A Phase 3, Randomized, Placebo-controlled, Double-blind Clinical Study of Pembrolizumab (MK-3475) With or Without Lenvatinib (E7080/MK-7902) to Evaluate the Safety and Efficacy of Pembrolizumab and Lenvatinib as 1L Intervention in a PD-L1 Selected Population of Participants With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) (LEAP-010).
Phase: PHASE3
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:           16-Aug-2024
A Phase 3, randomized, placebo-controlled, double-blind clinical 
study of pembrolizumab (MK-3475) with or without lenvatinib 
(E7080/MK-7902) to evaluate the safety and efficacy of 
pembrolizumab and lenvatinib as 1L intervention in a PD-L1 
selected population of participants with recurrent or metastatic 
head and neck squamous cell carcinoma (R/M HNSCC) 
(LEAP-010)
NCT05523323

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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, randomized, placebo-controlled, double-blind clinical study of 
pembrolizumab (MK-3475) with or without lenvatinib (E7080/MK-7902) to evaluate the 
safety and efficacy of pembrolizumab and lenvatinib as 1L intervention in a PD-L1 selected 
population of participants with recurrent or metastatic head and neck squamous cell 
carcinoma (R/M HNSCC) (LEAP-010).
Protocol Number: 010-06
Compound Number: MK-7902
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
This study is co-funded by MSD and Eisai.
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
04199104
EU CT
Not applicable
EudraCT
2019-003717-34
JAPIC-CT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
142277
Approval Date: 16 August 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 06
16-AUG-2024
This change was made to address incorrect 
standard text. Language was inadvertently 
removed in the previous amendment.
Amendment 05
19-OCT-2023
The study is being terminated based on the 
results of an interim analysis, which showed a 
lack of clinical benefit on overall survival (OS) 
of the of the pembrolizumab plus lenvatinib 
combination over pembrolizumab monotherapy. 
This amendment serves to incorporate 
instructions for discontinuation of study 
intervention, appropriate measures for safety 
follow-up of ongoing study participants, and the 
plan for analysis of study data going forward.
Amendment 04
05-JUL-2022
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck Sharp 
& Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name 
change and update to the address.
Amendment 03
28-May-2021
Global amendment to update the dose 
modification and toxicity management 
guidelines for irAEs. The protocol was also 
updated to comply with lenvatinib label 
requirements for osteonecrosis of the jaw, NG/G 
tube update, and FDA commitment to update 
imaging language.
Amendment 02
03-JUN-2020
To incorporate Health Authority feedback 
received to date, modify the driver of IA2, 
amend exclusion criteria to allow administration 
of lenvatinib suspension through a gastrostomy 
tube, add nonemergency unblinding to guide 
further treatment decisions of participants with 
centrally-verified PD, remove iRECIST 
assessments, and provide program-level updates, 
corrections, and clarifications.
Amendment 01
25-OCT-2019
Removed anticoagulants, NSAIDS and aspirin 
from the list of prohibited medications within the 
Concomitant Therapy Section, as on-study use 
of anticoagulants, NSAIDS and aspirin are 
allowed.
Original Protocol
14-OCT-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 06
Overall Rationale for the Amendment:
This change was made to provide correct language that was inadvertently removed in the 
previous amendment.
Summary of Changes Table
Section Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 10.3.5, Recording 
AE and SAE
Assessment of intensity/toxicity
Inserted language to assist the investigator in 
assessing the intensity of AEs/SAEs in 
accordance with NCI CTCAE version 5. This 
guidance provides the definitions for Grade 1 
through Grade 5 events.
This change was made to address incorrect 
standard text. Language was inadvertently 
removed in the previous amendment.
Section Number and 
Name
Description of Change
Brief Rationale
Other Changes in Amendment
Section 1.1, Synopsis
Provided new language indicating that 
participants in China may continue in the 
trial until regulatory commitments have been 
met. The new language also provides 
guidance for participants in China to enroll 
into an extension study.
To clarify how discontinuation of 
participants in China will be addressed
when all local regulatory commitments 
have been met.
Section 1.2, Schema
Expanded the introduction statement to 
include new language that participants in 
China may continue in the trial until 
regulatory commitments have been met. The 
new language also provides guidance for 
enrollment into an extension study.
Refer to Section 1.1 rationale.
Removed language regarding extension study 
from Figure 3 and Figure 4 footnotes.
Deleted redundant information. Option for 
extension study is explained in Section 1.1 
and in Section 6.8.
Section 6.7, Second Course
Inserted language stating that an OR or 
disease progression that occurs during the 
Second Course Phase will not be counted as 
an event for the primary analysis of in this 
study.
Refer to Section 10.3.5 primary reason 
rationale.
Section 7.3, Lost to 
Follow-up
Inserted language to help define participants 
who are considered lost to follow-up and the 
management of statistical data handling for 
these participants.
Refer to Section 10.3.5 (Assessment of 
intensity/toxicity) primary reason 
rationale.
Section 8.1.1, Informed 
Consent
Removed reference to FBR
FBR was not collected in this study.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 10.3.4, Additional 
Events Reported in the 
Same Manner as SAE
The section title and 1st paragraph were 
updated to provide consistent guidance in 
reporting AEs and SAEs.
Refer to Section 10.3.5 primary reason 
rationale (assessment of intensity/toxicity)
Section 10.3.5, Recording 
AE and SAE
Assessment of causality
Inserted language to assist the investigator in 
identifying the cause of the AE/SAE and the 
use of specific components in assessing the 
relationship between the product and the AE.
Refer to Section 10.3.5 primary reason 
rationale (assessment of intensity/toxicity)
Sectio 10.7.2, China
Section 1.1 Synopsis and Section 1.2 Schema
Provided new language indicating that 
participants in China may continue in the 
trial until regulatory commitments have been 
met. The new language also provides 
guidance for enrollment into an extension 
study.
Refer to Section 1.1 rationale.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities...........................................................................................23
1.3.1
Initial Treatment Phase ................................................................................24
1.3.2
Second Course Phase...................................................................................44
2
INTRODUCTION..........................................................................................................52
2.1
Study Rationale....................................................................................................52
2.2
Background ..........................................................................................................53
2.2.1
Pharmaceutical and Therapeutic Background .............................................54
2.2.1.1
Pembrolizumab ..................................................................................54
2.2.1.2
Lenvatinib ..........................................................................................54
2.2.1.3
Pembrolizumab Plus Lenvatinib........................................................55
2.2.2
Preclinical and Clinical Studies ...................................................................56
2.2.2.1
Completed Studies With Pembrolizumab and Lenvatinib.................56
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib .....................56
2.3
Benefit/Risk Assessment......................................................................................60
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................62
4
STUDY DESIGN............................................................................................................65
4.1
Overall Design......................................................................................................65
4.2
Scientific Rationale for Study Design.................................................................67
4.2.1
Rationale for Endpoints ...............................................................................67
4.2.1.1
Efficacy Endpoints.............................................................................67
4.2.1.1.1
RECIST 1.1..............................................................................67
4.2.1.2
Safety Endpoints................................................................................68
4.2.1.3
Exploratory Endpoints .......................................................................68
4.2.1.3.1
Rationale for Patient-reported Outcomes Endpoints ...............68
4.2.1.4
Pharmacokinetic Endpoints ...............................................................69
4.2.1.5
Pharmacodynamic Endpoints.............................................................69
4.2.1.6
Planned Exploratory Biomarker Research.........................................69
4.2.2
Rationale for the Use of Comparator/Placebo .............................................71
4.3
Justification for Dose...........................................................................................71
4.3.1
Pembrolizumab ............................................................................................71
4.3.2
Lenvatinib ....................................................................................................72
4.3.3
Starting Dose for This Study........................................................................73
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4.3.4
Maximum Dose Exposure for This Study ...................................................73
4.4
Beginning and End-of-Study Definition ............................................................73
4.4.1
Clinical Criteria for Early Study Termination .............................................74
5
STUDY POPULATION ................................................................................................75
5.1
Inclusion Criteria.................................................................................................75
5.2
Exclusion Criteria................................................................................................78
5.3
Lifestyle Considerations......................................................................................81
5.3.1
Meals and Dietary Restrictions....................................................................81
5.4
Screen Failures.....................................................................................................81
5.5
Participant Replacement Strategy......................................................................81
6
STUDY INTERVENTION............................................................................................82
6.1
Study Intervention(s) Administered...................................................................82
6.1.1
Treatment .....................................................................................................84
6.2
Preparation/Handling/Storage/Accountability .................................................84
6.2.1
Dose Preparation..........................................................................................84
6.2.2
Handling, Storage, and Accountability........................................................84
6.3
Measures to Minimize Bias: Randomization and Blinding..............................85
6.3.1
Intervention Assignment..............................................................................85
6.3.2
Stratification.................................................................................................85
6.3.3
Blinding........................................................................................................85
6.4
Study Intervention Compliance..........................................................................86
6.5
Concomitant Therapy..........................................................................................86
6.5.1
Rescue Medications and Supportive Care ...................................................87
6.5.2
Drug Interactions .........................................................................................87
6.6
Dose Modification (Escalation/Titration/Other)...............................................88
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................89
6.6.2
Dose Modification with Lenvatinib.............................................................94
6.6.2.1
Management of Hypertension............................................................96
6.6.2.2
Management of Proteinuria................................................................97
6.6.2.3
Management of Diarrhea ...................................................................98
6.6.2.4
Management of Hepatotoxicity..........................................................99
6.6.2.5
Management of Thromboembolic Events..........................................99
6.6.2.6
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome .......................................99
6.6.2.7
Management of Hypocalcemia ..........................................................99
6.6.2.8
Management of Hemorrhage ...........................................................100
6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation.100
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6.6.2.10
Management of QT Prolongation ....................................................100
6.6.2.11
Management of Osteonecrosis of the Jaw .......................................100
6.6.3
Dose Modifications for Overlapping Toxicities ........................................100
6.6.4
Other Allowed Dose Interruptions.............................................................101
6.7
Second Course....................................................................................................101
6.8
Intervention After the End of the Study..........................................................103
6.9
Clinical Supplies Disclosure..............................................................................103
6.10
Standard Policies................................................................................................103
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................104
7.1
Discontinuation of Study Intervention.............................................................104
7.2
Participant Withdrawal From the Study.........................................................106
7.3
Lost to Follow-up ...............................................................................................106
8
STUDY ASSESSMENTS AND PROCEDURES......................................................107
8.1
Administrative and General Procedures .........................................................107
8.1.1
Informed Consent.......................................................................................107
