the date of treatment initiation. Subsequent tumor imaging should be performed q6w
(42 days ±7 days) until Week 18 and then q9w thereafter or more frequently if clinically indicated. After 54 weeks (378 days ±7 days), participants who remain on treatment 
will have imaging performed q12w (84 days ±7 days) or sooner if clinically indicated until Week 102. After Week 102, imaging should be performed q24w or sooner if 
clinically indicated (details to be provided in the SIM). For participants discontinuing for reasons other than PD, imaging should be performed q6w until Week 18, q9w until 
Week 54 and q12w thereafter. After Week 102 of FU, imaging should be performed q24w. Imaging of any anatomy that shows disease either at screening or in subsequent 
evaluations will be required and should be submitted to the iCRO. Imaging at EOT is not required if the previous tumor imaging assessment was within 4 weeks before the 
EOT Visit. Imaging of any anatomy that shows disease either at screening or in subsequent evaluations will be required and should be submitted to the iCRO.
e
Clinical laboratory assessments may be conducted any time within 72 hours before the scheduled visit, unless otherwise specified. Procedures/assessments should be 
performed before administration of study treatment.
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2
INTRODUCTION
The purpose of this study is to determine the safety and efficacy in combining the 
programmed cell death 1 (PD-1) inhibitor pembrolizumab with the receptor tyrosine kinase 
inhibitor (RTKi) lenvatinib (also known as E7080 or MK-7902; hereafter referred to as 
lenvatinib) in participants with TNBC, ovarian cancer, gastric cancer, CRC, glioblastoma 
(GBM), BTC, or pancreatic cancer. 
2.1
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (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 intravenous (IV) immunotherapy for advanced malignancies. 
KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients across several 
indications.
Lenvatinib (also known as E7080 or MK-7902) inhibits the kinase activities of vascular 
endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and 
VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic 
angiogenesis, tumor growth, and cancer progression in addition to their normal cellular 
functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-
derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also showed
antiproliferative activity in cell lines dependent on activated FGFR signaling with a 
concurrent inhibition of FGF-receptor substrate 2α phosphorylation.
Once daily (qd) dosing of lenvatinib combined with pembrolizumab is currently being 
developed for the treatment of relapsed/refractory TNBC, ovarian cancer, gastric cancer, 
CRC, GBM or BTC.
Refer to the respective Investigator Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab and lenvatinib.
2.1.1
Pharmaceutical and Therapeutic Background
2.1.1.1
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 1 to 3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. and Hicklin, D. 
J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that FGF and 
its receptor tyrosine kinase, FGFR also play important roles for tumor angiogenesis [Cross, 
M. J. and Claesson-Welsh L. 2001] [Lieu, C., et al 2011] [Limaverde-Sousa, G., et al 2014].
Lenvatinib is a potent multiple RTK inhibitor that selectively inhibits VEGF receptors, 
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and 
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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 very important for tumor angiogenesis.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 
7.3 nmol/L, respectively. Analysis of the signal transduction molecules revealed that 
lenvatinib inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs 
triggered by activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) 
significantly inhibited both VEGF- and FGF-driven angiogenesis in a murine in vivo model 
[Yamamoto, Y., et al 2014]. In vivo, lenvatinib showed antitumor activity against various 
human tumor xenografts in athymic mice including 5 types of thyroid carcinomas 
(differentiated [papillary and follicular], anaplastic, squamous, and medullary thyroid 
carcinomas), renal cell carcinoma (RCC), HCC, melanoma, gastric cancer, non-small cell 
lung cancer (NSCLC), ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In addition, the 
antitumor activity of lenvatinib in combination with other anticancer agents in several 
xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals. These results suggest that lenvatinib may be 
a novel anticancer therapy through inhibition of angiogenesis and may be useful as either 
monotherapy or in combination with other anticancer drugs.
2.1.1.2
Pembrolizumab
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008]. The PD-1 receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control. The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene 
Pdcd1) is an Ig superfamily member related to CD28 and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling on 
engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald, R. J., et al 2005] [Okazaki, T., 
et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
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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 solid tumors.
2.1.1.3
Scientific Rationale for the Combination of Lenvatinib with Pembrolizumab
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of cluster of differentiation 8 
positive (CD8+) T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-
regs) correlates with improved prognosis and long-term survival in solid malignancies, such 
as ovarian cancer, CRC, pancreatic cancer, hepatocellular carcinoma, malignant melanoma,
and RCC.
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM) 
population, which is known as an immune-regulator in the tumor microenvironment. The 
decrease in TAM population was accompanied by increases in activated cytotoxic T-cell 
populations through stimulation of interferon-gamma signaling, resulting in increased 
immune activation [Kimura, T., et al 2018]. The immune-modulating effect of lenvatinib 
may result in a potent combination effect with PD-1/L1 signal inhibitors. The effect of 
combining lenvatinib with an anti-human PD-1 humanized mAb was investigated in 4 
murine tumor isograft models, which showed significant tumor growth inhibition compared 
with control. In the RAG murine tumor isograft tumor model, survival in the group treated 
with the combination was significantly longer than that of the respective monotherapy 
groups. In the CT26 murine tumor isograft model, treatment with the combination 
significantly increased the population of activated cytotoxic T-cells compared with that of the 
respective monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated and 
severe body weight loss was not observed.
Based on these results, an open-label, Phase 1b/2 study (Study E7080-A001-111 [Study 111])
to assess the safety and preliminary antitumor activity of the combination of lenvatinib +
pembrolizumab in participants with selected solid tumors is currently ongoing. Phase 1b of
this study determined the MTD and RP2D as 20 mg lenvatinib qd in combination with
200 mg of pembrolizumab given intravenously (IV) every 3 weeks (q3w). The safety and
efficacy of the combination at the lenvatinib RP2D is being assessed in the Phase 2 portion of
the study that includes 6 cohorts (ie, NSCLC, RCC, EC, urothelial carcinoma, melanoma, and
squamous cell carcinoma of the head and neck).
No dose reduction is allowed for pembrolizumab in this study.
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2.1.2
Preclinical and Clinical Studies
Refer to the respective IBs for preclinical and clinical study data for pembrolizumab and 
lenvatinib.
2.1.3
Ongoing Clinical Studies
Refer to the respective IBs for ongoing clinical study data for pembrolizumab and lenvatinib.
2.2
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and Informed Consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In participants with TNBC (Cohort A), ovarian cancer (Cohort B), gastric cancer (Cohort C), 
CRC (Cohort D), glioblastoma (GBM, Cohort E), BTC (Cohort F), or pancreatic cancer 
(Cohort G), the objectives and endpoints outlined below will be evaluated.
Efficacy analyses will be performed by cohort/tumor type and RECIST 1.1, modified to 
follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ (Section 
4.2.3.1), will be used for all tumor cohorts except GBM, which will use RANO Criteria 
(Section 4.2.3.1.3).
For Cohorts A-F, RECIST 1.1 (RANO for GBM) by investigator assessments will be used in 
the initial 30 enrolled participants. RECIST 1.1 (RANO for GBM) by BICR will be used in 
cohorts that expand to combine the initial 30 enrolled participants with the additional 70 to 
100 expansion participants. For Cohort G, which will enroll 100 participants, RECIST 1.1 by 
BICR will be used.
For participants receiving pembrolizumab (Arm 1 only), modified RECIST 1.1 for immune-
based therapeutics (iRECIST) will be used by investigators to assess tumor response and 
progression, and make treatment decisions, as well as for exploratory efficacy analyses 
(Section 4.2.3.1.2).
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Objectives
Endpoints
Primary

Objective: To evaluate objective 
response rate (ORR) of pembrolizumab 
in combination with lenvatinib per 
tumor cohort based on RECIST 1.1 by 
investigator assessments in initial 
cohorts and BICR in cohorts that 
expand combining the initial and 
expansion cohorts (Cohorts A-F). In 
Cohort G, RECIST 1.1 by BICR will be 
used in all participants.
(For participants with GBM, response 
will be assessed based on RANO 
criteria; all further references to 
RECIST 1.1 assessment apply to all 
cohorts except GBM.)

Objective response (OR), complete 
response (CR), or partial response (PR)

Objective: To assess safety and 
tolerability of treatment with 
pembrolizumab in combination with 
lenvatinib per tumor cohort assessed by 
the proportion of AEs.

AEs

Discontinuation due to AEs

Objective: To assess safety and 
tolerability of treatment with lenvatinib 
monotherapy assessed by the proportion 
of AEs.

AEs

Discontinuation due to AEs
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Objectives
Endpoints
Secondary

Objective: To evaluate disease control 
rate (DCR), duration of response 
(DOR), and progression-free survival 
(PFS) of pembrolizumab in combination 
with lenvatinib per tumor cohort based 
on RECIST 1.1 (RANO for GBM) by 
investigator assessments in initial 
cohorts and BICR in cohorts that 
expand combining the initial and 
expansion cohorts (Cohorts A-F). In 
Cohort G, RECIST 1.1 by BICR will be 
used in all participants.

Disease control, defined as best overall 
response of CR, PR, or stable disease

DOR, determined by disease assessment 
defined as the time from the earliest 
date of qualifying response until the 
earliest date of disease progression or 
death from any cause, whichever comes 
first.

PFS, defined as the time from the first 
day of study intervention to the day of 
the first documentation of disease 
progression or death from any cause, 
whichever occurs first.

Objective: To evaluate overall survival 
(OS) of pembrolizumab in combination 
with lenvatinib per tumor cohort.

OS, defined as the time from the first 
day of study intervention to the day of 
death from any cause.

Objective: To evaluate ORR, DCR, 
DOR, PFS, and OS of lenvatinib 
monotherapy (Cohort D) based on 
RECIST 1.1 by BICR.

OR

DCR

DOR

PFS

OS

Objective: To characterize the 
population pharmacokinetics (PK) of 
lenvatinib when coadministered with 
pembrolizumab in participants per 
tumor cohort (Cohorts A-F only).

Plasma concentration of lenvatinib.
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Objectives
Endpoints
Tertiary/Exploratory

Objective: To evaluate ORR, DCR, 
DOR, and PFS of pembrolizumab in 
combination with lenvatinib per tumor 
cohort based on iRECIST (non-GBM 
cohorts) by investigator assessments.

OR

DCR

DOR

PFS

Objective: To evaluate ORR, DCR, 
DOR, PFS, and OS of pembrolizumab 
in combination with lenvatinib relative 
to lenvatinib monotherapy per tumor 
cohort.

OR

DCR

DOR

PFS

OS

Objective: To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers per tumor cohort that may 
be indicative of clinical 
response/resistance, safety, and/or the 
mechanism of action of pembrolizumab 
and lenvatinib in all participants.

Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
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Objectives
Endpoints

Objective: To evaluate changes in 
patient-reported outcomes per tumor 
cohort from baseline using below PROs 
and to evaluate time to deterioration 
(TTD) in the EORTC-QLQ-C30 
subscales:
-
EORTC-QLQ-C30
-
EORTC QLQ-disease-specific:
◦
Breast (QLQ-BR23)
◦
Ovarian (QLQ-OV28)
◦
Gastric (QLQ-STO22)
◦
Colorectal (QLQ-CR29)
◦
GBM (QLQ-BN20)
◦
Biliary (QLQ-BIL21)
◦
Pancreatic (QLQ-PAN26)
-
EuroQol (EQ)-5D-5L

HRQoL will be assessed using the 
global score of the EORTC

Health utilities, assessed using the EQ-
5D-5L

TTD evaluated for EORTC QLQ-C30 
subscales
4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, open-label, Phase 2 study to evaluate the efficacy and safety of 
lenvatinib 20 mg qd in combination with pembrolizumab (Arm 1) in previously treated 
participants with TNBC (Cohort A), ovarian cancer (Cohort B), gastric cancer (Cohort C), 
CRC (Cohort D), GBM (Cohort E), BTC (Cohort F), or pancreatic cancer (Cohort G). The 
efficacy and safety of lenvatinib monotherapy (24 mg qd, Arm 2) will be evaluated in 
participants with CRC (Cohort D).
Initially, approximately 180 eligible participants will be stratified by tumor cohort 
(Cohorts A-F; 30 participants per cohort) and enrolled to receive lenvatinib 20 mg orally qd
plus pembrolizumab 200 mg (IV q3w) for up to 35 administrations or until disease 
progression per RECIST 1.1 or RANO for the GBM cohort, unacceptable toxicity, 
withdrawal of consent, initiation of new anticancer treatment, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to discontinue the 
participant, pregnancy, administrative reasons requiring cessation of treatment, or death.
Pembrolizumab treatment will be discontinued once the participant has received 
35 administrations (approximately 2 years). Participants in Arm 1 and Arm 2 may continue
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treatment with lenvatinib beyond 2 years if they experience clinical benefit according to the 
PI, with Sponsor consultation. Participants may discontinue treatment with pembrolizumab 
and lenvatinib if a CR has been attained per RECIST 1.1 (RANO for the GBM cohort) and 
they have been treated for at least 24 weeks, receiving at least 2 doses of pembrolizumab 
beyond the date when the initial CR was declared.
Potential for cohort expansion will be assessed for Cohorts A-F as described in Section 4.1.1.
Additionally, 100 eligible participants with pancreatic cancer (Cohort G) will be enrolled to 
receive lenvatinib 20 mg orally qd plus pembrolizumab 200 mg (IV q3w) as described above.
Enrollment into Cohort G will proceed as described in Section 4.1.2.
Participants will be permitted to continue treatment beyond RECIST 1.1- or RANO-defined 
progression (Arm 1 only) as long as investigator-assessed clinical stability is observed, the 
participant is tolerating study intervention (Section 8.2.1.5 or Section 8.2.1.6) and after 
obtaining documented informed consent addendum. Treatment beyond confirmed PD per 
iRECIST or RANO may be permitted on Sponsor consultation.
The primary objective of this study is to evaluate the ORR of pembrolizumab + lenvatinib for 
each indication/cohort separately. Additionally, the ORR of lenvatinib monotherapy will be 
evaluated to address a secondary objective, and the ORR of pembrolizumab + lenvatinib 
combination therapy relative to lenvatinib monotherapy will be evaluated to address a tertiary 
objective in participants with CRC (Cohort D). For all cohorts (except GBM), on-study 
imaging assessments will be performed every 9 weeks (q9w; 63 days ±7 days) from the date 
of treatment initiation until 54 weeks (378 days ±7 days). After 54 weeks, imaging will be 
performed every 12 weeks (84 days ±7 days) or sooner, if clinically indicated, until Week 
102. After Week 102, imaging should be performed q24w, or sooner if clinically indicated. 
For participants with GBM, imaging will be performed at 6 weeks (42 days to 49 days) from 
the date of treatment initiation. Subsequent tumor imaging should be performed every 6 
weeks (42 days ±7 days) until Week 18 and then every 9 weeks thereafter or more frequently 
if clinically indicated. After 54 weeks (378 days ±7 days), participants who remain on 
treatment will have imaging performed every 12 weeks (84 days ±7 days) or sooner if 
clinically indicated until Week 102. After Week 102, imaging should be performed q24w, or 
sooner if clinically indicated. Imaging should follow calendar days and be independent of 
treatment delays. RECIST 1.1 (or RANO for participants with GBM) will be used by the site 
for treatment decisions until the first radiologic evidence of PD. Participants who experience 
confirmed disease progression or start a new anticancer therapy will move into survival 
follow-up and should be contacted by telephone or visit approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
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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4.1.1
Cohort Expansion (Cohorts A-F)
Potential for cohort expansion will be assessed for each cohort using IAs for efficacy, based 
on investigator assessment. The IAs will occur after the initial 30 enrolled participants have 
been followed up for approximately 6 months after study entry. For cohorts with slow 
enrollment, IAs may take place when the majority of participants have been followed up for 
6 months from study entry. The results of each IA will be reviewed by the Sponsor, and 
recommendations for cohort expansion will be provided. Further details are provided in 
Section 9 – Statistical Analysis Plan (SAP).
If cohort expansion is recommended, the first 30 participants enrolled before the expansion 
may continue to receive treatment for up to 35 administrations of pembrolizumab from study 
entry or until disease progression per RECIST 1.1 (or RANO for the GBM cohort), 
unacceptable toxicity, withdrawal of consent, initiation of new anticancer treatment, 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to discontinue the participant, administrative reasons requiring cessation of treatment or 
death.
If cohort expansion is not recommended, participants experiencing response will be allowed 
to continue receiving treatment for up to 35 administrations of pembrolizumab from study 
entry or until disease progression per RECIST 1.1 (or RANO for the glioblastoma GBM 
cohort), unacceptable toxicity, withdrawal of consent, initiation of new anticancer treatment, 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to discontinue the participant administrative reasons requiring cessation of treatment or 
death.
Cohorts C, E, and F will each be expanded to include a total of approximately 
100 participants, 30 from the initial cohort and an additional 70 participants in the expansion
phase, each allocated to receive pembrolizumab + lenvatinib combination therapy to assess 
efficacy and safety in these disease states. Cohorts A (TNBC) and B (ovarian cancer) will not 
be included in the expansion phase due to changes which have occurred in the treatment 
landscape for these malignancies since the study was initiated.
Cohort D (CRC) will be expanded to include a total of 130 participants: 30 from the initial 
cohort and an additional 100 participants in the expansion phase. The last approximately 60 
participants will be randomized 1:1 to receive pembrolizumab + lenvatinib (Arm 1) or 
lenvatinib monotherapy (Arm 2). The goal of this randomization is to assess the contribution 
of lenvatinib in the overall treatment effect of the pembrolizumab + lenvatinib combination.
If a clinically meaningful response is not observed, the Sponsor may elect not to include a 
randomization arm and may stop enrollment.
4.1.2
Cohort G (Pancreatic Cancer)
Based on the efficacy results and manageable safety profile of pembrolizumab + lenvatinib 
noted in Study E7080-A001-111 (KEYNOTE-146; NCT02501096) and the LEAP program 
to date, as well as the high unmet need in pancreatic cancer (Section 4.2.2), 100 participants 
with pancreatic cancer will be enrolled into Cohort G. An IA will be performed when 
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approximately 30 participants in Cohort G have been followed up for approximately 
6 months. Enrollment will continue before and during the IA. If there is evidence of efficacy 
based on the IA, enrollment into Cohort G will continue to approximately 100 participants; 
otherwise, enrollment could be stopped (Section 9.7).
4.1.3
Early Termination of Cohort(s) and/or Discontinuation of Cohort Enrollment
Specific cohort(s) within the study may be terminated early and/or further enrollment stopped 
for 1 or both of the following reasons:

Extent (incidence and/or severity) of emerging effects/clinical endpoints is such that the 
risk/benefit ratio to the study population in the specific cohort(s) is unacceptable.