8.1.1.1
General Informed Consent...............................................................108
8.1.2
Inclusion/Exclusion Criteria ......................................................................108
8.1.3
Participant Identification Card...................................................................108
8.1.4
Medical History .........................................................................................109
8.1.5
Prior and Concomitant Medications Review.............................................109
8.1.5.1
Prior Medications.............................................................................109
8.1.5.2
Concomitant Medications................................................................109
8.1.6
Assignment of Screening Number.............................................................109
8.1.7
Assignment of Treatment/Randomization Number...................................109
8.1.8
Study Intervention Administration ............................................................110
8.1.8.1
Timing of Dose Administration.......................................................110
8.1.8.2
Compliance ......................................................................................110
8.1.9
Discontinuation and Withdrawal ...............................................................111
8.1.10
Participant Blinding/Unblinding................................................................111
8.1.11
Calibration of Equipment...........................................................................112
8.1.12
Tumor Tissue for Biomarker Status...........................................................112
8.2
Efficacy Assessments .........................................................................................113
8.2.1
Tumor Imaging and Assessment of Disease..............................................113
8.2.1.1
Initial Tumor Scans..........................................................................114
8.2.1.2
Tumor Scans During the Study........................................................114
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................115
8.2.1.4
Second Course (Retreatment) Tumor Scans....................................115
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8.2.1.5
RECIST 1.1 Assessment of Disease................................................116
8.2.2
Patient-reported Outcomes.........................................................................118
8.3
Safety Assessments.............................................................................................118
8.3.1
Physical Examinations...............................................................................118
8.3.1.1
Full Physical Examination...............................................................119
8.3.1.2
Directed Physical Examination........................................................119
8.3.2
Vital Signs..................................................................................................119
8.3.3
Electrocardiograms ....................................................................................120
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan...............................120
8.3.5
Clinical Safety Laboratory Assessments ...................................................120
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................121
8.3.5.1.1
Hematology and Clinical Chemistry......................................121
8.3.5.1.2
Urine Dipstick Testing/Urinalysis .........................................121
8.3.5.1.3
Thyroid Function Testing ......................................................122
8.3.5.2
Pregnancy Testing............................................................................122
8.3.6
Performance Assessments..........................................................................123
8.3.6.1
Eastern Cooperative Oncology Group Performance Status.............123
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................123
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................123
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....125
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.126
8.4.4
Regulatory Reporting Requirements for SAE ...........................................126
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................126
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................127
8.4.7
Events of Clinical Interest..........................................................................127
8.5
Treatment of Overdose......................................................................................127
8.6
Pharmacokinetics...............................................................................................128
8.7
Pharmacodynamics............................................................................................128
8.8
Biomarkers .........................................................................................................128
8.8.1
Planned Genetic Analysis Sample Collection............................................129
8.9
Future Biomedical Research Sample Collection.............................................129
8.10
Medical Resource Utilization and Health Economics.....................................129
8.11
Visit Requirements.............................................................................................129
8.11.1
Screening....................................................................................................129
8.11.2
Initial Treatment Phase ..............................................................................129
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8.11.2.1
Telephone or Contact Visit..............................................................129
8.11.3
Second Course Treatment Phase................................................................130
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................130
8.11.5
Posttreatment Visit.....................................................................................130
8.11.5.1
Safety Follow-up Visit.....................................................................130
8.11.5.2
Efficacy Follow-up Visits................................................................130
8.11.5.3
Survival Follow-up Contacts ...........................................................131
8.11.6
Vital Status.................................................................................................131
9
STATISTICAL ANALYSIS PLAN ...........................................................................132
9.1
Statistical Analysis Plan Summary...................................................................132
9.2
Responsibility for Analyses/In-house Blinding ...............................................135
9.3
Hypotheses/Estimation ......................................................................................136
9.4
Analysis Endpoints.............................................................................................136
9.4.1
Efficacy Endpoints.....................................................................................136
9.4.2
Safety Endpoints........................................................................................136
9.4.3
Patient-Reported Outcome Endpoints........................................................137
9.5
Analysis Populations..........................................................................................137
9.5.1
Efficacy Analysis Populations...................................................................137
9.5.2
Safety Analysis Populations ......................................................................137
9.5.3
Patient-Reported Outcome Analysis Populations......................................137
9.5.4
Population Pharmacokinetic Analysis Set .................................................137
9.6
Statistical Methods.............................................................................................138
9.6.1
Statistical Methods for Efficacy Analyses.................................................138
9.6.1.1
Objective Response Rate .................................................................138
9.6.1.2
Progression-free Survival.................................................................138
9.6.1.3
Overall Survival...............................................................................140
9.6.1.4
Duration of Response.......................................................................140
9.6.1.5
Analysis Strategy for Key Efficacy Variables.................................141
9.6.2
Statistical Methods for Safety Analyses ....................................................142
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses....................143
9.6.4
Demographic and Baseline Characteristics ...............................................144
9.7
Interim Analyses ................................................................................................144
9.7.1
Efficacy Interim Analyses..........................................................................144
9.7.2
Safety Interim Analysis..............................................................................145
9.8
Multiplicity .........................................................................................................145
9.8.1
Objective Response Rate ...........................................................................146
9.8.2
Progression-free Survival...........................................................................147
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9.8.3
Overall Survival.........................................................................................148
9.8.4
Safety Analyses..........................................................................................149
9.9
Sample Size and Power Calculations ...............................................................150
9.10
Subgroup Analyses.............................................................................................151
9.11
Compliance (Medication Adherence)...............................................................151
9.12
Extent of Exposure.............................................................................................151
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................152
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......152
10.1.1
Code of Conduct for Clinical Trials...........................................................152
10.1.2
Financial Disclosure...................................................................................155
10.1.3
Data Protection...........................................................................................155
10.1.3.1
Confidentiality of Data ....................................................................155
10.1.3.2
Confidentiality of Participant Records.............................................156
10.1.3.3
Confidentiality of IRB/IEC Information..........................................156
10.1.4
Committees Structure.................................................................................156
10.1.4.1
Scientific Advisory Committee (SAC)............................................156
10.1.4.2
Executive Oversight Committee......................................................156
10.1.4.3
External Data Monitoring Committee .............................................156
10.1.5
Publication Policy......................................................................................157
10.1.6
Compliance with Study Registration and Results Posting Requirements .157
10.1.7
Compliance with Law, Audit, and Debarment ..........................................158
10.1.8
Data Quality Assurance .............................................................................158
10.1.9
Source Documents .....................................................................................159
10.1.10
Study and Site Closure...............................................................................159
10.2
Appendix 2: Clinical Laboratory Tests............................................................160
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................162
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................162
10.3.2
Definition of AE ........................................................................................162
10.3.3
Definition of SAE ......................................................................................163
10.3.4
Additional Events Reported in the Same Manner as SAE.........................164
10.3.5
Recording AE and SAE .............................................................................164
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................168
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................169
10.5
Appendix 5: Contraceptive Guidance..............................................................170
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10.5.1
Definitions..................................................................................................170
10.5.2
Contraceptive Requirements......................................................................171
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................172
10.7
Appendix 7: Country-specific Requirements..................................................173
10.7.1
Canada........................................................................................................173
10.7.2
China..........................................................................................................173
10.7.3
Germany.....................................................................................................173
10.7.4
Japan ..........................................................................................................173
10.7.5
UK..............................................................................................................174
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................175
10.9
Appendix 9: ECOG Performance Status.........................................................176
10.10 Appendix 10: Abbreviations .............................................................................177
11
REFERENCES.............................................................................................................184
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LIST OF TABLES
Table 1
Initial Treatment Phase ................................................................................24
Table 2
Second Course Phase...................................................................................44
Table 3
Adequate Organ Function Laboratory Values .............................................78
Table 4
Study Interventions......................................................................................83
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations..........................................................89
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines....................................................................................................93
Table 7
Dose Modification Guidelines for Lenvatinib-Related Adverse Events .....95
Table 8
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ..........................................................................125
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS.................140
Table 10
Censoring Rules for DOR..........................................................................141
Table 11
Analysis Strategy for Key Efficacy Variables...........................................141
Table 12
Analysis Strategy for Safety Parameters....................................................143
Table 13
Summary of Interim and Final Analyses Strategy.....................................145
Table 14
Possible α Levels (One-Sided) and Approximate ORR Difference 
Required to Show Efficacy for Objective Response at IA1......................147
Table 15
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses ....................................................................................................148
Table 16
Efficacy Boundaries and Properties for Overall Survival Analyses..........149
Table 17
Protocol-required Clinical Laboratory Assessments .................................160
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LIST OF FIGURES
Figure 1
Original Study Design Initial Treatment Phase ...........................................21
Figure 2
Original Study Design Second Course Phase..............................................21
Figure 3
New Study Design Initial Treatment Phase.................................................22
Figure 4
New Study Design Second Course Treatment Phase ..................................22
Figure 5
Study Intervention Decision Making Process When Progression per 
RECIST 1.1 is Observed by Investigator (PFS endpoint).........................117
Figure 6
Multiplicity Diagram for Type I Error Control..........................................146
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, randomized, placebo-controlled, double-blind clinical study of 
pembrolizumab (MK-3475) with or without lenvatinib (E7080/MK-7902) to evaluate the 
safety and efficacy of pembrolizumab and lenvatinib as 1L intervention in a PD-L1 selected 
population of participants with recurrent or metastatic head and neck squamous cell 
carcinoma (R/M HNSCC) (LEAP-010).
Short Title: A Phase 3 study of pembrolizumab (MK-3475) with or without lenvatinib 
(E7080/MK-7902) as 1L intervention in a PD-L1 selected population with R/M HNSCC 
(LEAP-010)
Acronym: LEAP-010
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In males and females who are at least 18 years old, with a histologically confirmed diagnosis 
of R/M HNSCC that is biomarker positive (combined positive score (CPS ≥1)), and who are 
considered incurable by local therapies will be enrolled in this study.
Throughout this protocol, the term RECIST 1.1 refers to the adjustment of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.1 for further details.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-010 (data 
cutoff 30-MAY-2023), the study will be discontinued based on a lack of additional clinical 
benefit on overall survival (OS) of the combination of pembrolizumab plus lenvatinib over 
pembrolizumab monotherapy. At this interim analysis, the combination did not demonstrate 
an improvement in OS versus pembrolizumab alone, and the likelihood of reaching the 
protocol specified threshold for statistical significance for OS at a future analysis was 
evaluated and deemed to be low. Based upon these data, the study was unblinded on
16-AUG-2023. The prespecified third interim analysis and final analysis of the study 
described in the SAP will not be performed. Safety analysis will be performed at the end of 
the study; there will be no further planned analyses for efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter dated 25-AUG-2023, all study 
participants still receiving pembrolizumab should continue to receive pembrolizumab 
monotherapy on study and undergo modified protocol study procedures as specified in this 
amendment. Study participation should end after the 30-day Safety Follow-up Visit (last 
scheduled visit) with the following exceptions: participants who are potential candidates for 
Second Course treatment will continue in Efficacy Follow-up and all participants in China 
will continue in Efficacy Follow-up and Survival Follow-up. All participants should stop 
ongoing treatment with lenvatinib/placebo.
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Exceptions may be requested for lenvatinib for study participants who, in the assessment of 
their study physician, are benefiting from ongoing lenvatinib after consulting with the 
Sponsor. This applies to participants currently on pembrolizumab and lenvatinib and 
participants who have discontinued pembrolizumab and are currently continuing lenvatinib 
monotherapy. Participants who are considered by the investigator as candidates for continued
monotherapy with lenvatinib after completion of 35 cycles of pembrolizumab and lenvatinib 
require a separate communication with the Sponsor. Participants who discontinue 
pembrolizumab prior to completion of Cycle 35 (eg, due to an AE) must discontinue 
lenvatinib at the same time.
All participants beyond the 30-day Safety Follow-up Visit (except participants who are 
potential candidates for Second Course treatment and all participants in China) should be 
discontinued from the study; however standard safety reporting should continue, as 
applicable. As of Amendment 05, participants who are still on study treatment will no longer 
require ePRO assessments or tumor response assessments by BICR to be performed. Scans 
will no longer be submitted to the iCRO. (Note: tumor response assessments by BICR and 
submission of scans to the iCRO will continue for participants in China.) Participants who 
are still on study medication should continue tumor imaging and investigator assessments of 
imaging per protocol. Biomarker specimen collection is discontinued. The 30-Day Safety 
Follow-up Visit is the last required visit (except for participants who are potential candidates 
for Second Course treatment and all participants in China). Updated analyses are described in 
Section 9. Participants in China will continue participation this trial until all regulatory 
commitments have been met. Upon completion of all regulatory requirements, participants in 
China are to be discontinued and may be enrolled in an extension study using pembrolizumab 
in combination with compound (eg, lenvatinib) if available.
Primary Objective
Primary Endpoint
Objective: To compare pembrolizumab + 
lenvatinib to pembrolizumab + placebo with 
respect to ORR per RECIST 1.1 as assessed 
by BICR.
Hypothesis (H1): Pembrolizumab + 
lenvatinib is superior to pembrolizumab + 
placebo with respect to ORR per RECIST 
1.1 by BICR.
OR, defined as a BOR of CR or PR
Objective: To compare pembrolizumab + 
lenvatinib to pembrolizumab + placebo with 
respect to PFS per RECIST 1.1 as assessed 
by BICR.
PFS, defined as the time from 
randomization to the first documented PD or 
death due to any cause, whichever occurs 
first.
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Hypothesis (H2): Pembrolizumab + 
lenvatinib is superior to pembrolizumab + 
placebo with respect to PFS per RECIST 1.1 
as assessed by BICR.
Objective: To compare pembrolizumab + 
lenvatinib to pembrolizumab + placebo with 
respect to OS.
Hypothesis (H3): Pembrolizumab + 
lenvatinib is superior to pembrolizumab + 
placebo with respect to OS.
OS, defined as the time from randomization 
to the date of death due to any cause.
Secondary Objectives
Secondary Endpoints
Objective: To evaluate pembrolizumab + 
lenvatinib and pembrolizumab + placebo 
with respect to DOR per RECIST 1.1 as 
assessed by BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR until PD 
or death due to any cause, whichever occurs 
first.
Objective: To assess the safety and 
tolerability of study intervention with 
pembrolizumab + lenvatinib and 
pembrolizumab + placebo.
-AEs
-Study drug discontinuations due to AEs.
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Head and neck cancer metastatic
Treatment of participants with R/M HNSCC
Population
Participants with R/M HNSCC (CPS ≥1) 
who are eligible for 1L treatment
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Placebo
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Study Blinding
Double-blind
Blinding Roles
Investigator
Participants or Subjects
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 60 months from the 
time the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 500 participants will be randomized. Randomization will be stratified 
according to: PD-L1 tumor expression as determined by PD-L1 IHC (TPS <50% vs. ≥50%); 
HPV status for oropharynx cancer as determined by p16 IHC (positive vs. negative); and 
ECOG performance status (0 vs. 1). All randomized participants are included in the ITT 
analysis as described in Section 9. After enrollment of the global portion of the study is 
complete, the study may remain open to enrollment in China alone until the target number of 
participants in China has been enrolled to meet local regulatory requirements.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1
Lenvatinib
10 mg
4 mg
20 mg
Oral
QD, no 
treatment 
duration limit
Test Product
Arm 1
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Day 1 of each 
21-day cycle
Test Product
Arm 2
Matching 
placebo
N/A
N/A
Oral
QD, no 
treatment 
duration limit
Placebo
Arm 2
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Day 1 of each 
21-day cycle
Test Product
EEA = European Economic Area; IMP = investigational medicinal product; IV = intravenous; N/A – not applicable; 
NIMP/AxMP = noninvestigational/auxiliary medicinal product; 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.
4mg capsules provided for successive dose reduction of lenvatinib, if needed, as described in Section 6.6.2.
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Other current or former name(s) or alias(es) for study intervention(s) are as follows:
KEYTRUDA®, MK-3475, SCH 900475; LENVIMA®, MK-7902, and E7080.
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
from the time the participant provides 
documented informed consent through the 
final protocol-specified contact.
After a screening phase of up to 42 days, 
each participant will be assigned to receive 
study intervention until disease progression 
is verified by BICR, unacceptable adverse 
events, intercurrent illness that prevents 
further administration of study treatment, 
investigator’s decision to discontinue the 
participant, or administrative reasons 
requiring cessation of treatment.
All participants receiving pembrolizumab 
will discontinue treatment with 
pembrolizumab after receiving 35 
administrations. Participants who stop 
pembrolizumab after 35 administrations for 
reasons other than disease progression or 
intolerability or participants who stop 
pembrolizumab after attaining a Complete 
Response may be eligible for up to 17 
additional administrations of 
pembrolizumab upon experiencing BICR-
verified disease progression (Section 6.7). 
Participants who are receiving 
lenvatinib/placebo at the time disease 
progression is verified may continue to 
receive lenvatinib/placebo during Second 
Course treatment at the discretion of the 
investigator. Participants who discontinue 
lenvatinib/placebo prior to initiation of 
Second Course treatment will not restart 
lenvatinib/placebo.
After the end of treatment, each participant 
will be followed for the occurrence of 
adverse events and spontaneously reported 
pregnancy as described under Section 8.4.
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Participants who discontinue for reasons 
other than radiographic disease progression 
will have post-treatment follow-up imaging 
for disease status until disease progression 
is documented per RECIST 1.1 by BICR, 
the start of a new anti-cancer treatment, 
withdrawal of consent, pregnancy, death, or 
loss to follow-up. All participants will be 
followed by telephone for overall survival 
until death, withdrawal of consent, or the 
end of the study.
Upon study termination, participants are to 
be discontinued and may be enrolled in an 
extension study using pembrolizumab in 
combination with compound (e.g., 
lenvatinib) if available.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
As of Amendment 05, the Executive Oversight Committee and Data Monitoring Committee 
are no longer applicable.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 10.
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1.2
Schema
The original study design is depicted in Figure 1and Figure 2. The new study design per 
Amendment 05 is depicted in Figure 3 and Figure 4.
Participants in China will continue participation this trial until all regulatory commitments 
have been met. Upon completion of all regulatory requirements, participants in China are to 
be discontinued and may be enrolled in an extension study using pembrolizumab in 
combination with compound (eg, lenvatinib) if available. (See Appendix 7 for country-
specific requirements.)
Figure 1
Original Study Design Initial Treatment Phase
Abbreviations: CCRT = concomitant chemoradiotherapy; CPS = combined positive score; ECOG = Eastern 
Cooperative Oncology Group; HNSCC = head and neck squamous cell carcinoma; HPV = human papilloma virus; IV 
= intravenously; PD = progressive disease; PD-L1 = programmed cell-death-ligand 1; PO = orally; PS = performance 
status; Q3W = every 3 weeks; QD = daily; R/M = recurrent/metastatic; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors.
Figure 2
Original Study Design Second Course Phase
Abbreviations: IV = intravenously; PD = disease progression; PO = orally; Q3W = every 3 weeks; QD = daily.
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Figure 3
New Study Design Initial Treatment Phase
Abbreviations: CCRT = concomitant chemoradiotherapy; CPS = combined positive score; ECOG = Eastern 
Cooperative Oncology Group; HNSCC = head and neck squamous cell carcinoma; HPV = human papilloma virus; IV 
= intravenously; PD = progressive disease; PD-L1 = programmed cell-death-ligand 1; PI = primary investigator; PO = 
orally; PS = performance status; Q3W = every 3 weeks; QD = daily; R/M = recurrent/metastatic; RECIST 1.1 = 
Response Evaluation Criteria in Solid Tumors.
Figure 4
New Study Design Second Course Treatment Phase
Abbreviations: IV = intravenously; PD = disease progression; PI = primary investigator; PO = orally; Q3W = every 3 
weeks; QD = daily.
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1.3
Schedule of Activities
As of Amendment 05, participants who are still on study treatment will no longer require ePRO assessments to be performed. 
Biomarker samples (blood for genetic analysis, RNA analysis, plasma/serum biomarker analysis, ctDNA analysis and stool samples) 
are discontinued.
All participants who are still on study medication should continue tumor imaging and investigator assessments of imaging per 
protocol. Tumor response assessments by BICR will no longer be performed and scans will no longer be sent to the iCRO. Note: 
BICR assessments and submission of scans to the iCRO will continue for all participants in China. 
Efficacy Follow-up visits will only be conducted for participants who are potential candidates for Second Course treatment and for all 
participants in China. Survival Follow-up Visits will only be conducted for participants in China. 
Summary of changes in SoA:

Imaging: while still on treatment and during efficacy follow-up as described above

Physical Examination, Vital Signs: while still on treatment, then 30-day Safety FU

ECG, MUGA or ECHO: while still on lenvatinib treatment then 30-day Safety FU

Urinary laboratory tests, including 24-hour urine collection as specified per protocol: while still on lenvatinib treatment, then 
30-day Safety FU

Hematology/Chemistry: while still on treatment, then 30-day Safety FU

T3, Free T4, TSH: while still on treatment, then 30-day Safety FU

HIV, HBV, HCV: while still on treatment, then 30-day Safety FU

ECOG: while still on treatment, then 30-day Safety FU
The full SoA tables below are retained for reference.
The SoAs for the Initial Treatment Phase and the Second Course Phase are provided in Table 1 and Table 2, respectively.
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1.3.1
Initial Treatment Phase
Table 1
Initial Treatment Phase
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed Consent
X
Additional 
consent is 
required if 
pembrolizumab 
is discontinued 
due to toxicity 
and participant 
will be receiving 
lenvatinib/placeb
o alone.
Additional 
consent is 
required at 
disease 
progression if 
study treatment 
will continue 
and/or restart.
Inclusion/Exclusi
on Criteria
X
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Participant 
Identification 
Card
X
X
Identification 
card will be 
updated with 
randomization 
number.
Demographics 
and Medical 
History 
X
Includes smoking 
and tobacco use.
Prior Treatment 
for HNSCC
X
Prior/Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization 
X
It is strongly 
preferred that 
participants 
receive first dose 
of study 
intervention on 
day of 
randomization. 
Study 
intervention 
should begin 
within 3 days of 
randomization.
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Subsequent 
Antineoplastic 
Therapy Status
X
X
X
X
Survival Status
X
On Sponsor 
request, 
participants may 
be contacted for 
survival status at 
any time during 
the course of the 
study.
Study Intervention Administration
Lenvatinib/placeb
o Dispensing
X
X
X
X
X
X
X
Lenvatinib/placeb
o Administration
PO QD
Day 1 of each 
cycle dosed in 
clinic, 0-4 hours 
after 
pembrolizumab. 
Taken at home 
on all other days.
Lenvatinib/placeb
o container 
returned
X
X
X
X
X
X
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Pembrolizumab 
Administration
IV Q3W
X
X
X
X
X
X
Efficacy Procedure
Tumor Imaging
(head and neck, 
chest, abdomen)
and RECIST 
Assessment
Note:  Imaging of 
the brain and 
pelvis are optional 
(if clinically 
indicated).
X
X
X
X
X
X
X
BICR confirmation 
of measurable 
disease is required 
at Screening.
All imaging 
assessments will be 
calculated from the 
date of 
randomization. 
Imaging is 
performed at 
Screening, Week 6 
(42 to 49 days) and 
every 6 weeks (± 7 
days) during 
Year 1. After Year 
1, imaging is 
performed every 9 
weeks (± 7 days). 
This schedule will 
be maintained 
regardless of 
treatment delays.
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Patient-reported Outcomes (PRO)
EuroQoL EQ-5D-
5L
X
X
X
X
X
X*
X
X
It is a best 
practice and 
strongly 
recommended 
that ePROs are 
administered 
before any other 
visit procedures 
and in the order 
listed in the SoA, 
starting with 
EuroQoL EQ-
5D-5L. 
Collection begins 
at C1 and 
continues until 
C35 or treatment 
discontinuation, 
whichever occurs 
first. Specific 
Visit schedule is 
discussed in 
Section 8.2.2.
EORTC QLQ-
C30
X
X
X
X
X
X*
X
X
EORTC QLQ-
H&N35
X
X
X
X
X
X*
X
X
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Safety Procedures
AE/SAE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Report AEs 
occurring within 
30 days after the 
last dose of study 
intervention. 
Report SAEs 
occurring within 
90 days after the 
last dose of study 
intervention, or 
30 days after the 
last dose of study 
intervention if a 
new anticancer 
therapy is 
initiated, 
whichever is 
first.
Full Physical 
Examination 
X
X
Height
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Contact
X
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. 
08YMDW

PRODUCT: MK-7902
31
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Vital Signs 
(resting BP, heart 
rate, RR, and 
temp) and weight
X
X
X
X
X
X
X
X
X
X
X
X
The Day 15 visit 
is mandatory for 
C1 and C2.
During C3 and 
subsequent 
cycles, 
participants may 
return for the 
D15 visit if BP 
monitoring is 
required.
08YMDW

PRODUCT: MK-7902
32
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
12-lead ECG with 
QTcF 
Determination
X
X
X
X
X
X
X
Every 4 cycles. 
ECG at Screening, 
C1D1, C2D1, D1 
of every fourth 
cycle (12 weeks) 
thereafter (eg, C6, 
C10, C14, etc.), 
EOT, and safety 
follow-up. ECG at 
C1D1 and C2D1 
should be 
performed 
approximately 2 
hours post 
lenvatinib/placebo 
dose. For high-risk 
participants 
(Section 8.3.3), 
conduct ECG 
monitoring every 
cycle.
If 
lenvatinib/placebo 
is discontinued, 
ECGs are only 
required at the EOT 
and Safety Follow-
up visits.
08YMDW

PRODUCT: MK-7902
33
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
MUGA Scan or 
ECHO
X
X
Additional LVEF 
assessments may 
be performed as 
clinically 
indicated.
ECOG 
Performance 
Status
X*
X
X
X
X
X
X
X
X
X
Performance 
status obtained 
on C1D1 before 
randomization 
may also be used 
as the screening 
value to 
determine 
eligibility.
* Screening 
ECOG within 7 
days before 
initiation of study 
intervention.
08YMDW

PRODUCT: MK-7902
34
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Laboratory Procedures/Assessments (Local Laboratory)
Serum β-hCG or 
Urine Pregnancy 
Test (WOCBP 
only)
X
X
X
X
X
X
X
X
X
WOCBP require 
a negative test 
before 
randomization. If 
more than 
24 hours have 
elapsed before 
the first dose of 
study 
intervention, 
another 
pregnancy test is 
required. A 
serum or urine 
pregnancy test 
will be performed 
per Appendix 2.
Serum FSH
(WONCBP only)
X
In the absence of 
12 months of 
amenorrhea, 
confirmation 
with 2 FSH 
measurements in 
postmenopausal 
range is required.
08YMDW

PRODUCT: MK-7902
35
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
HIV, Hepatitis B, 
and Hepatitis C
X*
*Required at 
Screening only if 
mandated by 
local health 
authority
Hematology
X*
X
X
X
X
X
X
X
X
X
Labs obtained 
and reviewed on 
C1D1 before 
randomization 
may also be used 
as the screening 
value to 
determine 
eligibility.
*Perform 
screening 
laboratory tests 
within 7 days 
before the first 
dose.
Chemistry
X*
X
X
X
X
X
X
X
X
X
08YMDW

PRODUCT: MK-7902
36
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Thyroid Function 
Tests
(T3 or FT3, Free 
T4, TSH)
X*
X
X
X
X
X
Labs obtained 
and reviewed on 
C1D1 before 
randomization 
may also be used 
as the screening 
value to 
determine 
eligibility.
*Perform 
screening 
laboratory tests 
within 7 days 
before the first 
dose, then at C2 
and every 2 
cycles thereafter 
(C4, C6, C8, 
etc.).
08YMDW

PRODUCT: MK-7902
37
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Urine Dipstick 
Testing (or 
Urinalysis)
X*
X
X
X
X
X
X
X
X
X
After C1, collect 
samples at C1D15 
and C2 D15 and up 
to 3 days before D1 
of each cycle. If 
lenvatinib/ placebo 
is discontinued, 
urine dipstick 
testing no longer 
required.  Urine 
dipstick testing (or 
urinalysis) obtained 
and reviewed on 
C1D1 before 
randomization may 
also be used as the 
screening value to 
determine 
eligibility. If 24-
hour urine 
collection for 
quantitative 
assessment of 
proteinuria is 
required, 
randomization and 
C1D1 is postponed 
to after proteinuria 
result available.
08YMDW

PRODUCT: MK-7902
38
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
*Perform screening 
urinalysis tests 
within 7 days 
before the first 
dose. 
Urinalysis 
X*
X
X
X
Urinalysis obtained 
and reviewed on 
C1D1 before 
randomization may 
also be used as the 
screening value to 
determine 
eligibility. If 24-
hour urine 
collection for 
quantitative 
assessment of 
proteinuria is 
required, 
randomization and 
C1D1 is postponed 
to after proteinuria 
result available.
*Perform screening 
laboratory tests 
within 7 days 
before the first 
dose. Collect at C3, 
C6, C9, and every 
3 cycles.
08YMDW

PRODUCT: MK-7902
39
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
INR or PT and 
aPTT
X*
Labs obtained 
and reviewed on 
C1D1 before 
randomization 
may also be used 
as the screening 
value to 
determine 
eligibility. 
Additional 
testing is to be 
performed as 
clinically 
indicated for 
participants 
taking 
anticoagulants.
*Perform 
screening 
laboratory tests 
within 7 days 
before the first 
dose.
08YMDW

PRODUCT: MK-7902
40
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
HPV status using 
CINtec® p16 
Histology assay 
(oropharynx 
participants only)
X
Historical result 
may be used. If 
historical result 
not available or 
testing cannot be 
completed 
locally, central 
laboratory can 
perform this test.
Biomarkers (Central Laboratory)
Newly Obtained 
or Archival 
Tumor Tissue 
Collection
X
PD-L1 results 
must be available 
from the central 
laboratory before 
randomization.
Blood for Genetic 
Analysis
X
Collect pre dose 
on C1D1.
08YMDW

PRODUCT: MK-7902
41
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Blood for Plasma 
Biomarkers
X
X
X
X
X
X
X
Collect at pre 
dose on C1D1, 
C2D1, C3D1. 
After C3D1 
collection, the 
plasma samples 
should be 
collected within 
±7 days at 
subsequent 
imaging visits 
until EOT, 
including at the 
EOT visit.
Blood for Serum 
Biomarkers 
X
X
X
X
X
X
Collect pre dose 
on C1D1, 
C1D15, C2D1, 
C3D1, C5D1 and 
at EOT.
Blood for RNA 
Analysis
X
X
X
X
X
Collect pre dose 
on C1D1, C2D1, 
C3D1, C5D1, 
and at EOT.
08YMDW

PRODUCT: MK-7902
42
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treat-
ment
Posttreatment Visits
Notes
Visit 
Number/Title:
1/Screening
C1
C2
C3
C4
C5
C6 
to 
C35
≥
C36
Safety 
Follow-
up
Efficac
y
Follow-
up
Surviva
l FU
Cycle Day
1
8
15
1
15
1
1
1
1
1
Scheduling 
Window (days)
-42 
to -1
-28 
to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
At time 
of treat-
ment 
discon
Approx
30d 
after 
last 
dose 
Q6W 
(Y1) or
Q9W 
(Y2+)
(± 7d)
Q12W
(± 14d)
Blood for 
Circulating 
Tumor Nucleic 
Acids
X
X
X
X
X
X
X
Collect at pre 
dose on C1D1, 
C2D1, C3D1. 
After C3D1 
collection, the 
ctNA samples 
should be 
collected within 
±7 days at 
subsequent 
imaging visits 
until EOT, 
including at the 
EOT visit.
Stool Analysis 
(Optional)
X
X
X
X
Pre dose (at 
home within 1 
week before 
infusion) on 
C1D1, C2D1, 
C5D1 and at 
EOT.
08YMDW