Emerging information from other studies is such that the participant safety or the 
risk/benefit ratio to a cohort population is unacceptable.
Continuation of study intervention may be allowed for a study participant who benefits from 
ongoing study intervention, if justified by the investigator and documented in a Sponsor 
consultation form.
4.2
Scientific Rationale for Study Design
This multicenter, open-label, Phase 2 study was designed as a proof-of-concept in single 
treatment group disease cohorts whose lines of therapy have no defined standard of care to 
assess the efficacy and safety of lenvatinib in combination with pembrolizumab in 
participants with advanced: TNBC, ovarian cancer, gastric cancer, CRC, BTC, glioblastoma, 
and pancreatic cancer.
4.2.1
Cohorts A-F
The starting sample size of 30 participants per cohort (Cohorts A-F) is estimated based on the 
primary endpoint and the required target ORR to produce a confidence interval for the true 
ORR. A cohort which achieves its target ORR will be expanded to a total of 100 participants
(Cohorts C, E, and F) or 130 participants (Cohort D). See Section 9.9 for additional 
information regarding sample size.
The last approximately 60 participants in Cohort D (CRC) will be randomized 1:1 to receive 
either pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 2), as described 
in Section 4.1.1, to assess the contribution of lenvatinib in the overall treatment effect of the 
pembrolizumab + lenvatinib combination in these tumor types.
4.2.2
Cohort G (Pancreatic Cancer)
Pancreatic cancer is the fourth leading cause of cancer-related death in the US [Siegel, R. L., 
et al 2020] with adenocarcinoma representing approximately 90% of all pancreatic cancers. 
Surgical excision represents the only option for cure, however 80% of patients are diagnosed 
at an inoperable stage. There is a high unmet medical need for metastatic pancreatic cancer 
with a survival at 5 years of only 3%. Based on the efficacy observed across diseases to date 
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in the lenvatinib-pembrolizumab program and the poor outcomes in pancreatic cancer, the 
Sponsor is pursuing the impact of this combination in pancreatic cancer.
One hundred participants will be enrolled into Cohort G (pancreatic cancer). See Section 9.9 
for additional information regarding sample size.
4.2.3
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
This study will use OR as the primary endpoint based on RECIST 1.1 criteria (or RANO for 
GBM) as assessed by investigator in initial cohorts and by BICR for cohorts that expand
(Cohorts C-F) as well as for Cohort G. OR is an acceptable measure of clinical benefit for a 
late stage study that shows superiority of a new antineoplastic therapy, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use 
of BICR and RECIST 1.1 (or RANO for GBM) to assess OR is typically considered 
acceptable by regulatory authorities. Images will be read by BICR blinded to treatment 
assignment to minimize bias in the response assessments.
DCR, DOR, and PFS as assessed by BICR according to RECIST 1.1, modified to follow a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ and OS will serve 
as additional measures of efficacy and are commonly accepted endpoints by both regulatory 
authorities and the oncology community.
iRECIST may also be used by the local site to make treatment decisions once PD has been 
documented per RECIST 1.1 in non-GBM cohorts.
Measurable disease will be confirmed centrally at enrollment, before participant allocation, 
to ensure that the assessment of measurable disease is accurate. These endpoints have been 
chosen as ancillary markers of efficacy in a population with few treatment options.
4.2.3.1.1
RECIST 1.1
RECIST 1.1 (RANO for GBM) will be used by investigator assessment when determining 
eligibility and confirmed prospectively by BICR before allocation.
RECIST 1.1 (RANO for GBM) will be used by the BICR when assessing images for efficacy 
measures in cohorts that expand (Cohorts C-F), which will combine the initial cohort and the 
expansion cohort, as well as Cohort G. Although traditional RECIST 1.1 references 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.
Refer to Section 8.2.1.4 for details on RECIST 1.1 (for non-GBM cohorts) and Section 
8.2.1.6 on RANO (for GBM).
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4.2.3.1.2
Modified RECIST 1.1 for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
after treatment with immunotherapeutic agents (Section 8.2.1.5). Immunotherapeutic agents 
such as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents, and participants 
treated with pembrolizumab may manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Thus, standard RECIST 1.1 may not 
fully capture the treatment benefits from immunotherapeutic agents such as pembrolizumab. 
Based on an analysis of participants with melanoma enrolled in KEYNOTE-001, 7% of 
evaluable participants experienced delayed or early tumor pseudoprogression. Of note, 
participants who had PD by RECIST 1.1 but not by the immune-related response criteria 
[Wolchok, J. D., et al 2009] had longer OS than participants with PD by both criteria [Hodi, 
F. S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the 
benefit of pembrolizumab in approximately 15% of participants [Hodi, F. S., et al 2016]. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [Seymour, L., et 
al 2017]. The unidimensional measurement of target lesions, qualitative assessment of 
nontarget lesions, and response categories are identical to RECIST 1.1, until progression is 
seen by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression, and to make treatment decisions, as well as for 
exploratory efficacy analyses where specified.
For Cohorts A-G (combination therapy only), the ORR, DOR, DCR and PFS will also be 
evaluated per iRECIST by investigator assessment.
Refer to Section 8.2.1.5 for details on iRECIST.
4.2.3.1.3
Response Assessment in Neuro-Oncology (RANO)
RANO criteria have been the preferred criteria for assessing responses in GBM studies since 
their publication in 2010 [Wen, P. Y., et al 2010] and incorporate measurements of tumor 
size as shown by contrast-enhanced magnetic resonance imaging (MRI) with qualitative 
assessment of both enhancing and nonenhancing disease, and information on steroid dosing 
and participant functional performance status. Response assessments will be performed by
investigators and by BICR.
RANO also makes provisions for the pseudoprogression frequently seen after radiotherapy. 
The AVAglio study [Gilbert, M. R., et al 2014] (BO21990, NCT00943826) modified the 
Macdonald criteria by using T2/fluid-attenuated inversion recovery (FLAIR) imaging, 
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clinical assessment, and the qualitative review of all nonindex lesions to correct for 
non-contrast-enhancing lesions, residual disease, difficult to measure lesions, and 
pseudoprogression. The RANO Working Group further refined the measurements by 
relaxing criteria around clinical progression and in the timing, criteria, and confirmation of 
scans to detect pseudoprogression [Chinot, O. L., et al 2013].
The Radiation Therapy Oncology Group (RTOG) and American College of Radiology 
Imaging Network (ACRIN) (RTOG0625/ACRIN6677) evaluated the predictive ability of 
RANO in 107 patients with recurrent GBM treated with bevacizumab, irinotecan, or 
temozolomide [Boxerman, J. L., et al 2013]. The study concluded that progression observed 
at 8 and 16 weeks of bevacizumab treatment on 2D-T1 and 3D-T1 imaging, had highly 
significant prognostic value for OS. However, progression detected by FLAIR alone did not 
correlate with OS and added minimal additional benefit to other imaging technologies.
4.2.3.2
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) and serious AEs (SAEs) and changes in vital signs and 
laboratory values. AEs will be assessed as defined by the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), Version [4.0].
4.2.3.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities. 
As part of the analyses for this study, participants will provide information regarding their 
health-related quality of life (HRQoL) via the following assessment tools: European 
Organization for the Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) and European Quality of Life 5-dimension 5-level 
(EQ-5D-5L) questionnaires. In addition, the following cohort-specific assessments tools will 
be used: QLQ-BR23 (Breast), QLQ-OV28 (Ovarian), QLQ-STO22 (Gastric), QLQ-CR29 
(Colorectal), QLQ-BN20 (GBM), QLQ-BIL21 (Biliary), and QLQ-PAN26 (Pancreatic).
The PROs will be administered in the order below:

EORTC- QLQ-C30

EORTC- QLQ- disease-specific

EQ-5D-5L
These measures are not pure efficacy or safety endpoints because they are affected by both 
disease progression and treatment tolerability.
4.2.3.3.1
EORTC QLQ-C30
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, 
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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 status/quality of life (QoL) scale (items 29 and 30) [Aaronson, N. K., et al 1993]. The 
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing QoL in oncology studies [Aaronson, N. K., et al 1993].
4.2.3.3.2
EQ-5D-5L
The European Quality of Life 5-dimension 5-level (EQ-5D-5L) questionnaire is a 
standardized instrument for use as a measure of health outcome. The EQ-5D-5L will provide 
data for use in economic models and analyses including developing health utilities or quality 
adjusted life years. The 5 health state dimensions in this instrument include the following: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The 
EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the patient 
rates his or her general state of health at the time of the assessment. This instrument has been 
used extensively in cancer studies and published results from these studies support its 
validity and reliability [Pickard, A. S., et al 2007].
4.2.3.3.3
Cohort-Specific Patient-reported Outcomes
The EORTC QLQ-BR23, QLQ-OV28, QLQ-STO22, QLQ-CR29, QLQ-BN20, QLQ-BIL21, 
and QLQ-PAN26 are disease-specific questionnaires developed and validated to address 
measurements specific to breast, ovarian cancer, gastric cancer, colorectal, GBM, BTC, and 
pancreatic cancers, respectively. They are a few of multiple disease-specific modules 
developed by the EORTC QLG (Quality of Life Group) designed for use in clinical studies, 
to be administered in addition to the QLQ-C30 to assess disease-specific treatment 
measurements.
4.2.3.3.3.1
EORTC QLQ-BR23
EORTC QLQ-BR23 is a QoL questionnaire developed to assess the extent of symptoms or 
problems in participants receiving treatment for breast cancer. The tool is used in conjunction 
with the EORTC QLQ-C30 and follows the same 4-point scale described above. The tool 
consists of 23 questions containing 4 functioning scales (body image, sexual functioning, 
sexual enjoyment, future perspective) and 4 symptom scales (arm symptoms, breast 
symptoms, systemic therapy side effects, upset by hair loss). The recall period is one week 
for all questions except those on sexual functioning which have a recall period of 4 weeks.
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4.2.3.3.3.2
EORTC QLQ-OV28
The EORTC QLQ-OV28 is a cancer module meant for use among ovarian cancer patients 
varying in disease state and treatment modality (ie, surgical procedure, chemotherapy, 
radiotherapy, etc.). The module comprises 28 questions assessing functional scales including 
body image, sexuality, and attitude to disease/treatment as well as symptoms (including 
abdominal/GI issues, peripheral neuropathy, hormonal/menopausal symptoms, other 
chemotherapy side effects, and hair loss).
4.2.3.3.3.3
EORTC QLQ-STO22
The EORTC QLQ-STO22 is a disease-specific questionnaire developed and validated to 
address measurements specific to gastric cancer. It is one of multiple disease-specific 
modules developed by the EORTC QLG designed for use in clinical studies, to be 
administered in addition to the EORTC QLQ-C30 to assess disease-specific treatment 
measurements. It contains 22 items with symptoms of dysphagia (4 items), pain or 
discomfort (3 items), upper GI symptoms (3 items), eating restrictions (5 items), emotional 
(3 items), dry mouth, hair loss, and body image.
4.2.3.3.3.4
EORTC QLQ-CR29
The EORTC QLQ-CR29, a supplemental CRC-specific module, comprises multi-item and 
single-item measures of CRC-associated symptoms and impact. The measure includes 4 
scales assessing urinary frequency, stool frequency, blood and mucus in stool, and body 
image, and 19 single items assessing common problems after treatment of CRC.
4.2.3.3.3.5
EORTC QLQ-BN20
The EORTC QLQ-BN20 is a disease-specific questionnaire developed and validated to 
address measurements specific to brain cancer [Taphoorn, M. J. B., et al 2010]. It is one of 
multiple disease-specific modules developed by the EORTC QLG designed for use in clinical 
studies, to be administered in addition to the QLQ-C30 to assess disease-specific treatment 
measurements. It consists of 20 items containing 4 scales (“future uncertainties”, “visual 
disorder”, “motor dysfunction”, and “communication deficit”) and 7 single items.
4.2.3.3.3.6
EORTC QLQ-BIL21
The EORTC QLQ-BIL21 is a disease-specific questionnaire intended for use among patients 
with cholangiocarcinoma and gallbladder cancer, who vary in disease stage and treatments. 
The module comprises 21 questions assessing disease symptoms (including jaundice, eating, 
tiredness, pain and anxiety) and side effects of treatment.
4.2.3.3.3.7
EORTC QLQ-PAN26
The EORTC QLQ-PAN26 is a disease-specific questionnaire developed and validated to 
address HRQoL issues specific to pancreatic cancer and is intended to supplement the 
EORTC QLQ-C30. The module includes 26 questions evaluating symptoms related to 
disease and treatment (eg, pain, indigestion, altered bowel habit, and side effects), as well as 
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emotional difficulties related to pancreatic cancer (eg, body image, sexuality, and health care 
satisfaction). There are 7 multi-item scale scores consisting of 2 to 4 items and 10 single-item 
scores.
4.2.3.4
Pharmacokinetic Endpoints
Based on PK data obtained in this study and from other studies, a population PK analysis 
may be performed to characterize PK parameters of lenvatinib when coadministered with 
pembrolizumab to support the proposed dosing regimen. In addition, exposure-response 
(E-R) analyses for safety and efficacy endpoints for the indications studied in this protocol 
may be performed.
4.2.3.5
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.3.6
Planned Exploratory Biomarker Research
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CCI
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4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
Lenvatinib
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, the primary endpoint of which was to determine the 
MTD and RP2D for lenvatinib in combination with pembrolizumab 200 mg q3w. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg IV q3w: n=3; lenvatinib 
20 mg/day + pembrolizumab 200 mg: n=10) were enrolled in the Phase 1b portion of the 
study. Eight of the participants had RCC, 2 had NSCLC, 2 had EC, and 1 had melanoma. 
There were 2 dose-limiting toxicities (DLTs) at the dose of lenvatinib 24 mg/day + 
pembrolizumab 200 mg IV q3w (1 participant had Grade 3 arthralgia, and another had Grade 
3 fatigue); hence, this was defined as the toxic dose. No DLTs were reported in the next 10 
participants (expansion part), all of whom received the lenvatinib 20 mg/day +
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 [Taylor, M. H., et al 2016].
Based on the preclinical results, Study 111/KEYNOTE-146 was initiated. Study E7080-
A001-111/KEYNOTE-146 is an ongoing multicohort Phase 1b/2 clinical study to assess the 
safety and preliminary antitumor activity of lenvatinib in combination with pembrolizumab 
in 6 types of biomarker-unselected metastatic solid tumors, including NSCLC, that have 
progressed after treatment with approved therapies or for which there are no standard 
effective therapies available.
Phase 1b of this study determined the MTD and recommended Phase 2 dose (RP2D) as 
20 mg lenvatinib qd in combination with pembrolizumab 200 mg IV q3w. The primary 
endpoint of the initial part of Phase 2 is ORR after 24 weeks of treatment, with select 
secondary endpoints, including OR, DCR, PFS, and DOR. The safety and efficacy of the 
combination at the lenvatinib RP2D is being assessed in the Phase 2 portion of the study that 
includes 6 cohorts (NSCLC, RCC, endometrial carcinoma, urothelial carcinoma, melanoma, 
and squamous cell carcinoma of the head and neck).
Based on the promising antitumor efficacy and tolerable safety profile seen in both the EC 
and RCC expansion cohorts from Study 111/KEYNOTE-146 [Makker, V., et al 2018], two 
Phase 3 studies have been initiated for both of these tumor types, Study E7080-G000-
309/KEYNOTE-775 and Study E7080-G000-307/KEYNOTE-581.
Based on modeling of lenvatinib PK data, the safest dose of lenvatinib monotherapy that 
provides the highest efficacy is 25 mg qd. The dose selected for the lenvatinib monotherapy 
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arm, 24 mg qd, was selected to simplify the dose reduction scheme, and is the recommended 
dose in locally recurrent or metastatic, progressive, radioactive iodine-refractory 
differentiated thyroid cancer (refer to the lenvatinib IB).
4.3.1.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg q3w. Based on the totality of
data generated in the KEYTRUDA development program, 200 mg q3w is the appropriate
dose of pembrolizumab for adults across all indications and regardless of tumor type. As
outlined below, this dose is justified by:

Clinical data from 8 randomized studies showing flat dose- and exposure- efficacy 
relationships from 2 mg/kg q3w to 10 mg/kg q2w,

Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
q3w across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically based PK 
[PBPK] analysis) at 200 mg q3w.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg q3w versus 10 mg/kg
q3w (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies
compared 10 mg/kg q3w versus 10 mg/kg q2w (KN001 Cohort B3, KN001 Cohort F2 and
KN006). All of these studies showed flat dose- and exposure-response relationships across
the doses studied representing an approximate 5- to 7.5-fold difference in exposure.
The 2 mg/kg (or 200 mg fixed dose) q3w provided similar responses to the highest doses
studied. Subsequently, flat dose-exposure-response relationships were also observed in other
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical
Hodgkin Lymphoma, confirming 200 mg q3w as the appropriate dose independent of the
tumor type. These findings are consistent with the mechanism of action of pembrolizumab,
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg q3w. First, PK data
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively showed
saturation of PD-1 in systemic circulation at doses much lower than 200 mg q3w. Second, a
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg
q3w achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of
body weight and other participant covariates on exposure, has shown that the fixed-dosing
provides similar control of PK variability as weight-based dosing, with considerable overlap
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in the distribution of exposures from the 200 mg q3w fixed dose and 2 mg/kg q3w dose.
Supported by these PK characteristics, and given that fixed dose has advantages of reduced
dosing complexity and reduced potential of dosing errors, the 200 mg q3w fixed dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg q3w up to 
35 administrations. The maximum dose/exposure of lenvatinib allowed in this study is 20 mg 
qd for participants receiving pembrolizumab + lenvatinib combination therapy (Cohorts A-G) 
and 24 mg qd for participants receiving lenvatinib monotherapy (Cohort D only). Participants 
in Arm 1 may continue treatment with lenvatinib after discontinuation or completion of 35 
treatments (approximately 2 years) of pembrolizumab if they experience clinical benefit 
according to the PI with Sponsor consultation until disease progression or unacceptable 
toxicity. Participants in Arm 2 may continue treatment with lenvatinib beyond 2 years if they 
experience clinical benefit according to the PI with Sponsor consultation until disease 
progression or unacceptable toxicity.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related telephone-call or visit, withdraws consent, is lost to follow-
up (ie, the participant is unable to be contacted by the investigator), or the last participant on 
active treatment is consented in an extension study.
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory test result or at the time of final contact with the last participant, whichever 
comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Participants with TNBC, ovarian cancer, gastric cancer, CRC, GBM, BTC, or pancreatic 
cancer.
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1) this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have a histologically or cytologically documented, advanced (metastatic and/or
unresectable) solid tumor that is incurable and for which prior standard systemic therapy
has failed in one of the following cohorts:
Cohort A
Triple-Negative Breast Cancer
Cohort B
Ovarian Cancer
Cohort C
Gastric Cancer
Cohort D
Colorectal Cancer
Cohort E
Glioblastoma
Cohort F
BTC (intrahepatic, extrahepatic cholangiocarcinoma and gall bladder 
cancer; excludes Ampulla of Vater)
Cohort G
Pancreatic Cancer (ductal adenocarcinoma)
2. Participants must have fulfilled cohort-specific requirements regarding prior (line of 
therapy) treatments. Refer to Sections 5.1.1 through 5.1.7 for cohort-specific inclusion 
criteria).
Note: Merck will be using American Joint Committee on Cancer (AJCC) Staging manual 
(Eighth Edition) to review tumor node metastasis staging classification to ensure 
consistency of participant enrollment.
3. Participants must have progressed on or since the last treatment.
4. Have measurable disease per RECIST 1.1 (RANO for the GBM cohort) as assessed by 
the local site investigator/radiology and confirmed by BICR. Lesions situated in a 
previously irradiated area are considered measurable if progression has been shown in 
such lesions.
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5. Have provided a PD-L1 evaluable archival tumor tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin 
embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are 
preferred to archived tissue. Fine-needle aspiration biopsies are not acceptable.
Note: If participants have only 1 measurable lesion per RECIST 1.1, the biopsy specimen 
should be obtained from a nontarget lesion or archival tissue.
Demographics
6. Participants are at least 18 years of age; male or female for gastric cancer, GBM, TNBC, 
CRC, BTC, and pancreatic cancer cohorts; female only for ovarian cancer.
7. Life expectancy of 12 weeks or more.
Male Participants
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 7 days after the last dose of lenvatinib:

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.
-
Please note that 7 days after lenvatinib is stopped, if the participant is on 
pembrolizumab only, no male contraception measures are needed.
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Female Participants
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least 1 of the following conditions applies:
-
Is not a woman of childbearing potential (WOCBP)
OR
-
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. 
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
10. The participant (or legally acceptable representative if applicable) has provided
documented informed consent/assent for the study.
Additional Categories
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
assessed within 3 days before allocation/randomization.
12. Have adequate organ function as defined in the following table (Table 1). Samples must 
be collected within 7 days before the start of study intervention.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases and biliary tract cancer)
Albumin
≥3 g/dL
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
1Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
2Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
13. Have adequately controlled blood pressure (BP) with or without antihypertensive 
medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive 
medications within 1 week before randomization.
See Section 10.7 (Appendix 7) for country-specific requirements.
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5.1.1
Triple-Negative Breast Cancer-Specific Inclusion Criteria
To be eligible for inclusion in this study, the breast cancer participant must:
14. Have received one or 2 prior lines of therapy. Study medication will treat TNBC (2L/3L).
Note: Participants must have been treated with a taxane and anthracycline at some time 
during their course of treatment to meet eligibility.
Note: Prior surgical intervention +/- adjuvant chemotherapy is not considered a line of 
therapy unless such treatments were completed within 6 months before the current tumor 
recurrence.
Note: Prior therapy of metastatic or unresectable disease is considered a line of therapy.
Note: Definitive surgical procedures with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered prior lines of 
therapy.
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay 
in treatment is required for ≥2 months). Switching for toxicity will be considered a line of 
therapy change if there is a change in mechanism of action between the therapies. 
Interruptions (eg, oxaliplatin in FOLFOX) will NOT be considered a line of therapy 
change (unless the interruption is ≥2 months).
Note: Maintenance regimens administered with the purpose of maintaining response after
treatment will not be considered lines of therapy.
15. Have Lactate Dehydrogenase (LDH) <2.0 × ULN.
16. Have locally determined results for estrogen receptor, progesterone receptor, and human 
epidermal growth factor receptor 2 tumor analyses.
5.1.2
Ovarian Cancer-Specific Inclusion Criteria
To be eligible for inclusion in this study, the ovarian cancer participant must:
17. Have primary ovarian cancer and have received 3 prior lines of therapy. Study 
medication will treat ovarian cancer (4L).
Note: Neoadjuvant/adjuvant systemic cytotoxic chemotherapy used in the initial 
treatment is considered prior line of therapy.
Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a 
cytotoxic warhead, are considered prior lines of therapy.
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Note: Definitive surgical intervention with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered prior lines of 
therapy.
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay 
in treatment is required for ≥2 months). Switching for toxicity will be considered a line of 
therapy change if there is a change in mechanism of action between the therapies. 
Interruptions will NOT be considered a line of therapy change (unless the interruption is 
≥2 months, eg, rechallenge with platinum in ovarian cancer).
Note: Maintenance regimens administered with the purpose of maintaining CR or PR will 
not be considered lines of therapy.
5.1.3
Gastric Cancer-Specific Inclusion Criteria
To be eligible for inclusion in this study, the gastric cancer participant must:
18. Have received 2 prior lines of therapy. Study medication will treat gastric cancer (3L).
Note: Gastric cancer will include participants with both gastric and gastroesophageal 
junction (GEJ) adenocarcinoma. Participants with squamous cell carcinoma histology are 
not eligible.
Note: Prior neoadjuvant or adjuvant systemic cytotoxic chemotherapy used in the initial 
treatment is not considered a prior line of therapy unless such treatments were completed 
within 12 months before the current tumor recurrence.
Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a 
cytotoxic warhead, are considered prior lines of therapy.
Note: Definitive surgical intervention with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered prior lines of 
therapy.
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay 
in treatment is required for ≥2 months). Switching for toxicity will be considered a line of 
therapy change if there is a change in mechanism of action between the therapies. 
Interruptions will NOT be considered a line of therapy change (unless the interruption is 
≥2 months).
Note: Maintenance regimens administered with the purpose of maintaining response after
treatment will not be considered lines of therapy.
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5.1.4
Colorectal Cancer-Specific Inclusion Criteria
To be eligible for inclusion in this study, the CRC participant must:
19. Have received 2 prior lines of therapy. Study medication will treat CRC (3L).
Note: Participants must have received oxaliplatin and irinotecan in separate lines of 
therapy, these are usually provided with fluoropyrimidine (eg, FOLFOX and FOLFIRI).
Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior therapy 
(XOLFOX, XOLFIRI)
Note: Participants who have previously received fluoropyrimidine, oxaliplatin, and 
irinotecan as part of the same and only chemotherapy regimen, eg, FOLFOXIRI or 
FOLFIRINOX, will be considered 2L patients, and do not qualify for the study.
Note: Only the participants with the mutations listed below may receive FOLFOXIRI or 
FOLFIRINOX as a line of therapy which covers the oxaliplatin and irinotecan 
requirement. The participant must have also received ALL the following agents necessary 
to treat the underlying mutation, if approved and locally available in the country where 
the participant is enrolled, to achieve the 2 prior lines of therapy required to be eligible 
for the study.
a.
At least one of the anti-EGFR monoclonal antibodies (cetuximab or panitumumab) 
for RAS (KRAS/NRAS) WT participants.
For participants with ctDNA RAS mutant but RAS mutation negative in tissue, 
enrollment into the study before anti-EGFR administration is allowed.
b. BRAF inhibitor (in combination with cetuximab +/- binimetinib) for BRAF V600E 
mutated mCRC.
Note: Adjuvant and neoadjuvant chemotherapy counts as a first line of prior systemic 
therapy if there is documented disease progression within 6 months of chemotherapy 
completion.
Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a 
cytotoxic warhead, are considered prior lines of therapy.
Note: Definitive surgical intervention with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered prior lines of 
therapy.
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) will NOT be considered a line of therapy change (unless a delay in treatment
is required for ≥2 months). Switching for toxicity will be considered a line of therapy 
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change if there is a change in mechanism of action between the therapies. Interruptions 
will NOT be considered a line of therapy change (unless the interruption is ≥2 months).
Note: Maintenance regimens administered with the purpose of maintaining response after
treatment will not be considered lines of therapy.
Note: Hyperthermic intraperitoneal chemotherapy (HIPEC) or other locoregional 
therapies are allowed but will not be counted as prior lines of therapies.
5.1.5
GBM Specific Inclusion Criteria
To be eligible for inclusion in this study, the GBM participant must:
20. Have failed initial systemic therapy for newly diagnosed GBM. Study medication will 
treat GBM (2L)
Note: Previous first-line therapy with at least radiotherapy using standard dosing of 
central nervous system (CNS) radiation including 60 Gy in 30 fractions, 59.4 Gy in 1.8 
Gy per fraction or equivalent.
Note: Relapse is defined as progression after initial therapy (i.e., radiation ± 
chemotherapy).
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay 
in treatment is required for ≥2 months). Switching for toxicity will be considered a line of 
therapy change if there is a change in mechanism of action between the therapies. 
Interruptions will NOT be considered a line of therapy change (unless the interruption is 
≥2 months).
21. Have the following time periods elapsed before the projected start of scheduled study 
treatment:

At least 3 weeks from prior surgical resection
Participants having undergone recent resection of recurrent or progressive tumor
will be eligible as long as they have recovered from the effects of surgical 
intervention and have measurable residual disease before starting study therapy.

At least 1 week from stereotactic biopsy

At least 6 months from completion of prior radiotherapy
If participants have not passed an interval of at least 6 months, they may still be
eligible if they meet the following criteria: New area of enhancement outside the 80%
isodose line of the original radiation field as determined by the treating investigator.
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
At least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent

At least 4 weeks from cytotoxic therapy
-
Exceptions:
◦
At least 23 days for temozolomide
◦
At least 6 weeks from nitrosoureas
-
At least 4 weeks (or 5 half-lives, whichever is shorter) for daily administered 
chemotherapeutics