PRODUCT: MK-7902
43
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; BP = blood pressure; β-HCG; = β human chorionic gonadotropin; C = cycle; ctNA = 
circulating tumor nucleic acid; CXDY= Cycle X Day Y; d = day; discon = discontinuation; ePRO = electronic patient-reported outcome; ECG = electrocardiogram; ECOG 
= Eastern Cooperative Oncology Group; ECHO = echocardiogram; EORTC = European Organization for Research and Treatment of Cancer; EOT = end-of-treatment; 
EQ-5D-5L = European Quality of Life Five-Dimensional Five-Level Scale Questionnaire; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FU = follow-
up; HIV = human immunodeficiency virus; HNSCC = head and neck squamous cell carcinoma; INR = international normalized ratio; LVEF = left ventricular ejection 
fraction; MUGA = multigated acquisition; PRO = patient-reported outcome; PT = prothrombin time; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 
weeks; QLQ-C30 = Quality of Life Questionnaire Core 30 items; QTcF = QT interval corrected with Fridericia’s formula; RNA= ribonucleic acid; RR = respiratory rate; 
SAE = serious adverse event; SoA = schedule of activities; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing 
potential; WONCBP = women of nonchildbearing potential.
08YMDW

PRODUCT: MK-7902
44
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
1.3.2
Second Course Phase
Table 2
Second Course Phase
Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed Consent
X
Reconsent is required at the 
time of progression if study 
treatment will continue 
and/or restart.
Second Course 
Inclusion/Exclusion 
Criteria
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
Subsequent 
Antineoplastic Therapy 
Status
X
X
X
X
Survival Status
X
On Sponsor request, 
participants may be 
contacted for survival status 
at any time during the 
course of the study.
08YMDW

PRODUCT: MK-7902
45
PROTOCOL/AMENDMENT NO.: 010-06
MK-7902-010-06 FINAL PROTOCOL
16-AUG-2024
Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
Study Intervention Administration
Pembrolizumab 
Administration
IV Q3W
X
X
X
X
X
X
Lenvatinib/placebo 
Dispensing (Optional)
X
X
X
X
X
X
X
It is the investigator’s 
decision whether to continue 
lenvatinib/placebo during 
Second Course treatment.
Lenvatinib/placebo 
Dosing 
PO QD
(Optional)
It is the investigator’s 
decision whether to continue 
lenvatinib/placebo during 
Second Course treatment.
Lenvatinib/placebo 
container returned
X
X
X
X
X
X
X
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Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
Efficacy Procedures
Tumor Imaging
(head and neck, chest, 
abdomen) and RECIST 
Assessment
Note:  Imaging of the 
brain and pelvis are 
optional (if clinically 
indicated).
X*
X
X
X
X
X
*Baseline imaging is the CT 
or MRI showing centrally-
verified PD. Baseline 
imaging should be 
performed within 28 days 
before C1. 
The first scan should be 
performed at 6 weeks (42 to 
49 days) after restarting 
study intervention. 
Subsequent tumor scans are 
to be performed every 6 
weeks (42 days [±7 days]) 
or more frequently, if 
clinically indicated. After 1 
year (48 weeks), imaging 
will occur every 9 weeks 
(63 days ±7 days).
This schedule will be 
followed regardless of 
delays in study intervention. 
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Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
Safety Procedures
AE/SAE Review
X
X
X
X
X
X
X
X
X
X
Report AEs occurring 
within 30 days after the last 
dose of study intervention. 
Report SAEs occurring 
within 90 days after the last 
dose of study intervention, 
or 30 days after the last dose 
of study intervention if a 
new anticancer therapy is 
initiated, whichever is first.
Full Physical 
Examination 
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
Vital Signs (resting BP, 
heart rate, RR, and temp) 
and weight
X
X
X
X
X
X
X
X
X
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Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
12-lead ECG with QTcF 
Determination
(Only required for 
participants who receive 
lenvatinib/placebo in the 
Second Course treatment 
phase.)
X
X
X*
X
X
*D1 of every fourth cycle 
starting with C6.
For high-risk participants 
(Section 8.3.3), conduct 
ECG monitoring every 
cycle. 
If lenvatinib/placebo is 
discontinued, ECG is only 
required at EOT and Safety 
FU visit.
ECOG Performance 
Status
X*
X
X
X
X
X
X
X
X
* Perform within 7 days 
before C1 of Second Course 
treatment.
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Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
Laboratory Procedures/Assessments (Local Laboratory)
Pregnancy Test – urine 
or Serum β-hCG 
(WOCBP only)
(Required on D1 of 
every cycle for 
participants who receive 
lenvatinib/placebo in the 
Second Course treatment 
phase.)
X*
X
X
X
X
X
X
X
X
*Obtain a urine pregnancy 
test within 24 hours before 
the first dose for all 
participants
If a urine pregnancy test 
cannot be confirmed as 
negative, a serum pregnancy 
test is required.
Additional urine/serum 
testing may be performed if 
clinically warranted, and/or 
as defined by local 
regulations.
Hematology
X*
X
X
X
X
X
X
X
X
*Perform within 7 days 
before first dose in C1 to 
confirm Second Course 
eligibility.
Chemistry
X*
X
X
X
X
X
X
X
X
Thyroid Function Tests
(T3 or FT3, Free T4, 
TSH)
X*
X
X
X
X
X
*Perform within 7 days 
before first dose in C1, then 
every 2 cycles thereafter 
(C3, C5, C7, etc.).
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Study Period:
Intervention (21-Day Cycles)
End-of-
Treatme
nt
Posttreatment Visits
Notes
Visit/Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
≥ C18
Safety 
Follow-
up
Second 
Course
Efficacy 
Follow-
up
Survival 
FU
Cycle Day
1
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
±3
At time 
of 
treatmen
t discon
Approx.
30d after 
last dose
Q6W
(± 7d)
Q12W
(± 14d)
Urine Dipstick Testing
(or Urinalysis; only 
required if participant is 
continuing to receive 
lenvatinib/placebo in 
Second Course)
X*
X
X
X
X
X
X
X
*Perform screening 
urinalysis test within 7 days 
before first dose in C1. 
Participants taking 
lenvatinib/placebo should 
have urine dipstick testing 
on Day 1 of each cycle.
Urinalysis
(Only required after C1 
if participant is 
continuing to receive 
lenvatinib/placebo in 
Second Course)
X*
X
X
Collect at C3, C6, C9, and 
every 3 cycles if participant 
is receiving 
lenvatinib/placebo.
*Perform screening 
urinalysis tests within 7 days 
before first dose in C1 to 
confirm Second Course 
eligibility.
INR or PT and aPTT
X*
*Perform within 7 days 
before first dose in C1. 
Additional testing to be 
conducted as clinically 
indicated for participants 
taking anticoagulants.
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Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG; = β human chorionic gonadotropin; C = cycle; CBC = complete blood count; 
CXDY= Cycle X Day Y ; D = day; discon = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end-of-treatment; FT3 = 
free triiodothyronine; FU = follow-up; INR = international normalized ratio; IV = intravenous; MRI = magnetic resonance imaging; PD = progressive disease; PT = 
prothrombin time; PTT = partial thromboplastin time; Q9W = every 9 weeks; Q12W = every 12 weeks; QTcF = QT interval corrected with Fridericia’s formula; SAE = 
serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
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2
INTRODUCTION
Pembrolizumab, a PD-1 inhibitor, in combination with lenvatinib, an anti-angiogenic 
tyrosine kinase inhibitor, are being investigated for participants eligible for 1L treatment of 
R/M HNSCC in this randomized, international, parallel design, double-blind, Phase 3 study.
2.1
Study Rationale
Head and neck cancers describe an anatomically heterogeneous group of cancers that arise 
most often from the oral cavity, the oropharynx, the hypopharynx, and the larynx [Dorsey, K. 
2013]. More than 90% of head and neck cancers are squamous cell carcinomas, originating 
from the epithelium of the mucosal lining of the upper aerodigestive tract [Gupta, B., et al 
2016]. Head and neck cancers are the ninth most common malignancy in the world with high 
mortality rates in developing countries (age-standardized mortality rates of 7.9 and 2.2 per 
100,000 in males and females, respectively) [Gupta, B., et al 2016].
More than 90% of participants with HNSCC initially present with disease confined to the 
head and neck mucosa and/or to the regional cervical lymph nodes [Machiels, J. P. 2011]. 
Surgery and radiation therapy are markedly effective for participants with Stage I and II 
disease. However, despite intensive multimodal treatment, approximately 50% to 60% of 
participants with locally advanced Stage III or Stage IV HNSCC recur initially with 
locoregional disease. However, a significant proportion of these participants ultimately have 
incurable disease recurrence requiring palliative systemic treatment. The prognosis for 
participants with R/M HNSCC is dismal and OS is less than 1 year [Argiris, A., et al 2017].
Participants with R/M HNSCC present a therapeutic challenge. First-line treatment generally 
includes the combination of either cetuximab or docetaxel with a platinum-based 
chemotherapy with or without 5-FU. Participants who are asymptomatic usually are treated 
with monotherapy to balance the side-effects associated with combination regimens. Options 
for 1L single-agent treatment include platinum, 5-FU, paclitaxel, docetaxel, methotrexate, 
cetuximab, gemcitabine, or capecitabine [National Comprehensive Cancer Network 2018]. 
No Phase 3 randomized trial showed an improvement in OS for any regimen until the 
EXTREME trial [Vermorken, J. B., et al 2008]. This trial showed that the addition of 
cetuximab to the combination of platinum plus 5-FU improved median OS to 10.1 months 
from 7.4 months when compared with platinum plus 5-FU alone.
Data from the final analysis of KEYNOTE-048, an ongoing Phase 3, open-label trial to 
compare the efficacy and safety of pembrolizumab as monotherapy or in combination with 
chemotherapy (platinum plus 5-FU) versus the standard EXTREME chemotherapy regimen 
(cetuximab in combination with platinum plus 5-FU is provided in Section 2.2.3). In the 
population of all participants, there was a clinically meaningful difference in OS when 
comparing pembrolizumab plus chemotherapy with standard treatment. The pembrolizumab 
monotherapy group had more responders who achieved a CR and a more durable DOR.
In preclinical models, lenvatinib decreased the TAM population, which is known as an 
immune-regulator in the tumor microenvironment. By decreasing TAMs, expression levels of 
cytokines and immune-regulating receptors were changed to increase immune activation. The 
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immune-modulating effect of lenvatinib may result in a potent combination effect with PD-
1/PD-L1 signal inhibitors. The effect of combining lenvatinib with anti-PD-1/PD-L1 agents 
has been investigated in the CT26 colorectal cancer syngeneic model (anti-PD-L1 agent) as 
well as the LL/2 lung cancer syngeneic model (anti-PD-1 agent). Combination treatment with 
lenvatinib and either an anti PD-1 or anti-PD-L1 agent showed significant and superior 
antitumor effects compared with either compound alone in these 2 syngeneic models [Kato, 
Y., et al 2015].
The ongoing pembrolizumab + lenvatinib combination Study 111/KEYNOTE-146 (Section 
2.2.3) in participants with HNSCC has shown promising clinical activity and a manageable 
tolerability and safety profile [Taylor, M. H., et al 2018]. These results showed an ORR of 
40.9% and median PFS of 8.2 months that strongly suggest greater efficacy with the 
combination of lenvatinib plus pembrolizumab than with either single agent, a possibly 
additive effect.
The intended population of this Phase 3 trial represents participants with a high unmet 
medical need considering all of the participants have incurable disease. Based on results from 
the KEYNOTE-048 trial, which compared pembrolizumab monotherapy to current standard 
platinum-based chemotherapy plus cetuximab, pembrolizumab monotherapy may be 
considered a new standard-of-care treatment in 1L R/M HNSCC participants whose tumors 
express PD-L1 (CPS ≥1). Combination therapy with pembrolizumab plus lenvatinib would 
provide additional 1L treatment options for HNSCC participants.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD 
1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment of participants across a number of 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 exhibited 
antiproliferative activity in cell lines dependent on activated FGFR signaling with a 
concurrent inhibition of FGF-receptor substrate 2α phosphorylation.
Refer to the respective Investigator’s Brochure (IB)/approved labeling for detailed 
background information on pembrolizumab and lenvatinib.
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2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are Type-I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in R/M HNSCC.
2.2.1.2
Lenvatinib
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. VEGF and its family of receptors (VEGRs 1-3) 
play a major role in tumor angiogenesis [Ferrara, N., et al 2003] [Ellis, L. M. and Hicklin, D. 
J. 2008] [Tammela, T. and Alitalo, K. 2010]. Accumulated evidence suggests that FGF and 
its receptor tyrosine kinase, FGFR also play important roles for tumor angiogenesis [Cross, 
M. J. and Claesson-Welsh L. 2001] [Lieu, C., et al 2011] [Limaverde-Sousa, G., et al 2014].
Lenvatinib is a potent multiple RTK inhibitor that selectively inhibits VEGF receptors, 
VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), FGFR1-4, PDGFRα, KIT, and 
RET. Among known kinase inhibitors in clinical use, lenvatinib is one of the only inhibitors 
currently labeled with a mechanism of action as an inhibitor of not only VEGFRs but also 
FGFRs, both of which are currently believed to be very important for tumor angiogenesis.
Lenvatinib inhibited cell free kinase activities for VEGFR1-3 and FGFR1-3 with Ki values 
around 1 nmol/L, and 8-22 nmol/L, respectively. In cell-based assays, lenvatinib inhibited 
VEGF-derived and FGF-derived tube formation of HUVEC with IC50 values of 2.1 and 7.3 
nmol/L, respectively. Analysis of the signal transduction molecules revealed that lenvatinib 
inhibited both the MAPK pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by 
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activated VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited 
both VEGF- and FGF-driven angiogenesis in a murine in vivo model [Yamamoto, Y., et al 
2014]. In vivo, lenvatinib exhibited antitumor activity against various human tumor 
xenografts in athymic mice including 5 types of thyroid carcinomas (differentiated [papillary 
and follicular], anaplastic, squamous, and medullary thyroid carcinomas), RCC, HCC, 
melanoma, gastric cancer, NSCLC, ovarian cancer, Ewing’s sarcoma, and osteosarcoma. In 
addition, the antitumor activity of lenvatinib in combination with other anticancer agents in 
several xenograft models was greater than that of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in human umbilical vein endothelial cell (HUVEC) models. 
Antitumor activity of lenvatinib in vivo has been shown in numerous xenograft animals. 
These results suggest that lenvatinib may be a novel anticancer therapy through inhibition of 
angiogenesis and may be useful as either monotherapy or in combination with other 
anticancer drugs.
2.2.1.3
Pembrolizumab Plus Lenvatinib
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
In preclinical models, lenvatinib decreased the tumor-associated macrophage (TAM) 
population, which is known as an immune-regulator in the tumor microenvironment. The 
decrease in TAM population was accompanied by increases in activated cytotoxic T-cell 
populations through stimulation of interferon-gamma signaling, resulting in increased 
immune activation [Kimura, T., et al 2018]. The immune-modulating effect of lenvatinib 
may result in a potent combination effect with PD-1/L1 signal inhibitors. The effect of 
combining lenvatinib with an anti-human PD-1 humanized mAb was investigated in 4 