At least 6 weeks from antibodies

At least 4 weeks (or 5 half-lives, whichever is shorter) from other antitumor therapies and 
1 week for cancer vaccines
22. Be neurologically stable (eg, without a progression of neurologic symptoms or requiring 
escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable.
23. Has histologically confirmed World Health Organization Grade 4 glioblastoma.
5.1.6
Biliary Tract Cancer-Specific Inclusion Criteria
To be eligible for inclusion in this study, the BTC participant must:
24. Have received 1 prior line of therapy. Study medication will treat BTC (2L)
Note: Prior adjuvant systemic cytotoxic chemotherapy used in the initial treatment is not 
considered a prior line of therapy unless such treatments were completed within 6 months 
before the current tumor recurrence.
Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a 
cytotoxic warhead, are considered prior lines of therapy.
Note: Definitive surgical intervention with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered prior lines of 
therapy.
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay 
in treatment is required for ≥2 months). Switching for toxicity will be considered a line of 
therapy change if there is a change in mechanism of action between the therapies.
Interruptions (eg, oxaliplatin in FOLFOX) will NOT be considered a line of therapy 
change (unless the interruption is ≥2 months).
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Note: Maintenance regimens administered with the purpose of maintaining response after
treatment will not be considered lines of therapy.
Note: TACE or other locoregional therapies are allowed but will not be counted as prior 
lines of therapies.
25. Has Child-Pugh Score, Class A: well-compensated disease. Child-Pugh Score of 5 to 6.
5.1.7
Pancreatic Cancer-Specific Inclusion Criteria
To be eligible for inclusion in this study, the pancreatic cancer participant must:
26. Have pathologically (histologically or cytologically) confirmed pancreatic ductal 
adenocarcinoma that is metastatic at enrollment.
Note: Histology other than adenocarcinoma, including mixed histologies, is not allowed.
27. Have received one or 2 prior lines of therapy. Study medication will treat pancreatic 
cancer (2L/3L); the 3L pancreatic cancer population will be capped at 40%.
28. Have received prior therapy with at least 1 (platinum-containing regimen or gemcitabine-
containing regimen) but no more than 2 prior systemic therapies for unresectable or 
metastatic pancreatic cancer.
Note: Participants with known deleterious or suspected germline breast cancer 
susceptibility gene mutation (gBRCAm) metastatic pancreatic adenocarcinoma whose 
disease has not progressed on at least 16 weeks of a first-line platinum-based 
chemotherapy regimen should have received olaparib maintenance treatment to be 
eligible, if this agent is approved and locally available in the country where the 
participant is randomized.
Note: Prior adjuvant and neoadjuvant systemic cytotoxic chemotherapy used in the initial 
treatment is not considered a prior line of therapy unless such treatments were completed 
within 6 months before the current tumor recurrence.
Note: All systemic cytotoxic chemotherapy, including antibody–drug conjugates with a 
cytotoxic warhead, are considered prior lines of therapy.
Note: Definitive surgical intervention with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered prior lines of 
therapy.
Note: If a treatment regimen is discontinued for any reason and a different regimen is 
started, it should be considered a new line of therapy. Switching (eg, cisplatin to 
carboplatin) for toxicity will NOT be considered a line of therapy change (unless a delay 
in treatment is required for ≥2 months). Switching for toxicity will be considered a line of 
therapy change if there is a change in mechanism of action between the therapies. 
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Interruptions (eg, oxaliplatin in FOLFOX) will NOT be considered a line of therapy 
change (unless the interruption is ≥2 months).
Note: Locoregional therapies will not be counted as a line of therapy.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has gastrointestinal malabsorption or any other condition that might affect the absorption 
of lenvatinib.
2. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring 
drainage or diuretic drugs within 2 weeks before enrollment. The participant can receive
diuretic drugs as needed per the treating physician, outside the above-mentioned 
conditions.
Note: This exclusion applies to all cohorts except the ovarian cancer cohort.
3. Has radiographic evidence of encasement or invasion of a major blood vessel, or of 
intratumoral cavitation. The degree of proximity to major blood vessels should be
considered because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis after lenvatinib therapy.
Note: Participants with portal vein invasion (Vp4), inferior vena cava, or cardiac 
involvement based on imaging in the BTC cohort are not eligible for enrollment.
4. Has clinically significant hemoptysis or tumor bleeding within 2 weeks before the first 
dose of study intervention.
5. Has significant cardiovascular impairment within 12 months of the first dose of study 
intervention, such as history of congestive heart failure greater than New York Heart 
Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular 
accident (CVA), or cardiac arrhythmia associated with hemodynamic instability.
Note: Medically controlled arrhythmia would be permitted.
6. Has a history of arterial thromboembolism within 12 months of start of study 
intervention.
7. 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.
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8. Has a serious nonhealing wound, ulcer or bone fracture.
9. Has had a major surgical procedure within 3 weeks before the first dose of study 
interventions.
Note: Adequate wound healing after a major surgical procedure must be assessed 
clinically, independent of time elapsed for eligibility.
10. Has biologic response modifiers therapy (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.
11. Has pre-existing ≥Grade 3 gastrointestinal (GI) or nongastrointestinal fistula.
Prior/Concomitant Therapy
12. Has received prior therapy with lenvatinib, an anti-PD-1, anti-PD-L1, or anti-PD-L2 
agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, 
CTLA-4, OX-40, CD137).
Note: Prior therapy with bevacizumab is not exclusionary.
13. Has received prior systemic anticancer therapy including investigational agents within 
4 weeks before study treatment start.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy or ≤Grade 2 alopecia may 
be eligible.
14. Has not recovered adequately from the toxicity and/or complications from the 
intervention if participant received major surgical intervention before starting study 
treatment.
15. Has received prior radiotherapy within 2 weeks of start of study treatment. 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. Refer to Section 5.1.5 for
GBM specific inclusion criteria.
16. Has received a live vaccine within 30 days before the first dose of study intervention. 
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin 
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.
17. Has known intolerance to lenvatinib (and/or any of the excipients).
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Prior/Concurrent Clinical Study Experience
18. Has participated or is currently participating in a study of an investigational agent or has 
used an investigational device within 4 weeks before the first dose of study intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
19. Has urine protein ≥1 g/24h. Participants with proteinuria >1+ on urine dipstick testing 
will undergo 24-hour urine collection for quantitative assessment of proteinuria.
20. Has prolongation of QTc interval (calculated using Fridericia’s formula) to >480 ms.
Note: If the QTcF is prolonged to >480 ms in the presence of a pacemaker, contact the 
Sponsor to determine eligibility.
21. Has left ventricular ejection fraction (LVEF) <55% as determined by multigated 
acquisition scan (MUGA) or echocardiogram (ECHO).
22. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.
23. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable (ie, without evidence of progression by imaging) for at least 4 weeks by repeat 
imaging (note that the repeat imaging should be performed during study screening), 
clinically stable and without requirement of steroid treatment for at least 14 days before
first dose of study intervention. GBM participants are exempt.
Note: MRI brain scan will be conducted for all participants with stable brain metastases 
at screening. Brain CT scan should only be conducted when MRI is contraindicated.
24. Has tumors involving the brain stem.
25. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
26. 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.
27. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
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28. Has an active infection requiring systemic therapy.
29. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required unless mandated by local health authority.
30. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. (See Section 10.7 [Appendix 7] for country-specific requirements.)
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority. (See Section 10.7 [Appendix 7] for country-specific requirements.)
31. Has a known history of active tuberculosis (TB; Bacillus tuberculosis). (See Section 10.7 
[Appendix 7] for country-specific requirements.)
32. 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.
33. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperating with the requirements of the study.
Other Exclusions
34. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
35. Has had an allogenic tissue/solid organ transplant (large organ transplants, stem-cell 
transplant requiring chronic immunosuppressant therapy necessary to prevent graft 
rejection).
5.2.1
GBM Specific Exclusion Criteria
The GBM participant must be excluded from the study if the participant:
36. Has carcinomatous meningitis.
37. Has recurrent tumor greater than 6 cm in maximum diameter.
38. Has tumor primarily localized to the brainstem or spinal cord.
39. Has presence of multifocal tumor, diffuse leptomeningeal or extracranial disease.
40. Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than 
those that are ≤Grade 1 and either postoperative or stable on at least 2 consecutive MRI 
scans.
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41. Has received Optune® TTFields within 2 weeks of study intervention.
The GBM participant will not be excluded from the study for systemic steroid therapy, as 
long as dexamethasone or its steroid equipotent dosing equivalent is administered as ≤2 mg 
by mouth daily and stable for a period of 5 days at the time of enrollment.
5.3
Lifestyle Considerations
No restrictions are required.
5.3.1
Contraception
Lenvatinib and pembrolizumab may have adverse effects on a fetus in utero. Refer to 
Appendix 5 for approved methods of contraception.
5.3.2
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with study intervention, 
the participant will be immediately discontinued from study intervention. The site will 
contact the participant at least monthly and document the participant’s status until the 
pregnancy has been completed or terminated. The outcome of the pregnancy will be reported 
to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
experience (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study Investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. If a male participant impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy must be reported 
to the Sponsor and followed as described in Section 8.4.5.
5.3.3
Use in Nursing Women
It is unknown whether lenvatinib or pembrolizumab is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently allocated in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab and lenvatinib) will be packaged to support enrollment . 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/AxMP
Sourcing
Arm 
1
Experimental
Lenvatinib
Drug
Capsule
10 mg,
4 mga
20 mg
Oral
qd
Test 
Product
IMP
Central
Arm 
1
Experimental
Pembrolizumab
Drug
Vial
25 mg/mL
200 mg
IV Infusion
q3w
Test 
Product
IMP
Central
Arm 
2
Experimental
Lenvatinib
Drug
Capsule
10 mg, 
4 mg
24 mg
Oral
qd
Test 
Product
IMP
Central
EEA = European Economic Area; IMP = investigational medicinal product; IV = intravenous; NIMP/AxMP = noninvestigational/auxiliary medicinal product; q3w = once every 
3 weeks; qd = once daily.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the pharmacy 
manual. Lenvatinib is a capsule for oral administration and does not require preparation.
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 the pharmacy manual for additional information.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an IRT system. There are 2 
study intervention arms. Participants in Cohorts A through G will be allocated to receive 
pembrolizumab + lenvatinib (Arm 1), with the following exception. The last approximately 
60 participants in Cohort D will be assigned randomly in a 1:1 ratio to pembrolizumab + 
lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 2).
6.3.2
Stratification
Participants will be stratified by tumor cohort and enrolled to receive study intervention with 
pembrolizumab + lenvatinib (Cohorts A-G) or lenvatinib monotherapy (Cohort D only).
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, MSD, investigator and participant will 
know the treatment administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruption of pembrolizumab. Refer to 
Section 6.6.2 for dose modifications and toxicity management for AEs associated with 
lenvatinib; refer to Section 6.6.4 for other allowed dose interruption of lenvatinib.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant’s primary physician. However, the decision to continue the participant on study 
treatment requires the mutual agreement of the investigator, the Sponsor, and the participant.
Any medication (including over-the-counter medications) or therapy administered to the
participant during the study (starting at the date of informed consent) will be recorded on the 
appropriate case report form (CRF). The investigator will record the AE for which the 
concomitant medication/therapy was administered on the appropriate CRF. If the 
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concomitant medication/therapy is being administered for a medical condition present at the 
time of entry into the study, the investigator will record the medical condition on the 
appropriate CRF.
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study intervention and any concomitant therapy administered to the 
participant during the course of the study (starting at the date of informed consent) until 30
days after the final dose of study intervention (or 90 days if used to treat an SAE) will be 
recorded. Additionally, all diagnostic, therapeutic, or surgical procedures relating to 
malignancy should be recorded. Any medication that is considered necessary for the 
participant’s health and that is not expected to interfere with the evaluation of or interact with 
the study medication may be continued during the study.
See Section 10.7 (Appendix 7) for country-specific requirements.
6.5.1
Allowed Concomitant Medication(s)
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study medication. Antiemetic or any other prophylaxis should be 
considered in accordance with institutional guidelines.
The following concomitant medications are also allowed:

Hormone replacement therapy

Thyroid hormone suppressive therapy

Anticoagulants including low molecular weight heparin, warfarin, anti-Xa agents

Anti-inflammatory agents

Bisphosphonates or denosumab

Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the participant is enrolled)

Palliative radiotherapy is permitted to a single lesion on an exceptional case by case basis 
after consultation with the Sponsor if considered medically necessary by the treating 
physician (for up to a maximum of 2 lesions). These lesions can NOT be a RECIST 1.1 
or RANO-defined target lesion and the radiotherapy can NOT be administered for tumor 
control. Pembrolizumab should be held during the course of palliative radiotherapy and 
should be resumed no earlier than the next scheduled administration of study 
intervention; however, lenvatinib will be continued as planned during the palliative 
radiation.
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Any additional procedural or participant-specific particularities should be discussed with the 
investigator and the Sponsor.
6.5.2
Prohibited Concomitant Medication(s)
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:

Concurrent anticancer therapies such as chemotherapy, targeted therapies (eg, tyrosine 
kinase inhibitors, Optune® TTFields [GBM cohort]), antitumor interventions (surgical 
resection, surgical debulking of tumor, etc.), or cancer immunotherapy not specified in 
this protocol
Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma or squamous 
cell carcinoma) are allowed.

Other concurrent investigational drugs.

Live vaccines within 30 days and while participating in the study and within 90 days after
last dose of study intervention. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
that is suspected to have immunologic etiology. Physiologic doses of corticosteroids not 
exceeding 10 mg daily of prednisone equivalent may be used during the study.
-
Note: Inhaled steroids are allowed for management of asthma or seasonal allergies.
-
Note: Inhaled or topical steroids and adrenal replacement doses >10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune disease.
-
Note: Participants are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).
-
Note: A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or 
for treatment of nonautoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by contact allergen) is permitted.
-
Note: For the GBM cohort, the use of corticosteroids may be approved after 
consultation with the Sponsor. In the event pembrolizumab is held for corticosteroid 
use, pembrolizumab may not be restarted until participant is tolerating ≤2 mg
dexamethasone (or equipotent dosing) for one week before restarting pembrolizumab
and is clinically stable per investigator.
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
Radiation Therapy
Note: Radiation for pain or palliation may be acceptable (Section 6.5.1)

Anticancer herbal supplements or alternative medicines are strongly discouraged during 
the Screening and Treatment Phase of this study.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all end-of-treatment assessments and continue to be followed 
for survival in the follow-up period.
6.5.3
Drug Interactions
A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma 
concentrations of midazolam (a sensitive CYP3A and P-gp substrate) were not altered in a 
clinically meaningful manner in the presence of lenvatinib. No significant DDI is therefore 
expected between lenvatinib and other CYP3A4/P-gp substrates.
Nonclinical studies identify CYP3A4 as the important CYP isozyme responsible for human 
hepatic metabolism of lenvatinib. However, clinical studies conducted showed that 
coadministration of lenvatinib with either inducers or inhibitors of CYP3A4/P-gp are not of 
clinical concern. Please refer to Appendix 8 and http://medicine.iupui.edu/flockhart/table.htm 
for the most current information.
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 (lenvatinib IB).
6.5.4
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. For participants receiving pembrolizumab + lenvatinib, suggested
supportive care measures for the management of AEs with potential immunologic etiology 
are outlined in Table 3 in Section 6.6.1.1, along with the dose modification guidelines in
Table 5 in Section 6.6.2. For participants receiving lenvatinib monotherapy, suggested 
supportive care measures and dose modification guidelines are outlined in Section 6.6.2.
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, 
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attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab or lenvatinib.
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 3, Table 4, 
and Table 5 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
AEs will be graded using NCI CTCAE Version v4.0. For participants receiving combination 
therapy (Arm 1), investigators will decide the probability of the event being related to one or 
both drugs as to whether dose modification of one or both drugs is required.
Participants who interrupt or discontinue one drug in the 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.
6.6.1
Pembrolizumab
6.6.1.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
See Section 10.7 (Appendix 7) for country-specific requirements.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
   Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
   Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
   Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer anti-
hyperglycemic in participants 
with hyperglycemia
   Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
   Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
   Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
   Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b     Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs
(eg, vasculitis and sclerosing cholangitis).
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6.6.1.2
Dose Modification and Toxicity Management of Infusion-Reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.
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Table 4
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 h
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/h to 
50 mL/h). Otherwise dosing will be held until symptoms resolve and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further study 
drug treatment
Participant may be premedicated 1.5 h 
(± 30 minutes) prior to infusion of 
pembrolizumab with:
-
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
-
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to:
-
Epinephrine**
-
IV fluids
-
Antihistamines
-
NSAIDs
-
Acetaminophen
-
Narcotics
-
Oxygen
-
Pressors
-
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant 
is deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study drug 
treatment.
No subsequent dosing
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NCI=National Cancer Institute; NSAIDs=nonsteroidal 
anti-inflammatory drugs; PO=by mouth.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov
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6.6.1.3
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks of the originally scheduled 
dose and within 42 days of the previously administered dose, unless otherwise discussed with 
the Sponsor. The reason for interruption should be documented in the participant’s study 
record. Imaging should not be delayed for delays in cycle treatment.
6.6.2
Lenvatinib
Lenvatinib dose reduction and interruption for participants who experience lenvatinib- or 
lenvatinib-pembrolizumab combination therapy-related toxicity will be in accordance with 
the dose modification guidelines described in Table 5. An interruption of study treatment for 
more than 28 days will require Sponsor approval before treatment can be resumed.
The starting dose of lenvatinib is 20 mg/day for participants enrolled in the combination 
therapy arm (Arm 1). Lenvatinib dose reductions for Arm 1 occur in succession based on the 
previous dose level (14, 10, and 8 mg/day). Any dose reduction below 8 mg/day must be 
discussed with the Sponsor. 
The starting dose of lenvatinib is 24 mg/day for participants enrolled in the monotherapy arm 
(Arm 2). Lenvatinib dose reductions for Arm 2 will take place in succession based on the 
previous dose level (20, 14, and 10 mg/day). Any dose reduction below 10 mg/day must be 
discussed with the Sponsor.
For both Arm 1 and Arm 2, 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 
(Table 5). For overlapping toxicities of pembrolizumab and lenvatinib, please refer to Section 
6.6.3.
See Section 10.7 (Appendix 7) for country-specific requirements.
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Table 5
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
Arm 1: Reduce lenvatinib dose 
from 20 mg QD to 14 mg QD
(1-level reduction)
Arm 2: Reduce lenvatinib dose 
from 24 mg QD to 20 mg QD 
(1-level reduction)
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Arm 1: Reduce lenvatinib dose 
from 14 mg QD to 10 mg QD
(1-level reduction)
Arm 2: Reduce lenvatinib dose 
from 20 mg QD to 14 mg QD 
(1-level reduction)
Third occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Arm 1: Reduce lenvatinib dose 
from 10 mg QD to 8 mg QD (1-
level reduction)
Arm 2: Reduce lenvatinib dose 
from 14 mg QD to 10 mg QD 
(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; QD=once daily.
Note: For grading see CTCAE version 4.0. Collect all AE grades (ie, decreasing and increasing CTCAE 
grade). 
a. An interruption of study treatment for more than 28 days will require Sponsor’s approval before 
treatment can be resumed.
b. Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea 
prior to any lenvatinib interruption or dose reduction. 
c. Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d. Obese participants (BMI ≥30) with weight loss do not need to return to the baseline weight or within 10% 
of their baseline weight (ie, Grade 1 weight loss). These participants may restart study intervention at a 
lower dose once their weight remains stable for at least 1 week and they reach at least a BMI of 25. The 
new stable weight should be used as the new baseline for further dose reductions.
e. For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are 
not considered clinically relevant by the investigator, continuation of treatment should be discussed with 
Sponsor.
f.
For Grade 3 thromboembolic event, permanently discontinue lenvatinib. See Section 6.6.2.5.
g. Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
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6.6.2.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that participants enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mm Hg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before C1D1. Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.
Regular assessment of BP should be as detailed in the SoA (Section 1.3). Hypertension will 
be graded using NCI CTCAE v4.0, based on BP measurements only (and not on the number 
of antihypertensive medications).
If the participant’s initial BP measurement is elevated (ie, systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 5 minutes later.
One BP assessment is defined as the mean value of 2 measurements at least 5 minutes apart. 
If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes 
apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory 
assessment should be obtained at least 30 minutes later by performing 2 measurements (at 
least 5 minutes apart) to yield a mean value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 
30 minutes apart. For those participants already on antihypertensive medication, treatment 
modification may be necessary if hypertension persists.
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has significant risk factors for severe complications of 
uncontrolled hypertension (eg, BP ≥160/100 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant comorbidities). Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 (or more frequently as clinically indicated) until systolic BP 
has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment 
cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles.
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The following guidelines should be followed for the management of systolic BP ≥160 mm 
Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 30 minutes apart:
1. Continue study drug and institute antihypertensive therapy for participants not already 
receiving this.
2. For those participants already on antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added. Study treatment can be continued without dose 
modification.
3. If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 dose level reduction only when systolic BP ≤150 mm Hg and diastolic 
BP ≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours.
o
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.
o
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.
o
Additional dose reduction should be discussed with 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
See Section 10.7 (Appendix 7) for country-specific requirements.
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6.6.2.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 1.3). 
Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick testing or urinalysis per the SoA (Section 1.3). Urine dipstick 
testing is the preferred method for testing for urinary protein, however, urinalysis may 
be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 hours 
(or an immediate spot urine protein-to-creatinine ratio [UPCR] test) is required in the 
following situations:
o
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine dipstick 
(or urinalysis) while on study drug
o
A subsequent increase in severity of urine dipstick or urinalysis proteinuria 
occurring on the same lenvatinib dose level
o
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 v4.0 will be based on the 24-hour urinary protein 
result if one has been obtained. Management of lenvatinib administration will be based 
on the grade of proteinuria according to Table 5.
Monitoring:

Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ (≥100 mg/dL)
should be performed on D15 (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 5 should be followed.
6.6.2.4
Management of Hepatotoxicity
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin 
levels) should be conducted as detailed in the SoA (Section 1.3) and as clinically indicated. If 
signs/symptoms indicating liver injury occur, instructions contained in Table 5 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
hepatic failure 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 5 should be 
followed. Appropriate supportive care should be provided together with close monitoring. If 
a participant experiences a Grade 3 or a life-threatening (Grade 4) thromboembolic reaction, 
including pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
treatment discontinuation.
6.6.2.6
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Encephalopathy Syndrome/ Reversible Posterior Leukoencephalopathy 
Syndrome
Posterior Reversible Encephalopathy Syndrome/Reversible Encephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome (PRES/RPLS) is a neurological 
disorder that can present with headache, seizure, lethargy, confusion, altered mental function, 
blindness, and other visual or neurological disturbances. Mild to severe hypertension may be 
present. MRI is necessary to confirm the diagnosis of PRES/RPLS. Appropriate measures 
should be taken to control BP. In participants with signs or symptoms of PRES/RPLS, 
instructions in Table 5 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). Corrected serum calcium 
should be used to assess the grade of hypocalcemia per CTCAE v4.0, using the following 
formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
6.6.2.8
Management of Hemorrhage
Instructions in Table 5 should be followed for the management of hemorrhage. Either resume 
at a reduced dose or discontinue lenvatinib depending on the severity and persistence of 
hemorrhage.
6.6.2.9
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.
See Section 10.7 (Appendix 7) for country-specific requirements.
6.6.2.10
Management of QT Prolongation
Lenvatinib should be withheld in the event of development of QT interval prolongation 
greater than 500 msec. Lenvatinib should be resumed at a reduced dose when QTc 
prolongation is resolved to <480 msec or baseline. Monitor potassium, calcium and 
magnesium, and replenish as appropriate.
6.6.2.11
Management of Osteonecrosis of the Jaw
Perform an oral examination prior to treatment with lenvatinib and periodically during 
lenvatinib treatment. Advise participants regarding good oral hygiene practices. Avoid 
invasive dental procedures, if possible, while on lenvatinib treatment, particularly in 
participants at higher risk. For participants requiring invasive dental procedures, 
discontinuation of bisphosphonate treatment may reduce the risk of ONJ. Withhold 
lenvatinib if ONJ develops and restart based on clinical judgement of adequate resolution 
(See Section 6.6.4).
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6.6.3
Dose Modifications for Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab and lenvatinib, certain 
treatment-related AEs are uniquely associated with one drug versus the other. For example, 
hypertension, arterial thrombotic events, proteinuria, and hemorrhagic events are known risks 
for lenvatinib treatment, while immune-related AEs are risks for pembrolizumab treatment. 
However, certain AEs, such as such as diarrhea, hypothyroidism, and liver enzyme elevation, 
may be initially considered attributable to either study drug. Therefore, evaluation of
attribution is important for determining the study drug most likely related to the AE, or an 
alternative etiology, and subsequently proper clinical management. The following aspects 
should be considered: 
1. Timing of AE onset
Since lenvatinib is dosed daily and continuously due to a relatively short half-life 
(28 hours), and pembrolizumab is dosed Q3W due to a long half-life, lenvatinib can 
be interrupted to assess whether an AE improves/resolves with dechallenge (ie, 
interruption of treatment) based on the following 2 scenarios:
o
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab 
doses), only lenvatinib dose interruption is needed. 
o
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (ie, 
positive dechallenge), the event is more likely to be related to lenvatinib. Otherwise, 
after excluding other alternative explanations, an immune-related AE should be 
considered. 
2. Severity of AE
If an AE is suspected to be treatment-related and is severe/life-threatening at the time 
of onset or is rapidly worsened, action including interrupting both drugs and initiating 
treatment with a corticosteroid (with exception of hypothyroidism, TIDM) and other 
supportive care should be taken promptly.
3. Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study therapy if any of the following occur: 

ALT or AST >5 X ULN for more than 2 weeks.
Pembrolizumab will have already been permanently discontinued per Table 3, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met 
and must be permanently discontinued immediately.
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
ALT or AST >3 × ULN and (TBL >2 × ULN or INR >1.5)
Although Table 3 advises pembrolizumab to be withheld (interrupted), and Table 
5 advises lenvatinib to have no dose modification or a reduction, if this criterion is 
met, both drugs must be permanently discontinued immediately.
6.6.4
Other Allowed Dose Interruptions
If the participant is receiving treatment with lenvatinib and requires surgery during the study, 
the stop time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 2 weeks after, once there is evidence of adequate healing and no 
risk of bleeding.

For scheduled dental surgery or invasive dental procedures, stop lenvatinib for at least 1 
week before the procedure, then restart lenvatinib when deemed clinically appropriate.
The reason for interruption should be documented in the participant’s study record.
6.7
Intervention After the End of the Study
The study is complete upon consent of the last active treatment participant in an extension 
study using pembrolizumab monotherapy, coformulations, or in combination with a 
compound (eg, Lenvatinib), if available.
All study related procedures and data collection as defined per protocol will be terminated at 
study completion. In addition, survival follow-up will be stopped upon study completion as 
defined in Section 4.4.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
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who discontinue study intervention prior to completion of the protocol-specified treatment 
period regimen will still continue to participate in the study as specified in Section 1.3 (SoA) 
and Section 8.10.4.
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 8.1.10.
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.

Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Sections 6.6.1, 6.6.2, and 
6.6.4 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.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a positive serum or urine pregnancy test at any time during the course 
of the study.

Initiation of a new anticancer treatment.

Administrative reasons requiring cessation of treatment.

Any progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment. Exceptions to secondary malignancy include basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, new nonulcerated primary 
melanoma <1 mm in depth with no nodal involvement, or carcinoma in situ (eg, breast 
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy. 
Exceptions should be discussed with the Sponsor before continuing therapy or remaining 
in follow-up.

Confirmed radiographic disease progression outlined in Section 8.2.1.5 or Section 
8.2.1.6.
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Note: Participants will be permitted to continue treatment beyond iRECIST- or RANO-
defined progression (Arm 1 only) after confirming informed consent addendum has been 
documented and after Sponsor consultation.

Unacceptable AE(s).
A participant may be discontinued from study intervention but continue to be monitored in
the study for the following reason:

PD as determined by the investigator.
Note: Participants will be permitted to continue treatment beyond RECIST 1.1- or 
RANO-defined progression (Arm 1 only) as long as investigator-assessed clinical 
stability is observed, the participant is tolerating study intervention (Section 8.2.1.5 or
Section 8.2.1.6) and after obtaining documented informed consent addendum. Treatment 
beyond confirmed PD per iRECIST or RANO may be permitted on Sponsor consultation.
Participants receiving the combination therapy (pembrolizumab + lenvatinib) must 
discontinue study therapy if any of the following occur:
ALT or AST elevation meeting the following criteria:

ALT or AST >5 × ULN for more than 2 weeks
Pembrolizumab will have already been permanently discontinued per Table 3 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)
Although Table 3 advises pembrolizumab to be withheld (interrupted), and Table 5 advises 
lenvatinib to have no dose modification or a reduction, if this criterion is met, both 
interventions must be permanently discontinued immediately.
Completion of pembrolizumab q3w consists of 35 treatments (approximately 2 years). 
Note: participants experiencing a clinical benefit, according to the PI, may continue on 
lenvatinib beyond this time point with Sponsor consultation. Discontinuation of treatment 
may be considered for participants who have attained a confirmed CR and have been treated 
for at least 8 cycles (at least 24 weeks), receiving 2 cycles of the combination including 
2 doses of pembrolizumab and at least 80% of the planned doses of lenvatinib beyond the 
date when the initial CR was declared.
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7.2
Participant Withdrawal From the Study
It has been well-documented that a higher rate of withdrawal can render a study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
As clinical event data are important study endpoints, participants who discontinue study 
intervention prior to completion of the treatment period should be encouraged to continue all 
remaining study visits for follow-up and vital status assessment as outlined in the SoA and 
Section 8.10.4.
The investigator is to inform the participants that:

they may discontinue from study intervention at any time during the study, and

they are encouraged to continue visits in the study for follow-up, imaging, and vital status 
assessment.
If participants elect to stop study procedures, they are encouraged to continue to be followed, 
which allows periodic survival follow-up and vital status data to be collected.
If a participant fails to return for scheduled visits and/or if the study site is unable to contact 
the participant after multiple attempts (ie, is lost to follow-up), the procedures to be 
performed are outlined in Section 7.3.
If a participant decides not to continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants who withdraw consent during the study
If the participant or participant’s legally acceptable representative withdraws consent, the 
participant must be withdrawn from the study.
Section 8.1.10 delineates the specific procedures performed 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.
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 
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known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).

All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
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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 Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or the participant’s legally acceptable representative’s dated signature. If the 
investigator recommends continuation of study intervention beyond disease progression, the 
participant or their legally acceptable representative will be asked to provide documented 
informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Disease-specific Biomarker Data Collection
Where available, the following will be collected:
Cohort
Biomarker
GBM
Isocitrate dehydrogenase 1
Isocitrate dehydrogenase 2
MGMT
PD-L1
CRC
Microsatellite instability
Mismatch repair
BRAF
RAS
Epidermal growth factor receptor
TMB
PD-L1
Gastric
Microsatellite instability
Mismatch repair
PD-L1
Human epidermal growth factor receptor 2/neu
Biliary
None
Ovarian
BRCA 1
BRCA 2
TNBC
BRCA 1
BRCA 2
Pancreatic
BRCA 1
BRCA 2
Microsatellite instability
Mismatch repair
BRAF = proto-oncogene B-Raf; BRCA = breast cancer susceptibility gene; MGMT = O-6-methylguanine-DNA 
methyltransferase; PD-L1 = programmed cell death ligand 1; RAS = Rat Sarcoma Viral Oncogene Homolog; TMB = 
tumor mutational burden.
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8.1.6
Prior and Concomitant Medications Review
8.1.6.1
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 Cycle 1 Day 1.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Concomitant medications will be recorded for 30 days after the last dose (or 
for up to 90 days for SAEs).
8.1.7
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 allocation. Each participant will 
be assigned only 1 screening number. Screening numbers must not be re-used for different 
participants.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be nonrandomly allocated and will receive a treatment number. 
The treatment number identifies the participant for all procedures occurring after treatment. 
Once a treatment number is assigned to a participant, it can never be reassigned to another 
participant.
A single participant cannot be assigned more than 1 treatment number.
8.1.9
Study Intervention Administration
Pembrolizumab will be administered by the investigator and/or study staff according to the 
specifications within the pharmacy manual.
Study intervention should begin within 3 days of allocation/randomization.
Lenvatinib may be administered at home, except on Day 1 of Cycles 1 and 2 (required clinic 
visit for ECG testing, per SoA) and on Day 15 of Cycle 1 (lenvatinib PK sample collection, 
per SoA), for participants in Arm 1 only. Please refer to Section 8.1.9.1.1 for further details.
8.1.9.1
Timing of Dose Administration
8.1.9.1.1
Lenvatinib
Lenvatinib is provided as 4 mg or 10 mg capsules. Lenvatinib 20 mg (Arm 1) or 24 mg 
(Arm 2) once daily will be taken orally with water (with or without food) at approximately 
the same time each day in each 21-day cycle. However, for participants in Arm 1, lenvatinib 
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will be administered 0 to 4 hours after completion of pembrolizumab administration on 
Day 1 of Cycles 1 and 2.
If a lenvatinib dose is missed and cannot be taken within 12 hours, then that dose should be 
skipped and the next dose should be taken at the usual time of administration.
8.1.9.1.2
Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day 
cycle. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: –5 minutes/
+10 minutes).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle due to administrative reasons.
8.1.9.2
Compliance
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
Discontinuation and Withdrawal
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End of Treatment Visit at the time of withdrawal.
If discontinuation occurs ≥30 days after the last dose of study treatment, a Safety Follow-up 
Visit (Section 8.10.4.1) is not required. In this situation, all procedures required at the 30-day 
Safety Follow-up Visit and end of treatment (EOT) Visit are performed once and entered into 
the EOT Visit only.
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.1.13
Antineoplastic Treatment
The investigator or qualified designee will review all new antineoplastic treatment initiated 
after the last dose of study treatment. Once new antineoplastic treatment has been initiated, 
the participant will move into survival follow-up. All antineoplastic treatment will be 
recorded until time of death or termination of survival follow-up. If a clinic visit is not 
feasible, follow-up information may be obtained via telephone or email.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image acquisition, collection and transmission to the iCRO can be found in 
the Site Imaging Manual (SIM). Sites should follow the image acquisition guidelines 
described in the SIM to acquire diagnostic quality images. For cohorts other than GBM, 
tumor imaging of chest, abdomen and pelvis is strongly preferred to be acquired by 
computed tomography (CT). For the abdomen and pelvis, contrast-enhanced MRI may be 
used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. For GBM, an industry-standard brain tumor imaging protocol will be used
[Ellingson, B. M.,Bendszus, M., et al 2015] (see SIM). For breast cancer, nuclear medicine 
bone scan should be performed at screening, and if bone metastases are present, every 27 
weeks, or more often if clinically indicated. If CR is suspected based on anatomic imaging, a 
bone scan is required to confirm clearance of bone metastases either within the same imaging 
visit as the anatomic imaging, or on the next anatomic scan. For ovarian cancer, CT oral 
contrast must be used besides the use of IV contrast (see SIM).
The same imaging technique regarding modality and the use of contrast should be used in a 
participant throughout the study to optimize the reproducibility of the assessment of existing 
and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. Note: for the purposes of assessing tumor imaging, the term 
“investigator” refers to the local investigator at the site and/or the radiological reviewer at the 
site or at an offsite facility.
Expedited confirmation of measurable disease based on RECIST 1.1 (or RANO for GBM) by 
BICR at Screening will be used to determine participant eligibility. Confirmation by BICR
that the participant’s imaging shows at least 1 lesion that is appropriate for selection as a 
target lesion per RECIST 1.1 (or RANO for GBM) is required before participant allocation.
All scheduled images for all study participants from the sites will be submitted to the BICR. 
In addition, images (including via other modalities) that are obtained at an unscheduled time 
point to determine disease progression, as well as imaging obtained for other reasons, but 
which shows radiologic progression, should also be submitted to the iCRO.
When the investigator identifies radiographic progression per RECIST 1.1, but elects to 
implement iRECIST, the investigator will assess for confirmation of progression by iRECIST 
at subsequent time points. Images should continue to be submitted to the BICR until the start 
of new anticancer therapy, death, or withdrawal of consent.
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8.2.1.1
Initial Tumor Imaging
The screening images must be submitted to the iCRO for confirmation of measurable disease 
per RECIST 1.1 (or RANO for GBM) for eligibility before allocation.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days before
the date of first dose and can be assessed by the iCRO.
For non-GBM, if brain imaging is performed to document the stability of existing metastases, 
MRI should be used if possible. If MRI is medically contraindicated, CT with contrast is an 
acceptable alternative.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment for all cohorts (except GBM) should be performed at 
9 weeks (63 days ±7 days) from the date of treatment initiation. Subsequent tumor imaging 
should be performed every 9 weeks (63 days ±7 days) or more frequently if clinically 
indicated. After 54 weeks (378 days ±7 days), participants who remain on treatment will 
have imaging performed every 12 weeks (84 days ±7 days) or sooner if clinically indicated 
until Week 102. After Week 102, imaging should be performed q24w, or sooner if clinically 
indicated. 
For participants with GBM, the first on-study imaging assessment should be performed at 6 
weeks (42 days to 49 days) from the date of treatment initiation. Subsequent tumor imaging 
should be performed every 6 weeks (42 days ±7 days) until Week 18 and then every 9 weeks 
thereafter or more frequently if clinical indicated. After 54 weeks (378 days ±7 days), 
participants who remain on treatment will have imaging performed every 12 weeks (84 days 
±7 days) or sooner if clinically indicated until Week 102. After Week 102, imaging should be 
performed q24w, or sooner if clinically indicated.
Imaging timing should follow calendar days from treatment initiation and should not be 
adjusted for delays in cycle starts. Imaging should continue to be performed until disease 
progression is identified by the investigator (unless the investigator elects to continue 
treatment and follow iRECIST), the start of new anticancer treatment, withdrawal of consent, 
death, or notification by the Sponsor, whichever occurs first. All supplemental imaging must 
be submitted to the iCRO.
For participants with GBM, brain MRI is required at baseline and all time points for efficacy 
assessments. For non-GBM cohorts, participants with previously treated brain metastases are 
required to have a brain MRI at screening and at all subsequent tumor assessment time 
points. A brain MRI is also required for all participants when clinically indicated.
OR should be confirmed by a repeat imaging assessment. Tumor imaging to confirm PR or 
CR should be performed at least 4 weeks after the first indication of a response is observed. 
Participants will then return to regular scheduled imaging, starting with the next scheduled 
imaging time point. Participants who receive additional imaging for confirmation do not need 
to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging 
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may resume at the subsequent scheduled imaging time point. Note: Response does not 
typically need to be verified in real time by the BICR.
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 
8 weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site provided they have 
met the conditions detailed in Section 8.2.1.5. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study treatment. Exceptions are detailed in Section 8.2.1.5.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4-week window). If previous imaging was obtained 
within 4 weeks before the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of first dose
(Section 8.2.1.2) until the start of a new anticancer treatment, disease progression, pregnancy, 
death, withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease (Non-GBM Cohorts)
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.
8.2.1.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 9. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
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Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 9, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with the Sponsor and after obtaining signed informed consent 
addendum. In this case, if study intervention is continued, tumor imaging should continue to 
be performed following the intervals as outlined in Section 1.3 and submitted to the iCRO.
A description of the adaptations and iRECIST process is provided in Appendix 9, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 6 and illustrated as a flowchart in Figure 2.
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Table 6
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue study 
intervention at the 
investigator’s 
discretion and after 
the participant’s 
consent.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
investigator 
assessment.
No additional 
imaging 
required.
Discontinue 
treatment (exception 
is possible on 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
investigator 
assessment.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if 
condition has improved 
and/or clinically stable 
per investigator’s 
discretion. Next tumor 
imaging should occur 
according to the regular 
imaging schedule.
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST 
unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 
1.1.
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-Based Therapeutics; PD =
progressive disease; RECIST = Response Evaluation Criteria in Solid Tumors.
8.2.1.6
Response Assessment in Neuro-Oncology (RANO)
RANO criteria have been the preferred criteria for assessing responses in GBM studies since 
their publication in 2010 [Wen, P. Y., et al 2010] and incorporate measurements of tumor 
size as shown in contrast-enhanced MRI with qualitative assessment of both enhancing and 
nonenhancing disease, and information on steroid dosing and participant functional 
performance status. Response assessments will be performed by investigators and by BICR. 
RANO also makes provisions for the pseudoprogression frequently seen after radiotherapy. 
The implementation of RANO is described in detail in Appendix 10, and in the iCRO 
imaging charter.
If disease progression is established by the investigator, the process continues as follows:

Participants will be permitted to continue treatment as long as investigator-assessed 
clinical stability is observed, the participant is tolerating study intervention and after
obtaining documented informed consent addendum. 
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
If the participant continues treatment, the tumor imaging for confirmation of progression 
may be performed at the earliest 4 weeks after the first indication of progression, or at the 
next scheduled scan, whichever is clinically indicated. All scans are to be sent to the
iCRO.

Treatment beyond confirmed PD may be permitted on Sponsor consultation.
For the purpose of this decision process, lack of clinical stability is defined as:

unacceptable toxicity

clinical signs or symptoms indicating clinically significant disease progression

decline in performance status

rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention.
8.2.2
Patient-reported Outcomes
Health-related QoL will be assessed at Cycle 1 Day 1 (before the first dose of study 
intervention), every cycle through Cycle 13, Cycle 17, Cycle 21, at the time of 
discontinuation (EOT Visit), and the 30-day Safety Follow-up Visit (See SoA in Section 1.3 
for electronic patient-reported outcomes [ePRO] administration schedule). If the EOT Visit 
occurs 30 days from the last dose of study treatment, a Safety Follow-up Visit is not required, 
ePROs do not need to be repeated. 
HRQoL questionnaires will be administered by trained site personnel and completed 
electronically by participants in the following order: EORTC QLQ-C30 first, then the cohort-
specific ePROs listed below, and EuroQoL EQ-5D last: 

Breast (QLQ-BR23)

Ovarian (QLQ-OV28)

Gastric (QLQ-STO22)

Colorectal (QLQ-CR29)

GBM (QLQ-BN20)

Biliary (QLQ-BIL21)

Pancreatic (QLQ-PAN26)
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) are administered to allocated participants prior to drug administration, AE 
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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. 
If at the time of enrollment of a participant, the translated version of any PRO measure is not 
available for that language/country, and therefore cannot be completed by the participant at 
Cycle 1 Day 1, then the PRO measure will not be required for this participant at any point 
during the study. The other study PRO measures must be completed as scheduled. 
NOTE: For some sites, the translated PRO measure might become available after study 
startup and should be administered to participants at their time of enrollment; for some sites, 
the PRO measure translation might not be available for the entire duration of the study.
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 laboratory 
manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Physical examinations (full physical or symptom-directed) including oral examination will be 
conducted by an investigator or medically qualified designee (consistent with local 
requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination
including oral examination during Screening. 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. Height and weight will also be measured and recorded.
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8.3.1.2
Symptom-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 before the administration of the study intervention. A
symptom-directed physical examination may be performed at any time during the study, as 
clinically indicated. New clinically significant abnormal findings should be recorded as AEs.
8.3.2
Vital Signs
Vital sign measurements (ie, systolic and diastolic BP [mm Hg], heart rate [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade]), weight (kg), and 
height (cm) will be obtained at the visits designated in the SoA (Section 1.3) by a validated 
method.
BP and heart rate will be measured after the participant has been resting for 5 minutes. All 
BP measurements should be performed on the same arm, preferably by the same person.
Only 1 BP measurement is needed for participants with systolic BP <140 mm Hg and 
diastolic BR <90 mm Hg. If the participant’s initial BP measurement is elevated (ie, systolic 
BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP measurement should be repeated at 
least 5 minutes later. One BP assessment is defined as the mean value of 2 measurements at 
least 5 minutes apart. If the BP assessment (ie, the mean of the 2 BP measurements obtained 
at least 5 minutes apart) 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.
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 investigator/site may provide a diary as a 
tool to aid the participant in collecting BP evaluations between clinic visits. The Sponsor will 
not provide diaries to the site. If BP result raises concerns, the investigator may require 
additional follow-up, including an on-site BP retest, or other clinically appropriate 
intervention(s).
8.3.3
Electrocardiograms
Electrocardiograms (ECGs) will be obtained as designated in the SoA (Section 1.3). 
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3 × 4 lead 
format are to be used. In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously. Participants must be in the recumbent position for a 
period of 5 minutes before the ECG. The Fridericia correction method for calculating QTc 
will be used.
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An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF.
QTc prolongation has been seen in some lenvatinib studies. Monitor ECGs every cycle (as 
specified in the SoA) in participants with congenital long QT syndrome, congestive heart 
failure, bradyarrhythmias, or those who are taking drugs known to prolong the QTc interval 
(including class Ia and III antiarrhythmics). Refer to the lenvatinib IB.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed to 
assess 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 on institutional reports.
8.3.5
Child-Pugh Score
Originally developed in 1973, the Child-Pugh score was used to estimate the risk of operative 
mortality in patients with bleeding esophageal varices. It has since been modified, refined, 
and become a widely used tool to assess prognosis in patients with chronic liver disease and 
cirrhosis. The score considers 5 factors, 3 of which assess the synthetic function of the liver 
(ie, Tbil level, serum albumin, and coagulation parameters [INR or PT]) and 2 of which are 
based on clinical assessment (ie, degree of ascites and degree of hepatic encephalopathy). 
A total Child-Pugh score of 5 to 6 is considered Child-Pugh Class A (well-compensated 
disease); 7 to 9 is Class B (significant functional compromise); and 10 to 15 is Class C 
(decompensated disease). These classes correlate with one- and two-year patient survival: 
Class A: 100 and 85%; Class B: 80 and 60%; and Class C: 45 and 35%.
The BTC cohort will include participants only with a Class A Child-Pugh score.
8.3.6
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
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
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.6.1
Laboratory Safety Assessments 
Hematology, clinical chemistry, routine urinalysis and other laboratory safety assessments 
are specified in Appendix 2 and will be performed according to the SoA.
The results of laboratory safety assessments scheduled before the administration of study 
intervention must be reviewed before the 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 
treatment.
8.3.6.2
Urine Dipstick
Urine dipstick testing will be performed locally within 7 days before the start of treatment. 
Participants with >1+ 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.
Once participants are allocated, urine dipstick testing for participants with proteinuria ≥2+ 
should be performed until the results have been 1+ or negative for 2 consecutive treatment 
cycles. Urine dipstick testing should be performed at the investigational site. If a new event 
of proteinuria ≥2+ occurs, the participant must resume the Day 15 urine dipstick testing for 
evaluation of proteinuria until results are 1+ or negative for 2 consecutive treatment cycles.
For participants with proteinuria ≥2+, see Section 6.6.2.2.
8.3.7
Eastern Cooperative Oncology Group Performance Status
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 status within 3 days of 
allocation/randomization, before the administration of each cycle of study intervention, and 
during the follow-up period, as specified in the SoA (Section 1.3).
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8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.

All AEs from the time of intervention allocation/randomization through 30 days
following cessation of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days 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 treatment
allocation/randomization through 120 days following pembrolizumab or 30 days 
following cessation of lenvatinib, whichever occurs last, must be reported by the 
investigator. If the participant initiates new anticancer therapy following discontinuation 
of study intervention, the time period for reporting pregnancies and exposure during 
breastfeeding is reduced to 30 days following cessation of study intervention.
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
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.
Participants who enter the Extension Study:
From the time of intervention randomization up to the signing of consent to the extension 
study, all AEs, SAEs, and other reportable safety events must be reported by the investigator 
in this protocol (parent study). Laboratory values that meet criteria for reporting as AEs 
performed during parent study will be collected in the parent study.
Note: Once consented to the extension study, safety events, including those considered 
related to study intervention, will be collected as instructed in the extension study.
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 7.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 7
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:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes exclusion
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
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study is 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.
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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.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study. Any suspected endpoint that on 
review is not progression of the cancer under study will be forwarded to Global 
Pharmacovigilance as an SAE within 24 hours of determination that the event is not 
progression of the cancer under study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1.
An overdose of Sponsor's product, as defined in Section 8.5. Lenvatinib overdose 
without an associated adverse event is not considered an ECI.
2.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance 
for assessment and follow up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).
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8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:

Pembrolizumab: ≥5 times the protocol-specified dose

Lenvatinib: any dose above the protocol-specified dose if associated with an AE
There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer and RCC.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib. In the event of overdose, the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper. Reports of pembrolizumab overdose without any 
associated clinical symptoms or abnormal laboratory results, should be reported using the 
terminology “accidental or intentional overdose without adverse effect.”
8.6
Pharmacokinetics
Blood samples will be collected as specified in the SoA (Section 1.3). Study sites must have 
appropriately trained staff and adequate equipment for procuring and processing specimens. 
Instructions for the collection, handling, and shipping procedures of PK samples will be 
provided in the laboratory manual.
To evaluate the immunogenicity and exposure of pembrolizumab in these indications, blood 
samples for PK and antidrug antibodies will be collected and may be stored only at this time. 
Further analysis may be performed if required and reported separately if conducted. 
Blood samples will be collected from all participants. Plasma concentrations of lenvatinib 
when coadministered with pembrolizumab will be measured. Lenvatinib will be analyzed 
using a population PK approach.
Lenvatinib will be quantified by use of validated High-Performance Liquid Chromatography 
-tandem mass spectroscopy method.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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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 as specified in the SoA:

Blood for serum biomarkers

Blood for genetic analysis

Blood for RNA analysis

Blood for plasma biomarkers

Blood for circulating tumor nucleic acids

Tumor blocks or slides
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes.
Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.9
Health Economics Medical Resource Utilization and Health Economics
Medical resource use and health economics data, associated with medical encounters, will be 
collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include
all-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation/randomization through 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention, if the participant initiates new 
anticancer therapy, whichever is earlier. 
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.10.1
Screening
Written consent must be obtained before performing any protocol-specific procedure. Results 
of a test performed before the participant providing documented 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 before the 
first dose of study intervention except for the following:

Laboratory tests are to be performed within 7 days before the first dose of study 
intervention. An exception is Hepatitis testing which may be performed up to 28 days 
before the first dose of study intervention.

Evaluation of ECOG performance status is to be performed within 3 days before
allocation/randomization.

For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 hours before the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).