murine tumor isograft models, which showed significant tumor growth inhibition compared 
to control. In the RAG murine tumor isograft tumor model, survival in the group treated with 
the combination was significantly longer than that of the respective monotherapy groups. In 
the CT26 murine tumor isograft model, treatment with the combination significantly 
increased the population of activated cytotoxic T cells compared to that of the respective 
monotherapy groups [Kato, Y., et al 2019]. All treatments were well tolerated and severe 
body weight loss was not observed.
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2.2.2
Preclinical and Clinical Studies
2.2.2.1
Completed Studies With Pembrolizumab and Lenvatinib
Refer to the respective IBs for preclinical and clinical study data for pembrolizumab [IB 
Edition 17 2019] and lenvatinib [IB Edition 16 2019].
2.2.3
Ongoing Clinical Studies of Pembrolizumab and Lenvatinib
There is an expansive ongoing research program of clinical studies evaluating 
pembrolizumab in patients with a number of hematological and solid malignancies, including 
HNSCC. The clinical program for HNSCC consists of the completed and ongoing studies for 
recurrent/metastatic disease: KN012, KN055, KN040, and KN048, as well as this study, 
LEAP-010.
Lenvatinib is undergoing studies in participants with different types of solid tumors, 
including HNSCC, in combination with other therapies including PD-1 targeted therapies. 
Full lists of ongoing studies are in the respective IBs for pembrolizumab and lenvatinib.
Ongoing Clinical Studies of Pembrolizumab in HNSCC
KEYNOTE-012 (KN012) 
KN012 is a Phase 1B, multicohort study evaluating the single-agent activity of 
pembrolizumab in various solid tumors, including 2 cohorts of participants (Cohorts B and 
B2) with R/M HNSCC. Cohort B consisted of 60 participants with PD-L1 positive HNSCC 
who received pembrolizumab 10 mg/kg Q2W. Cohort B2 consisted of 132 participants 
regardless of PD-L1 status, who received pembrolizumab 200 mg Q3W [Mehra, R., et al 
2016]. Responses were seen in both HPV-positive and HPV-negative participants. This was 
the first immunotherapy demonstrating clinically meaningful antitumor activity in a heavily 
pretreated incurable HNSCC population with recurrent/metastatic disease. Enrollment is 
closed, but participants are ongoing in the study.
The efficacy and safety results after long-term follow-up based on pooled data from Cohorts 
B and B2 were presented at ASCO 2016 [Mehra, R., et al 2016]. In the recurrent/metastatic 
HNSCC population (n=192), the ORR was 21.9% (95% CI; 12.5% to 34.0%) in HPV-
positive participants and 15.9% (95% CI: 10.0% to 23.4%) in HPV-negative participants. In 
a separate publication, when PD-L1 expression analyses were restricted to only tumor cells 
(tumor proportion scoring, TPS), there was no statistically significant increase ORR with PD-
L1 positive (≥1%) versus negative (<1%) tumors. Conversely, when immune cells were 
included in the scoring system (CPS), PD-L1 expression on tumor and immune cells 
significantly correlated with ORR, PFS, and OS [Chow, L. Q., et al 2016]. Median OS was 
8.5 months (95% CI: 6.5 to 10.5). The 6-month PFS rate was 24.9% [Mehra, R., et al 2016].
Importantly, the responses seen with pembrolizumab were durable. Among participants with 
recurrent/metastatic HNSCC, the DOR ranged from 1.8+ to 21.8+ months, and the median 
was not reached. Among participants who responded (n=34), 85% were in response for at 
least 6 months, and 71% of responders had ongoing responses [IB Edition 17 2019]. These 
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results show the consistent durability of responses seen with pembrolizumab treatment and 
compare favorably to SOC chemotherapy or epidermal growth factor receptor inhibitors. 
These results of KN012 show consistent and clinically meaningful activity of pembrolizumab 
in heavily pretreated participants with HNSCC and show a robust and unprecedented 
antitumor activity observed compared with available current SOC chemotherapy agents. The 
prolonged DOR seen in the majority of participants that respond to pembrolizumab is 
substantially distinct from what is expected with chemotherapy in previously treated patients 
with HNSCC.
KEYNOTE-055 (KN055)
KN055 is a Phase 2, nonrandomized, single cohort study of pembrolizumab (200 mg Q3W) 
monotherapy in a heavily pretreated population of patients with recurrent/metastatic HNSCC 
who have progressed on prior platinum and cetuximab therapy. Results from 171 participants 
treated with pembrolizumab were presented by Bauml et al [Bauml, J., et al 2017]. When 
confirmed responses were evaluated, the ORR was 16% (CR, n=1; PR, n=27; 95% CI: 11% 
to 23%) with a median DOR of 8 months (range, 2+ to 12+ months); the stable disease rate 
was 19% (n=33; 95% CI: 14% to 26%). Response rates were slightly higher in participants 
that were PD-L1 positive; 18% of participants with CPS ≥1% PD-L1 expression responded 
to pembrolizumab compared with 12% of participants with CPS <1% expression. 
Nonetheless, PD-L1–negative participants responded to pembrolizumab at a rate that is 
clinically meaningful; 6- and 12-month PFS and OS rates were relatively similar between 
PD-L1–negative and PD-L1–positive participants. The results presented by Bauml et al 
[Bauml, J., et al 2017], confirm findings from KN012 in the recurrent/metastatic HNSCC 
population; pembrolizumab monotherapy (200 mg Q3W) demonstrates consistent and 
clinically meaningful activity in heavily pretreated participants with HNSCC.
KEYNOTE-040 (KN040) 
KN040 is an ongoing Phase 3, randomized, active-controlled, open-label study of 
pembrolizumab versus the choice of 3 different SOC therapies in participants with R/M 
HNSCC. Four hundred and ninety-five participants with R/M HNSCC were randomized 1:1 
to receive pembrolizumab 200 mg Q3W or the investigator’s choice of one of the following 
therapies chosen before randomization: single agent methotrexate, single agent docetaxel, or 
single agent cetuximab. Randomization was stratified by ECOG performance status (0 vs. 1), 
HPV status (oropharynx – p16 positive vs. oropharynx – p16 negative or 
larynx/hypopharynx/oral cavity HNSCC), and PD-L1 status (strong positive or not; strong 
positive was defined as TPS ≥50% PD-L1 testing by IHC). The primary objective of the 
study was to evaluate OS in participants with R/M HNSCC treated with pembrolizumab 
compared with SOC treatment. Enrollment is closed, but participants are ongoing in the 
study.
The efficacy and safety data from the final analysis were reported, and at the time of the final 
analysis, 181 (73%) of 247 participants in the pembrolizumab group and 207 (83%) of 248 
participants in the SOC group had died. The median OS in the ITT population was 8.4 
months (95% CI 6.4 to 9.4) with pembrolizumab and 6.9 months (5.9 to 8.0) with SOC (HR 
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= 0.8, 0.65 to 0.98; nominal p=0.0161). In the ITT population, the median DOR was 18.4 
months in the pembrolizumab group compared with only 5 months for SOC [Cohen, E. E. 
W., et al 2019].
For participants with a PD-L1 CPS≥1 tumor score, the HR for OS was 0.74 (95% CI 0.58 to 
0.93; nominal p=0.0049), with a median survival of 8.7 months (95% CI 6.9 to 11.4) for 
pembrolizumab versus 7.1 months (5.7 to 8.3) with SOC. In participants whose tumor had 
PD-L1 TPS ≥50% expression, the HR for death was 0.53 (95% CI 0.35 to 0.81; nominal 
p=0.0014), and median OS was 11.6 months (95% CI 8.3 to 19.5) compared with 6.6 months 
(4.8 to 9.2) for pembrolizumab and SOC, respectively. 
Fewer participants treated with pembrolizumab than with SOC had treatment-related AEs 
(63% vs. 84%), as well as higher toxicity AEs (Grade ≥3 treatment-related AEs 13% vs. 
36%).
KEYNOTE-048 (KN048)
KN048 is an ongoing Phase 3, randomized, active-controlled, open-label study of 
pembrolizumab, or pembrolizumab plus platinum plus 5-FU chemotherapies versus platinum 
plus 5-FU plus cetuximab (EXTREME regimen) in participants with 1L R/M HNSCC. A 
total of 882 participants with 1L R/M HNSCC were randomized worldwide 1:1:1 between 
the 3 arms of the study to examine the efficacy and safety of pembrolizumab (n=301 
participants), or pembrolizumab plus chemotherapy (n=281 participants) versus SOC with 
cetuximab and chemotherapy (n=300 participants) [Burtness, B., et al 2018] [CSR P048 
2020]. The primary endpoints of the study are PFS per RECIST 1.1 as assessed by BICR, 
and OS. Participants are ongoing in the study [CSR P048 2020].
Data from the second interim analysis for KEYNOTE-048 were presented at the 2018 ESMO 
Congress [Burtness, B., et al 2018]. The cutoff date for this final PFS/interim OS analysis 
was13-JUN-2018, with a minimum follow-up of approximately 17 months. For OS, 
pembrolizumab monotherapy was superior to the EXTREME regimen in participants with a 
CPS ≥20, HR = 0.61 (95% CI 0.45-0.83, p=0.0007), and yielded a median OS that was 
longer with pembrolizumab (14.9 months) than the EXTREME regimen (10.7 months). 
Statistical significance was also achieved for pembrolizumab monotherapy in participants 
whose tumors had PD-L1 expression of CPS ≥1 with HR = 0.78 (95% CI 0.64 to 0.96, 
p=0.0086) and a median OS of 12.3 months versus 10.3 months in participants receiving the 
EXTREME regimen [Burtness, B., et al 2018].
Confirmed ORR for pembrolizumab versus EXTREME was 23% versus 36% for CPS ≥20 
with a more durable DOR of 20.9 versus 4.2 months, and 19% versus 35% for CPS ≥1 with a 
median DOR of 20.9 versus 4.5 months for CPS ≥1 [Burtness, B., et al 2018].
Pembrolizumab monotherapy had a more favorable toxicity profile compared with the 
EXTREME regimen with few treatment-related AEs (58.3% vs. 96.9%), fewer treatment-
related Grade 3 to 5 AEs (16.7% vs. 69.0%), and fewer treatment-related AEs that led to 
treatment discontinuation (4.7% vs. 19.9%) [CSR P048V01MK3475 2018].
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Data cutoff of the final analysis was 25-FEB-2019 (approximately 25 months after the last 
participant was randomized) [CSR P048 2020]. In participants whose tumors had PD-L1 
expression, OS results further confirmed the statistically and clinically meaningful results 
observed at the second interim analysis, with an OS HR = 0.74 (95% CI: 0.61, 0.90) for CPS 
≥1 and HR = 0.58 (95% CI: 0.44, 0.78) for CPS ≥20 [CSR P048 2020]. In the population of 
all participants, there was a clinically meaningful difference in OS when comparing 
pembrolizumab plus chemotherapy with standard treatment. The pembrolizumab 
monotherapy group had more responders who achieved a complete response and a more 
durable DOR (22.6 vs. 4.5 months) [Rischin, D., et al 2019]. The safety results at the final 
analysis were similar to those observed at the second interim analysis.
At the second interim analysis, pembrolizumab + chemotherapy significantly improved OS in 
the total population (HR = 0.77 [95% CI 0.63-0.93]; p=0.00335) [CSR P048V01MK3475 
2018]. Additionally, the safety profiles for pembrolizumab + chemotherapy and the 
EXTREME regimen were comparable (95.3% vs. 96.9% treatment-related AEs; 71.0% vs 
69.0% treatment-related Grade 3 to 5 AEs; and 22.8% vs 19.9% treatment-related AEs that 
led to treatment discontinuation) [CSR P048V01MK3475 2018]. 
At the final analysis, pembrolizumab + chemotherapy OS results (HR = 0.72 [95% CI: 0.60, 
0.87]) [CSR P048 2020] further confirmed the statistically significant and clinically 
meaningful OS observed at the second interim analysis. In the population of participants who 
tumors express PD-L1, OS was statistically significant and clinically meaningful in PD-L1 
CPS ≥1 (HR = 0.65 [95% CI: 0.53, 0.80], p=0.00002) and in CPS ≥20 (HR = 0.60 [95% CI: 
0.45, 0.82], p=0.00044) [CSR P048 2020]. Furthermore, in participants whose tumors had 
PD-L1 expression, ORR and median time to response were similar, but the pembrolizumab + 
chemotherapy group had more durable DOR of 6.7 versus 4.3 months for CPS ≥1 and 7.1 
versus 4.2 months for CPS ≥20 [Rischin, D., et al 2019]. The safety results at the final 
analysis were similar to those observed at the second interim analysis.
In summary, for 1L R/M HNSCC, pembrolizumab monotherapy significantly improved OS 
over the EXTREME regimen in both the CPS ≥20 and CPS ≥1 populations. Responses to 
pembrolizumab were durable with a more favorable toxicity profile compared with the 
EXTREME regimen. Pembrolizumab plus chemotherapy improved OS in the total 
population and in participants whose tumors had PD-1 expression, with a comparable safety 
profile. Therefore, pembrolizumab-based treatment may be considered a new 1L standard of 
care for R/M HNSCC.
Study 111/KEYNOTE-146
Study 111/KEYNOTE-146 is a multicenter, open-label, Phase 1b/2 clinical study being 
conducted to evaluate the efficacy and safety of lenvatinib in combination with 
pembrolizumab in selected solid tumors (ie, HNSCC, NSCLC, RCC, endometrial cancer, 
urothelial carcinoma, and melanoma) [IB Edition 16 2019]. The Phase 1b portion of this 
study has been completed and Phase 2 is ongoing. During the Phase 1b portion of the study, 
the MTD was determined to be 20 mg lenvatinib daily in combination with 200 mg of 
pembrolizumab IV Q3W. The safety and efficacy of the combination at the lenvatinib RP2D 
is being assessed in the Phase 2 portion of the study.
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As of 01-DEC-2017, 22 study participants with measurable, confirmed metastatic HNSCC 
and ECOG performance status of 0 or 1 were enrolled in this cohort and received lenvatinib 
(20 mg/day orally) + pembrolizumab (200 mg IV Q3W). Participants were not preselected 
based on PD-L1 status. Tumor assessments were performed by study investigators using 
irRECIST. Of the participants, 9.1% had received no prior anticancer therapy, 63.6% had 
received 1 prior line of anticancer therapy, and 13.6% had received 2 prior lines of anticancer 
therapies and 13.6% had received ≥3 prior lines of anticancer therapies, respectively. At data 
cutoff (01-DEC-2017), ORR was 40.9% (95% CI: 20.7, 63.6); ORR (at Week 24) was 36.4% 
(95% CI: 17.2, 59.3), including 1 (4.5%) CR, 8 (36.4%) PR, 11 (50%) SD, 0 (0%) PD, and 2 
(9.1%) unknown; median PFS of 8.2 months (95% CI: 4.3, NE); and PFS rate at 12 months 
was 41.9 % (95% CI: 17.6, 64.7) [Taylor, M. H., et al 2018].
Grade 3 or 4 treatment-related AEs occurred in 72.7% of participants (Grade 3 treatment-