Tumor tissue must have been obtained before allocation.
8.10.2
Rescreening
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.10.3
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1. 
8.10.3.1
Phone 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). 
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8.10.4
Post treatment Visit
8.10.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first. If EOT Visit occurs ≥30 days from last dose of study treatment, a 
Safety Follow-up Visit is not required. In this situation, all procedures required at the 30-day 
Safety Visit and EOT are performed once and entered into the EOT Visit only.
8.10.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will move into the 
Efficacy Follow-up Phase and should be assessed according to the same imaging schedule 
used while on treatment. Calculated from the date of first dose, imaging should be performed 
every 9 weeks (63 days ±7 days), or more frequently if clinically indicated. After 54 weeks 
(378 days ±7 days), participants will have imaging performed every 12 weeks (84 days ±7 
days) or sooner if clinically indicated until Week 102. After Week 102, imaging should be 
performed every 24 weeks, or sooner if clinically indicated, to monitor disease status. For 
participants with GBM, imaging to be performed at 6 weeks (42 days to 49 days) from the 
date of treatment initiation. Subsequent tumor imaging should be performed every 6 weeks 
(42 days ±7 days) until Week 18 and then every 9 weeks thereafter or more frequently if 
clinical indicated. After 54 weeks (378 days ±7 days), participants who remain on treatment 
will have imaging performed every 12 weeks (84 days ±7 days) or sooner if clinically 
indicated until Week 102. After Week 102, imaging should be performed q24w, or sooner if 
clinically indicated. Imaging timing should follow calendar days from treatment initiation.
Participants who completed all efficacy assessments and/or will not have further efficacy 
assessments must enter the Survival Follow-up Phase.
If a clinic visit is not feasible, the participant may be contacted by telephone or email. Every 
effort should be made to collect information regarding disease status until the start of new 
anticancer therapy, disease progression, death, end of study. Information regarding poststudy 
anticancer treatment will be collected if new treatment is initiated. Participants will also be 
asked to complete HRQoL questionnaires as outlined in Section 8.2.2.
All participants who discontinue study intervention before disease progression will continue 
to undergo tumor assessments in the imaging follow-up phase until disease progression or a 
new anticancer therapy is initiated, unless the participant withdraws consent. 
8.10.4.3
Survival Follow-up Assessments
Participant survival follow-up status will be assessed approximately every 12 weeks until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
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The first survival follow-up assessment should be scheduled as described below:
    For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up Phase, the first survival follow-up contact will be scheduled 
12 weeks after the discontinuation visit and/or Safety Follow-up Visit (whichever is last).
    For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
8.10.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested before but not limited to interim and/or 
final analysis. On Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor-defined time period will be contacted for their 
survival status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to the primary and/or key objectives/endpoints or 
statistical methods related to those objectives/endpoints, then the protocol will be amended 
(consistent with ICH Guideline E9). Changes to analyses made after the protocol has been 
finalized, but before final database lock, will be documented in a supplemental statistical 
analysis plan (sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.2 to 9.12.
Study Design Overview
A Multicenter, Open-label Phase 2 Study of Lenvatinib (E7080/MK-7902) 
Plus Pembrolizumab (MK-3475) in Previously Treated Subjects with 
Selected Solid Tumors (LEAP-005)
Treatment Assignment
Pembrolizumab 200 mg q3w and Lenvatinib 20 mg qd
Lenvatinib 24 mg qd
Analysis Populations
Efficacy and Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
1)
OR per RECIST 1.1 or RANO (GBM) by investigator assessments in 
initial cohorts and by BICR in cohorts that expand combining the 
initial and expansion cohorts (Cohorts A-F). For Cohort G, OR per 
RECIST 1.1 by BICR assessment.
2)
Safety
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Key Secondary Endpoints
3)
Disease control
4)
DOR
5)
PFS
6)
OS
Statistical Methods for Key 
Efficacy Analysis
The point estimate and exact Clopper-Pearson confidence interval (CI) 
will be provided for ORR.
Statistical Methods for Key 
Safety Analyses
Safety will be evaluated using descriptive statistics.
Interim Analyses
For Cohorts A-F, interim analyses, based on investigator assessments of 
efficacy, will be performed when the first 30 participants within a tumor 
cohort have been followed up for approximately 6 months from study entry. 
The results of each IA will be reviewed by the Sponsor, and 
recommendations for cohort expansion will be provided.
For Cohort G, an IA will be performed when the first 30 participants 
enrolled have been followed up approximately 6 months. The results will be 
reviewed by the Sponsor, and recommendations to stop or continue 
enrollment will be provided.
Multiplicity
No multiplicity adjustment is planned
Sample Size and Power 
Cohorts A-F: Approximately 180 participants will be enrolled in the study
initially; that is, 30 participants per tumor type. Based on the interim 
analysis, the sample size for Cohorts A, B, C, E and F may be increased to 
a total of 100 participants to receive pembrolizumab + lenvatinib (Arm 1). 
After the IA, Cohorts A (TNBC) and B (ovarian cancer) discontinued 
enrollment.
Based on the IA, the sample size for Cohort D (CRC) may be increased to 
a total of 130 participants, with the first 40 after initial 30 (total 70)
participants to receive pembrolizumab + lenvatinib (Arm 1) and the last 60 
participants in Cohort D randomized in a 1:1 ratio to receive 
pembrolizumab + lenvatinib (Arm 1) or lenvatinib monotherapy (Arm 2).
Cohort G will enroll a maximum of 100 participants to receive 
pembrolizumab + lenvatinib.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as an open-label study, ie, 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. Independent radiologist(s) will perform the central imaging review 
without knowledge of participant-level treatment status.
For Cohort D (CRC), the last 60 participants will be randomized in a 1:1 ratio between Arm 
1 and Arm 2. The Sponsor will generate the randomized allocation schedule(s) for study 
intervention assignment for this protocol, and the randomization will be implemented in IRT.
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9.3
Hypotheses/Estimation
The objectives of the study are stated in Section 3. There is no formal hypothesis for this 
open-label study.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
9.4.1
Efficacy Endpoints
The primary efficacy endpoint is OR. For Cohorts A-F, response for the primary analysis will 
be determined by investigator assessments in initial cohorts and by BICR in cohorts that 
expand (combining the initial and expansion cohorts), with confirmatory assessment as 
required per RECIST 1.1 and RANO. For Cohort G, response for the primary analysis will be 
determined by BICR, with confirmatory assessment as required per RECIST 1.1. The ORR,
defined as the proportion of participants who have a best overall response of either CR or PR
using RECIST 1.1 (or RANO for GBM participants) at any time during the study, will be 
analyzed. Participants with unknown or missing response information will be treated as 
nonresponders.
Secondary Efficacy Endpoints
1. Disease control, defined as the best overall response of CR, PR, or stable disease based 
on RECIST 1.1.
2. DOR, defined in the subset of participants with a CR or PR, based on RECIST 1.1 (or 
RANO for GBM participants), as the time from first documented evidence of CR or PR 
until the first documented sign of disease progression or death due to any cause, 
whichever occurs first.
3. PFS, defined as the time from date of study treatment to the first documented disease 
progression based on RECIST 1.1, modified to follow a maximum of 10 target lesions 
and a maximum of 5 target lesions per organ (or RANO for GBM participants) or death 
due to any cause, whichever occurs first. 
4. OS, defined as the time from the date of study treatment to the date of death due to any 
cause. 
OR, DCR, DOR, and PFS based on iRECIST by investigator assessment are exploratory 
endpoints in participants who received pembrolizumab + lenvatinib combination therapy. 
The details on these exploratory endpoints will be provided in the supplemental SAP.
9.4.2
Safety Endpoints
A description of safety endpoint assessment is provided in Section 4.2.3.2.
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The primary safety endpoints are treatment-emergent AEs, serious AEs, and discontinuation 
due to AEs. The AEs are graded using NCI CTCAE (Version 4.0).
Other safety endpoints include laboratory safety assessment and vital signs.
9.4.3
Patient-reported Outcome Endpoints
The PRO endpoints are based on the following questionnaires:

EORTC QLQ-C30

EORTC-QoL-disease-specific
-
Breast (QLQ-BR23)
-
Ovarian (QLQ-OV28)
-
Gastric (QLQ-STO22)
-
Colorectal (QLQ-CR29)
-
GBM (QLQ-BN20)
-
Biliary (QLQ-BIL21)
-
Pancreatic (QLQ-PAN26)

EQ-5D-5L
The multi-item scales and single items (as introduced in Section 4.2.3.3) on EORTC
QLQ-C30, disease-specific EORTC instruments, and on EQ-5D-5L will be summarized. The 
scoring algorithm of the multi-item scale(s) for each instrument will be provided in the sSAP. 
TTD will be evaluated for EORTC QLQ-C30 scales. Data will be summarized for 
pre-specified time points. Details will be provided in the sSAP.
9.5
Analysis Populations
Participants are enrolled/randomized in the study when they have received an allocation 
number via IRT (Section 6.3.1).
The efficacy and safety analyses populations will be defined for each tumor cohort. 
9.5.1
Efficacy Analysis Populations
Efficacy Analyses will be conducted in the APaT population, which consists of all 
enrolled/randomized participants who received at least 1 dose of study intervention
(pembrolizumab + lenvatinib combination therapy or lenvatinib monotherapy).
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For the evaluation of the efficacy of pembrolizumab + lenvatinib combination therapy and 
lenvatinib monotherapy, the analysis population will be based on all treated participants that 
are allocated to the corresponding treatment arm. 
The evaluation of the efficacy of the combination therapy relative to the lenvatinib
monotherapy will include all treated participants from the randomized subcohort.
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the APaT population, which consists of all 
enrolled/randomized participants who received at least 1 dose of study intervention
(pembrolizumab + lenvatinib combination therapy or lenvatinib monotherapy).
In the APaT population for safety analysis, participants will be included in the treatment arm 
corresponding to the study intervention that they actually received. For most participants, this 
will be the treatment arm to which they are randomized. Participants who take incorrect 
study intervention for the entire treatment period will be included in the treatment arm 
corresponding to the study intervention actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO Per Protocol Treated (PRO PPT) population, 
defined as all allocated participants who have PRO assessments available at both baseline 
and the specified postbaseline timepoint for the specific endpoint and have received at least 
one dose of the study intervention.
9.6
Statistical Methods
Both efficacy and safety analyses will be assessed by arm within each cohort. 
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements. All safety analyses will be 
performed in the APaT population by treatment arm within each cohort.
Adverse Events
Events will be summarized based on number and proportion of total participants by system 
organ class and preferred term. Separate summaries with descriptive statistics (counts and
percentage) will be given for all AEs, treatment-related AEs, AEs by toxicity grade, SAEs 
and AEs leading to discontinuation of study intervention and dose modification.
ECIs will be identified and additional summaries provided.
The incidence of deaths and the primary cause of death will be summarized. 
Further details on the statistical approach of safety analysis will be described in the sSAP.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Baseline characteristics will be assessed by the use of tables and/or graphs. The number and 
percentage of participants screened and enrolled/randomized and the primary reasons for 
screening failure and discontinuation will be displayed. Demographic variables (eg, age,
gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment arm either by descriptive statistics or 
categorical tables.
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9.8
Multiplicity
There will be no hypothesis testing performed in this study. For the primary and secondary
objectives in this Phase 2 study, no adjustment to control for Type I error is planned.
9.9
Sample Size and Power Calculations
The study will initially enroll 30 participants per cohort in Cohorts A-F. Based on the IA,
70 additional participants may be enrolled in Cohorts A, B, C, E and F to receive 
pembrolizumab + lenvatinib combination therapy. However, after IA, Cohorts A (TNBC) 
and B (ovarian cancer) discontinued enrollment.
Based on the IA, 100 additional participants may be enrolled in Cohort D. The first 70 
participants will receive pembrolizumab + lenvatinib combination therapy and the last 
approximately 60 participants will be randomized in a 1:1 ratio to either pembrolizumab + 
lenvatinib combination therapy (Arm 1) or lenvatinib monotherapy (Arm 2). Additionally, up 
to 100 participants will be enrolled in Cohort G. Table 11 shows the CIs when N=30 and 
N=100, given different numbers of responders. Table 12 shows the true ORR required to 
achieve at least 80% probability that the exact 95% CI of ORR is above historical 
ORR/current therapies.
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9.10
Subgroup Analyses
If data warrant, subgroup analysis will be performed for participants receiving 
pembrolizumab + lenvatinib combination therapy in cohorts with enrollment expansion and 
Cohort G if the full enrollment of 100 participants occurs:

Gender (except ovarian cancer)

Race

Age (<65, ≥65)

Exploratory analysis may be performed for subgroups defined by biomarkers (eg, PD-L1 
expression).
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as number of cycles and days in which the 
participant receives the study intervention. Summary statistics will be provided on the extent 
of exposure for the APaT population for each arm.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
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If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
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from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 15 will be performed by the local laboratory.
Clinical laboratory assessments may be conducted any time within 72 hours before the 
scheduled visit, unless otherwise specified. Procedures/assessments should be performed 
before administration of study treatment.
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.
Pregnancy testing:

Pregnancy testing requirements for study inclusion are described in Section 5.1 and 
Section 8.10.1.

All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of 
the first dose of study intervention

Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at monthly intervals during intervention.

Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at the end of relevant systemic exposure and correspond with the time frame for female 
participant contraception in Section 5.1.

Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study.
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Table 15
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
Blood Urea Nitrogen 
(BUN)c
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum Glutamic
Oxaloacetic Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin if total 
bilirubin is elevated 
above the upper limit of 
normal)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinined
Sodium
Alanine Aminotransferase 
(ALT)/ Serum Glutamic
Pyruvic Transaminase 
(SGPT)
Total Protein
Glucose nonfasting
Calcium
Alkaline phosphatase
Magnesium
Amylase
Lipase
Lactate 
dehydrogenase
Routine 
Urinalysis/Urine 
dipstick testinge
    Specific gravity
    pH, glucose, proteinf,g, blood, and ketones by dipstick
   Microscopic examination (if blood or protein is abnormal)
Other Laboratory 
Tests
    Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)
    Serology (HIV antibody, Hepatitis B surface antigen [HBsAg], and Hepatitis C virus antibody)
    Thyroid-stimulating hormone (TSH), Free thyroxine (FT4), Triiodothyronine (T3)h
   INR or PT, aPTTi and Fibrinogeni
aPTT = activated partial thromboplastin time; C1 = cycle 1; GFR = glomerular filtration rate; HIV = human 
immunodeficiency virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; MCV = mean 
corpuscular volume; PT = prothrombin time; RBC = red blood cell (count); T3 = triiodothyronine; T4 = 
tetraiodothyronine; TSH = thyroid-stimulating hormone; WBC = white blood cell (count); WOCBP = woman of 
childbearing 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. GFR (measured or calculated) or creatinine clearance can be used in place of creatinine
e. If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity should be performed at the institution’s laboratory
f. If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria occurring on 
the same lenvatinib dose level), then a 24-hour urine collection or an immediate spot urine protein-to-creatinine 
(UPCR) test should be performed to quantify the 24-hour urine protein excretion. 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.
g. Participants with >1+ 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.
h. Free T4, T3, and TSH levels will be performed during screening and then repeated on Day 1 of every other cycle 
(starting Cycle 2), at the time of discontinuation (end of treatment), and at the Safety-Follow-up visit. Free T3 is 
acceptable where T3 cannot be determined. There may be instances when sites are unable to obtain thyroid function 
testing results before the scheduled dosing. After C1, review of thyroid function test results after dosing is acceptable.
i. Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulation therapy
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
See Section 10.7 (Appendix 7) for country-specific requirements.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect." Lenvatinib 
overdose without an associated adverse event is not reportable as an AE. Refer to Section 
8.5 for the definition of overdose.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
    The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
    Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
    The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
    This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
    In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
    Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
    Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose
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10.3.5
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of causality
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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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile after menarche and until becoming postmenopausal unless 
permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, 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 follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol defined time frame in Section 5.1:

Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.

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.
The following are not acceptable methods of contraception:

Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM).

Male condom with cap, diaphragm, or sponge with spermicide.

Male and female condom cannot be used together.
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 penetration.
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Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb
Intrauterine hormone-releasing system (IUS)c
Intrauterine device (IUD)
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
c) IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (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).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
After initiation of treatment additional pregnancy testing will be performed every 30 days 
during the treatment period and 120 days post last dose of study medication or the start of a 
new anticancer therapy, whichever comes first, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
See Section 10.7 (Appendix 7) for country-specific requirements.
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10.6
Appendix 6: NYHA Criteria
The NYHA Cardiac Disease Classification provides a functional and therapeutic 
classification for the prescription of physical activity for cardiac participants. On the basis of 
NYHA definitions, participants are to be classified as follows:
Class
Definition
Class I
Participants with no limitation of activities; they suffer no symptoms from ordinary 
activities.
Class II
Participants with slight, mild limitation of activity; they are comfortable with rest or with 
mild exertion.
Class III
Participants with marked limitation of activity; they are comfortable only at rest.
Class IV
Participants who should be at complete rest, confined to bed or chair; any physical activity 
brings on discomfort and symptoms occur at rest.
Adapted from The Criteria Committee of the New York Heart Association, 1994 [Dolgin, M., et al 1994] 
[Dolgin, M., et al 1994a].
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10.7
Appendix 7: Country-specific Requirements
10.7.1
France
Section 5.1
Inclusion Criteria
13. Adequately controlled BP with or without antihypertensive medications, defined as BP
≤140/90 mm Hg at Screening and no change in antihypertensive medications within 1 
week before C1D1.
Section 6.5
Concomitant Therapy
Drugs known to prolong the QTc interval must be used cautiously. Please refer to
https://www.crediblemeds.org for a list of QTc prolonging medications.
Section 6.6.1.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated With Pembrolizumab
Participants should be discontinued from study treatment if any of the following AEs occur:

Recurrent Grade 3 colitis

Grade 4 rash

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Please refer to the current pembrolizumab Summary of Product Characteristics (SmPC) for 
additional guidance on management of immune-related AEs associated with pembrolizumab.
Please refer to the current lenvatinib SmPC for additional guidance on management of AEs 
associated with lenvatinib administration and other contraindications.
Section 6.6.2
Lenvatinib (Dose Modification)
Per the SmPC for lenvatinib, please note the increased risk of QT prolongation especially in 
patients with resting heart rates less than 50 bpm.
Hypomagnesemia
Serum magnesium should be monitored per the SoA (Section 1.3). Hypomagnesemia should 
be treated per institutional guidelines.
Hypokalemia
Serum potassium should be monitored per the SoA (Section 1.3). Hypokalemia should be 
treated per institutional guidelines.
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Section 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 ≤140/90 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.
10.7.2
Germany
Section 1.3
Schedule of Activities
SAEs will be monitored for 120 days after the last dose of study intervention.
Pregnancy testing will be continued for 120 days after the last dose of study intervention, 
regardless of initiation of subsequent anticancer therapy.
Section 5.2
Exclusion Criteria

Has a known history of HIV infection. HIV testing is required at Screening.

Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. Testing for Hepatitis B or Hepatitis C is required at Screening.

Has a known history of active tuberculosis (TB; Bacillus tuberculosis). Testing for 
tuberculosis is required at Screening.
Section 10.2 Appendix 2: Clinical Laboratory Tests

Other screening tests: tuberculosis
10.7.3
United Kingdom
Section 1.3
Scheduled of Activities / Section 10.5.3 Pregnancy Testing
A pregnancy test is required every cycle for WOCBP, and if urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):

Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
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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.
10.7.4
Canada
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.
Section 5.1
Inclusion Criteria
13. Have adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week 
before randomization.
Note: Eligibility of a participant receiving ≥3 antihypertensive medications before study 
entry will require consultation with the Sponsor.
Section 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 3 fistula.
10.7.5
Argentina
Section 1.3
Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 1.3
Schedule of Activities - Screening and Treatment Phase
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
Section 10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
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10.8
Appendix 8: Clinical Studies Evaluating Drug-Drug Interactions With 
Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme 
responsible for metabolism of lenvatinib. Clinical studies were conducted to test these 
findings. 
Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly (15% to 
19%) increases systemic exposure to lenvatinib [Shumaker, R., et al 2015]. Since no change 
was observed in half-life, Tmax, or lag time (Tlag), the slight increase in systemic exposure is 
probably related to a decrease in first pass metabolism. However, since the magnitude of 
change is small, coadministration of lenvatinib with CYP3A4/P-gp inhibitors is not of 
clinical concern. 
The influence of P-gp inhibition on lenvatinib PK has been investigated. P gp inhibition was 
accomplished by coadministering a single dose of rifampin with a single dose of lenvatinib. 
Preliminary results suggest P-gp inhibition increases systemic exposure to lenvatinib 26% to 
32%. Thus, coadministration of lenvatinib with P-gp inhibitors only causes a small increase 
in lenvatinib exposure. 
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been 
investigated. Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK 
was accomplished by administering rifampin qd for 21 days [Shumaker, R. C., et al 2014]. A 
single dose of lenvatinib was coadministered with the 15th dose of rifampin. Based on 
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib 
exposure as mean Cmax increased about 8% while the area under the concentration-time curve 
(AUC) decreased about 7% coadministration of lenvatinib with CYP3A4/P-gp inducers is 
not of clinical concern. 
The main metabolic pathways for lenvatinib in humans were identified as enzymatic 
(CYP3A and aldehyde oxidase) and nonenzymatic processes (Lenvima® Package Insert). 
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10.9
Appendix 9: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained (using iRECIST for participant management 
(see Table 6 and Figure 2). This decision by the investigator should be based on the 
participant’s overall clinical condition.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at  
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit      , an exception to continue 
study intervention may be considered following consultation with the Sponsor. In this case, if 
study intervention is continued, tumor imaging should continue to be performed following 
the intervals as outlined in Section 1.3 and submitted to the central imaging vendor.
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.

Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.

New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.10 Appendix 10: Response Assessment in Neuro-Oncology (RANO) Response 
Criteria
Treatment response assessment will be based on the RANO criteria (Wen 2010), using a 
combination of clinical and imaging data. At baseline, tumor burden is documented by 
selection of lesions that will be followed quantitatively (target lesions) and qualitatively 
(nontarget). At each visit afterward, imaging assessment consists of evaluating target and 
nontarget lesions, searching for new lesions, and review of the abnormalities on T2/FLAIR 
images. These assessments are combined into a radiographic response, which is then 
combined with clinical performance status and steroid dose information to determine the 
overall response for each visit. Endpoint information, such as the best overall response, is 
determined from the sequence of visit responses as described in the SAP.
Scan acquisition
Imaging will be acquired using the standardized brain tumor imaging protocol (Ellingson 
2015). It will include pre- and post-contrast T1-weighted MRI, as well as T2/FLAIR and 
diffusion-weighted imaging. The same technique should be used at baseline and all follow-up 
scans.
Lesion measurements
Lesions should be measured on T1 weighted postgadolinium images, in the axial plane. The 
2 maximal perpendicular outer diameters of each enhancing lesion should be measured. In 
lesions which have cystic components, areas of necrosis, or surgical cavities, every effort 
should be made to measure only the solid portions of the lesion, excluding the nonsolid 
components. In particular, if a patient has a surgical cavity surrounded by enhancement, the 
cavity should not be included in the measurement. If there is nodular enhancement associated 
with the cavity, the nodular component alone should be measured.
Baseline tumor documentation
Reviewers will document baseline tumor on postcontrast T1-weighted and T2/FLAIR 
images. They first identify all lesions, determine whether they are measurable (can be 
measured), and from these choose target lesions (will be measured throughout the study). To 
be considered measurable, a lesion has to show enhancement, have 2 perpendicular diameters 
≥10 mm, and be suitable for reproducible repeated measurements. Enhancing nonmeasurable
lesions include all other enhancement that is strongly believed to represent tumor, but that 
does not meet the requirements above. Up to 5 lesions can be selected as target. Selected 
target lesions are measured, and the sum of products of diameters (SPD) calculated. 
Enhancing nontarget lesions are identified by location only. Because T2/FLAIR 
abnormalities are typically more diffuse than tumor enhancement, the T2/FLAIR images will 
be used for comparison when evaluating later visits, without identification of discrete lesions.
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Radiographic response assessment
Target lesion response (Table 16) is determined by the change in the sum of diameters from 
baseline and from nadir (smallest measurement seen until the visit being evaluated):
Table 16
Target Lesion Response
Response
Definition
Complete response
All target lesions have completely disappeared.
Partial response
SPD decreased by ≥50% from baseline value
Stable disease
SPD <50% decreased from baseline, but <25% increased from nadir
Progressive disease
SPD increased by ≥25% from nadir value 
Nonevaluable
The sum of diameters cannot be meaningfully evaluated (for example, because 
of technical factors such as scan quality that obscure one or more target lesions).
Nontarget lesion response (Table 17) is determined by visual inspection of enhancing 
nontarget lesions collectively and classification into a response category.
Table 17
Lesion Response for Enhancing Nontarget Lesions
Response
Definition
Complete response
All enhancing nontarget lesions have disappeared completely
Stable disease
Enhancing lesions present, showing no definite growth from the visit where they 
were smallest
Progressive disease
Unequivocal progression of enhancing lesions (see below)
Nonevaluable
The sum of diameters cannot be meaningfully evaluated (for example, because of 
technical factors such as scan quality that obscure one or more target lesions)
Note on progressive disease: The general approach is that nontarget lesions can be the basis for a determination of 
progressive disease if it is clear, in the context of the entire scan, that there has been a sufficient increase in the tumor 
burden to show that treatment has failed.
New lesions are assessed in a binary yes/no fashion. If any new enhancing lesions are 
present, and the reviewer is confident that these are due to the presence of new malignancy, 
the response is “Yes,” otherwise, it is “No.” New lesions do not need to meet the size criteria 
for being considered measurable at baseline, but must, in the best judgment of the reviewer, 
be true tumor lesions rather than benign or incidental findings, or caused by some 
comorbidity. If the lesion is uncertain, it should be followed. If later scans reveal it to be a 
true lesion, the record can be retrospectively updated to show the new lesion at the time it 
was first identified.
The T2/FLAIR images are reviewed to determine whether there has been an unequivocal 
increase in tumor-related T2/FLAIR abnormality. This is performed with reference to the 
scan at which the T2/FLAIR abnormality is smallest (analogous to the nadir measurement for 
target lesions), and classified as increase, decreased, or unchanged. Because of the frequently 
diffuse nature of the T2/FLAIR abnormality, it is performed at the scan level rather than by 
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evaluation of discrete T2/FLAIR lesions. The reviewer must be confident that any recorded 
increase in T2/FLAIR abnormality is due to tumor rather than some alternative etiology 
(such as infection, infarction, demyelination, or other causes). If there is question about 
whether a change seen on T2/FLAIR represents progression, the participant continues to the 
next scheduled scan. If the subsequent scan confirms progression, the date of progression is
assigned retrospectively to the visit where the T2/FLAIR changes were first observed.
Target, nontarget, and new lesions are combined into a radiographic response (Table 18) as 
follows:
Table 18
Radiographic Response
Target lesions
Enhancing Nontarget 
lesions
FLAIR/T2 lesions
New lesions
Radiographic
Response
CR
CR
No increase
No
CR
CR
SD or NE
No increase
No
PR
PR
CR, SD, or NE
No increase
No
PR
SD
CR, SD, or NE
No increase
No
SD
NED
CR, SD, or NE
No increase
No
NE
PD
Any
Any
Yes/No
PD
Any
PD
Any
Yes/No
PD
Any
Any
Any
Yes
PD
Any
Any
Increased
Yes/No
PD
NA
CR
No increase
No
CR
NA
SD
No increase
No
SD
NA
NA
No increase
No
NED
CR = complete response; FLAIR = fluid-attenuated inversion recovery; NA = no lesions of this type were present at 
baseline; NED = no evidence of disease (no enhancing lesions were present at baseline, and no new lesions have 
appeared); PD = progressive disease; PR = partial response; SD = stable disease.
Pseudoprogression associated with radiotherapy
If new or increased enhancement is seen within 12 weeks of the completion of radiation 
therapy, but the participant is clinically stable and the investigator believes that the changes 
may be due to pseudoprogression, the participant may remain on treatment. A second scan 
should be performed, at least 6 weeks after the initial scan. If the enhancement continues to 
grow on this scan, progression is considered to have been confirmed at the time of the initial 
scan that showed increased enhancement. If the enhancement has stabilized or decreased on 
this second scan, the initial scan will be considered to have been confirmed as 
pseudoprogression. For endpoint assessment purposes, the initial scan will be equivalent to 
stable disease. On subsequent scans, in cases of confirmed pseudoprogression, all scans 
before the scan at which pseudoprogression was seen will be excluded when choosing the 
nadir value against which the size of enhancing lesions is compared. 
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If the new or increased enhancement occurs in an area that is known to be outside the 
irradiated area (outside the 80% isodose line), or if the participant shows clinical 
deterioration not caused by a comorbid condition or changes in steroid dosing, 
pseudoprogression will not be considered.
Overall Response
To make a final response determination, the radiographic response (from table above) is 
combined with assessments of clinical status and of corticosteroid dose. 
Clinical status is measured using the Karnofsky Performance Scale. A participant’s status is 
considered “stable” if there has been no definite decline in age-adjusted performance from 
their baseline state, and is considered “worsening” if there has been definite decline in age-
adjusted performance that is not attributable to a non-tumor-related cause. Examples of 
definite decline include a decline from 100 or 90 to 70 or less, a decline of at least 20 points 
from 80 or less, or a decline from any baseline to 50 or less, unless attributable to comorbid 
events or changes in corticosteroid dose.
Steroid dose is defined as the average daily dose since last visit. A dose of “none” means no 
corticosteroids above physiologic replacement dose. The dose is considered “stable” if it is 
unchanged or decreased from the visit at which the scans showed the smallest tumor burden. 
The dose is considered “increased” if it has increased from the visit at which the scans 
showed the smallest tumor burden.
For any overall response except PD, all the components of the definition (radiological, 
neurological, and steroid dose) must be present (Table 19). However, either radiological 
progression or clinical deterioration (not attributable to a nontumor-related cause) qualifies a 
participant for PD. However, an increase in steroid dose alone is not sufficient for an overall 
visit response of PD in the absence of clinical or radiological evidence of progression. A 
participant with a radiological response of stable disease, and without neurological evidence 
of progression, but requiring an increased dose of steroids, would still be considered stable 
disease overall at that visit (because increase in steroids alone is not PD). However, the 
participant will be reassessed at the next visit. If either radiological or neurological 
progression is documented at that next visit, the visit at which the increased dose was first 
observed would be retroactively reassessed as PD overall.
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Table 19
Overall Response
Radiographic 
Response
Clinical Performance
Steroid Dose
Overall Response
CR
Stable 
None
CR
CR
Stable
Stable or increased
PR
PR
Stable
Stable
PR
PR
Stable
Increased
SD
SD
Stable
Stable
SD
SD
Stable
Increased
SD or PDa
PD
Any
Any
PD
Any
Worsening
Any
PD
NE 
Stable
Increased
NE or PDa
NED
Stable
Increased
NED or PDa
CR = complete response; NA = no lesions of this type were present at baseline; NED = no evidence of disease (no 
enhancing lesions were present at baseline, and no new lesions have appeared); PD = progressive disease; PR = partial 
response; SD = stable disease.
a PD should not be based on an increase in steroid dose alone, unless confirmed by radiographic or clinical 
deterioration. If the steroid dose is increased while the radiographic assessment and clinical performance 
are stable, the participant should be re-evaluated at the next visit. If clinical or radiographic deterioration 
has occurred, progression can be retrospectively assigned at the visit when the steroid dose was increased.
Pseudoresponse and response confirmation
Pseudoresponse is a phenomenon observed in patients treated with antiangiogenic therapy, 
and manifests as a transient decrease in tumor enhancement that does not reflect a true 
reduction in tumor burden. To avoid mistaken reporting of pseudoresponse as OR, a visit 
response of PR or CR must be confirmed with a scan performed at least 4 weeks later that 
shows the same category of response or better. That is, a PR can be confirmed with a 
subsequent PR or CR, and a CR must be confirmed with a subsequent CR.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
1L
first-line
2L
second-line
ACRIN
American College of Radiology Imaging Network 
ADL
activities of daily living  
AE
adverse event 
AJCC
American Joint Committee on Cancer 
ALT
alanine aminotransferase 
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BP
blood pressure
BRCA
breast cancer susceptibility gene
BTC
biliary tract cancer
BW
body weight
CI
confidence interval
CPK
creatine phosphokinase
CR
complete response
CD28
cluster of differentiation 28 
Cmax
maximum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials 
CRC
colorectal cancer 
CrCl
creatinine clearance
CRF
Case Report Form 
CRU
clinical research unit
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CVA
cerebrovascular accident
CYP
cytochrome P450
DCR
disease control rate
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLTs
dose-limiting toxicities 
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
EDC
electronic data collection 
ELISA
enzyme-linked immunoassay 
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
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Abbreviation
Expanded Term
EORTC
European Organisation for the Research and Treatment of Cancer
EOT
end of treatment
EQ-5D-5L
European Quality of Life 5-dimension 5-level
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded 
FGF
fibroblast growth factor 
FGFR
fibroblast growth factor receptor
FLAIR
fluid-attenuated inversion recovery 
FSH
follicle-stimulating hormone 
FU
follow-up
GBM
glioblastoma 
gBRCAm
germline breast cancer susceptibility gene mutation
GCP
Good Clinical Practice 
GEJ
gastroesophageal junction
GFR
glomerular filtration rate
GI
gastrointestinal
HBsAg
Hepatitis B surface antigen 
HCV
Hepatitis C virus
HIV
human immunodeficiency virus 
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
imaging Contract Research Organization
IEC
Independent Ethics Committee
Ig
immunoglobulin 
IgG4
immunoglobulin G4
IgV-type
Ig-variable–type 
IHC
immunohistochemistry 
IL-10
interleukin 10
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
INR
international normalized ratio
IRB
Institutional Review Board 
iRECIST
modified RECIST 1.1 for immune-based therapeutics
IRT
interactive response technology 
iSD
iRECIST stable disease
IUD
intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic 
LVEF
left ventricular ejection fraction 
mAb
monoclonal antibody
MMR
mismatch repair
mRNA
messenger RNA 
MRI
magnetic resonance imaging
MSI
microsatellite instability
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Abbreviation
Expanded Term
MTD
maximum tolerated dose 
MUGA
multigated acquisition scan 
NCI
National Cancer Institute 
NDA
New Drug Application 
NIMP
Non-Investigational Medicinal Product
NOAEL
no-observed-adverse-effect level 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non–small cell lung cancer 
NYHA
New York Heart Association
OR
objective response
ORR
objective response rate
OS
overall survival
P-gp
P-glycoprotein
PARP
poly (ADP-ribose) polymerase
PBPK
physiologically based PK
PD
progressive disease
PD-1
programmed cell death 1 
PDGFR
platelet-derived growth factor receptor
PD-L1
programmed cell death ligand 1 
PD-L2
programmed cell death ligand 2 
PE
physical examination
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta 
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
q3w
once every 3 weeks
qd
once daily
QoL
quality of life
QLG
Quality of Life Group
QLQ
Quality of life Questionnaire
RANO
Response Assessment in Neuro-Oncology
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose 
RPLS
reversible posterior leukoencephalopathy syndrome
RTKi
receptor tyrosine kinase inhibitor
RTOG
Radiation Therapy Oncology Group 
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
statistical analysis plan
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase 
SIM
site imaging manual
SmPC
Summary of Product Characteristics
SoA
schedule of activities
sSAP
Supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
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Abbreviation
Expanded Term
TAM
tumor-associated macrophage
T1DM
type 1 diabetes mellitus
TAM
tumor-associated macrophage 
TGFβ
transforming growth factor, beta 1 
Tlag
lag time
Tmax
time to maximum plasma concentration
TMB
tumor mutational burden
TMDD
target-mediated drug disposition
TNBC
triple-negative breast cancer
T-regs
regulatory T-cells 
TTD
time to deterioration
UDS
urine drug screen
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio 
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
Vp4
portal vein invasion
WOCBP
woman/women of childbearing potential 
w/v
weight/volume
ZAP70
zeta-chain-associated protein kinase
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