related AEs in 15 participants [68.2%] and Grade 4 treatment-related AEs in 1 participant 
[4.5%]). The most common treatment-related AEs were fatigue (50.0%; Grade 3: 4.5%), 
hypertension (40.9%, Grade 3: 18.2%), and diarrhea (36.4%, Grade 3: 4.5%). Five 
participants experienced serious treatment-related AEs including hypertension, acute kidney 
injury, dehydration, hemoptysis and pulmonary edema. There were 5 fatal AEs reported; 
none were deemed treatment-related [Taylor, M. H., et al 2018].
Overall, the study showed promising clinical activity and manageable toxicities, supporting 
further evaluation of the lenvatinib + pembrolizumab in participants with HNSCC [Taylor, 
M. H., et al 2018a]. Interim analysis results for NSCLC, urothelial carcinoma, melanoma, 
endometrial carcinoma and RCC study arms produced similar response rates and acceptable 
safety and tolerability [Brose, M., et al 2018] [Vogelzang, N., et al 2018] [Taylor, M., et al 
2018] [Makker, V., et al 2018] [Lee, C. H., et al 2018]. From these studies, the combination 
of pembrolizumab and lenvatinib showed promising clinical activity and a manageable safety 
profile that is consistent with the safety profile of each agent when administered as 
monotherapy.
Based on Study 111/KEYNOTE-146, lenvatinib 20 mg QD in combination with 
pembrolizumab 200 mg IV Q3W was the dose selected for this Phase 3 study.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
With the results of the KEYNOTE-048 clinical trial demonstrating survival benefit with 
pembrolizumab for 1L R/M HNSCC, there is rationale for treating the participants with 
pembrolizumab monotherapy in the CPS ≥1 biomarker population. Therefore, 
pembrolizumab will be used in both the control and experimental arms, and all participants 
can be considered to be receiving clinically beneficial therapy. The existing data suggest that 
inhibiting angiogenesis in combination with PD-1 blockade is a promising therapeutic 
strategy, and the benefit/risk assessment for participants in this study is considered to be 
favorable, making the combination of pembrolizumab + lenvatinib a promising therapeutic 
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option to test in participants with 1L R/M HNSCC whose tumor demonstrates PD-L1 
expression.
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.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-010 (data 
cutoff 30-MAY-2023), the study will be discontinued based on a lack of additional clinical 
benefit on OS of the combination of pembrolizumab plus lenvatinib over pembrolizumab 
monotherapy. At this interim analysis, the combination did not demonstrate an improvement 
in OS versus pembrolizumab alone, and the likelihood of reaching the protocol specified 
threshold for statistical significance for OS at a future analysis was evaluated and deemed to 
be low. Based upon these data, the study was unblinded on 16-AUG-2023. The prespecified 
third interim analysis and final analysis of the study described in the SAP will not be 
performed. Safety analysis will be performed at the end of the study; there will be no further 
planned analyses for efficacy and ePRO endpoints.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In males and females who are at least 18 years old, with a histologically confirmed diagnosis 
of R/M HNSCC that is biomarker positive (combined positive score (CPS ≥1)), and who are 
considered incurable by local therapies will be enrolled in this study.
Throughout this protocol, the term RECIST 1.1 refers to the adjustment of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.1 for further details.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-010 (data 
cutoff 30-MAY-2023), the study will be discontinued based on a lack of additional clinical 
benefit on OS of the combination of pembrolizumab plus; lenvatinib over pembrolizumab 
monotherapy. At this interim analysis, the combination did not demonstrate an improvement 
in OS versus pembrolizumab alone, and the likelihood of reaching the protocol specified 
threshold for statistical significance for OS at a future analysis was evaluated and deemed to 
be low. Based upon these data, the study was unblinded on 16-AUG-2023. The prespecified 
third interim analysis and final analysis of the study described in the SAP will not be 
performed. Safety analysis will be performed at the end of the study; there will be no further 
planned analyses for efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter dated 25-AUG-2023, all study 
participants still receiving pembrolizumab should continue to receive pembrolizumab 
monotherapy on study and undergo modified protocol study procedures as specified in this 
amendment. Study participation should end after the 30-day Safety Follow-up Visit (last 
scheduled visit) with the following exceptions: participants who are potential candidates for 
Second Course treatment will continue in Efficacy Follow-up and all participants in China 
will continue in Efficacy Follow-up and Survival Follow-up. All participants should stop 
ongoing treatment with lenvatinib/placebo.
Exceptions may be requested for lenvatinib for study participants who, in the assessment of 
their study physician, are benefiting from ongoing lenvatinib after consulting with the 
Sponsor. This applies to participants currently on pembrolizumab and lenvatinib and 
participants who have discontinued pembrolizumab and are currently continuing lenvatinib 
monotherapy. Participants who are considered by the investigator as candidates for continued 
monotherapy with lenvatinib after completion of 35 cycles of pembrolizumab and lenvatinib 
require a separate communication with the Sponsor. Participants who discontinue 
pembrolizumab prior to completion of Cycle 35 (eg, due to an AE) must discontinue 
lenvatinib at the same time.
All participants beyond the 30-day Safety Follow-up Visit (except participants who are 
potential candidates for Second Course treatment and all participants in China) should be 
discontinued from the study; however standard safety reporting should continue, as 
applicable. As of Amendment 05, participants who are still on study treatment will no longer 
require ePRO assessments or tumor response assessments by BICR to be performed. Scans 
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will no longer be submitted to the iCRO. (Note: tumor response assessments by BICR and 
submission of scans to the iCRO will continue for participants in China.) Participants who 
are still on study medication should continue tumor imaging and investigator assessments of 
imaging per protocol. Biomarker specimen collection is discontinued. The 30-Day Safety 
Follow-up Visit is the last required visit (except participants who are potential candidates for 
Second Course treatment and all participants in China). Updated analyses are described in 
Section 9.
Primary Objective
Primary Endpoint
Objective: To compare pembrolizumab + 
lenvatinib to pembrolizumab + placebo with 
respect to ORR per RECIST 1.1 as assessed 
by BICR.
Hypothesis (H1): Pembrolizumab + 
lenvatinib is superior to pembrolizumab + 
placebo with respect to ORR per RECIST 
1.1 by BICR.
OR, defined as a BOR of CR or PR
Objective: To compare pembrolizumab + 
lenvatinib to pembrolizumab + placebo with 
respect to PFS per RECIST 1.1 as assessed 
by BICR.
Hypothesis (H2): Pembrolizumab + 
lenvatinib is superior to pembrolizumab + 
placebo with respect to PFS per RECIST 1.1 
as assessed by BICR.
PFS, defined as the time from 
randomization to the first documented PD or 
death due to any cause, whichever occurs 
first.
Objective: To compare pembrolizumab + 
lenvatinib to pembrolizumab + placebo with 
respect to OS.
Hypothesis (H3): Pembrolizumab + 
lenvatinib is superior to pembrolizumab + 
placebo with respect to OS.
OS, defined as the time from randomization 
to the date of death due to any cause.
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Secondary Objectives
Secondary Endpoints
Objective: To evaluate pembrolizumab + 
lenvatinib and pembrolizumab + placebo 
with respect to DOR per RECIST 1.1 as 
assessed by BICR.
DOR, defined as the time from the first 
documented evidence of CR or PR until PD 
or death due to any cause, whichever occurs 
first.
Objective: To assess the safety and 
tolerability of study intervention with 
pembrolizumab + lenvatinib and 
pembrolizumab + placebo.
-AEs
-Study drug discontinuations due to AEs.
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
Objective: To evaluate pembrolizumab + 
lenvatinib and pembrolizumab + placebo 
with respect to changes from baseline in 
HRQoL using the EORTC QLQ-C30 and 
EORTC QLQ-H&N35.
Scores from the EORTC QLQ-C30 and 
EORTC QLQ-H&N35. Global health 
status/quality of life and physical 
functioning scores of the EORTC QLQ-C30 
will be evaluated as overall measures of 
HRQoL.
Objective: To evaluate pembrolizumab + 
lenvatinib and pembrolizumab + placebo 
with respect to health status as assessed 
using the EuroQoL EQ-5D-5L 
questionnaire, and to generate utility scores 
for use in economic models.
Health status and health utilities assessed 
using the EuroQoL EQ-5D-5L.
Objective: To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, and/or the 
mechanism of action of pembrolizumab and 
lenvatinib.
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue.
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4
STUDY DESIGN
4.1
Overall Design
Original protocol text that is contained in this section has been retained for reference.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-010 (data 
cutoff 30-MAY-2023), the study will be discontinued based on a lack of additional clinical 
benefit on OS of the combination of pembrolizumab plus lenvatinib over pembrolizumab 
monotherapy. At this interim analysis, the combination did not demonstrate an improvement 
in OS versus pembrolizumab alone, and the likelihood of reaching the protocol specified 
threshold for statistical significance for OS at a future analysis was evaluated and deemed to 
be low. Based upon these data, the study was unblinded on 16-AUG-2023. The prespecified 
third interim analysis and final analysis of the study described in the SAP will not be 
performed. Safety analysis will be performed at the end of the study; there will be no further 
planned analyses for efficacy and ePRO endpoints.
NOTE: In alignment with the study-specific investigator letter dated 25-AUG-2023, all study 
participants still receiving pembrolizumab should continue to receive pembrolizumab 
monotherapy on study and undergo modified protocol study procedures as specified in this 
amendment. Study participation should end after the 30-day Safety Follow-up Visit (last 
scheduled visit) with the following exceptions: participants who are potential candidates for 
Second Course treatment will continue in Efficacy Follow-up and all participants in China 
will continue in Efficacy follow-up and Survival Follow-up. All participants should stop 
ongoing treatment with lenvatinib/placebo. 
Exceptions may be requested for lenvatinib for study participants who, in the assessment of 
their study physician, are benefiting from ongoing lenvatinib after consulting with the 
Sponsor. This applies to participants currently on pembrolizumab and lenvatinib and 
participants who have discontinued pembrolizumab and are currently continuing lenvatinib 
monotherapy. Participants who are considered by the investigator as candidates for continued 
monotherapy with lenvatinib after completion of 35 cycles of pembrolizumab and lenvatinib 
require a separate communication with the Sponsor. Participants who discontinue 
pembrolizumab prior to completion of Cycle 35 (eg, due to an AE) must discontinue 
lenvatinib at the same time.
All participants beyond the 30-day Safety Follow-up Visit (except participants who are 
potential candidates for Second Course treatment and all participants in China) should be
discontinued from the study; however standard safety reporting should continue, as 
applicable. As of Amendment 05, participants who are still on study treatment will no longer 
require ePRO assessments or tumor response assessments by BICR to be performed. Scans 
will no longer be submitted to the iCRO. (Note: tumor response assessments by BICR and 
submission of scans to the iCRO will continue for participants in China.) Participants who 
are still on study medication should continue tumor imaging and investigator assessments of 
imaging per protocol. Biomarker specimen collection is discontinued. The 30-Day Safety 
Follow-up Visit is the last required visit (except participants who are potential candidates for 
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Second Course treatment and all participants in China). Updated analyses are described in 
Section 9. 
This is a randomized, placebo-controlled, double-bind, parallel design, multisite study of 
pembrolizumab plus lenvatinib versus pembrolizumab plus placebo as 1L intervention in 
participants with R/M HNSCC whose tumors express PD-L1 (CPS ≥1). This Phase 3 study 
will be conducted in participants who have measurable disease per RECIST 1.1 as assessed 
by BICR, an ECOG performance status of 0 or 1, and have tumors that express PD-L1 CPS 
>1 by immunohistochemistry testing.
The original study design is shown in Figure 1 (Initial Treatment) and Figure 2 (Second 
Course). The new study design per Amendment 05 is depicted in Figure 3 and Figure 4.
Approximately 500 participants will be randomized 1:1 to Arm 1 (pembrolizumab + 
lenvatinib) or Arm 2 (pembrolizumab + placebo). Stratification factors for this study are:
•
PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (TPS <50% vs. 
≥50%)
•
HPV status for oropharynx cancer as determined by p16 immunohistochemistry (positive 
or negative); HPV status for participants without oropharynx cancer (eg, cancers of the 
oral cavity, hypopharynx and larynx) is considered HPV negative.
•
ECOG performance status (0 vs. 1)
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
Participants will be evaluated with radiographic imaging to assess response to study 
intervention every 6 weeks from randomization through Year 1, and every 9 weeks after 
Year 1. All imaging obtained during the study will be submitted to the iCRO for 
determination of ORR and PFS (Section 4.2.1.1.1). Tumor imaging showing site-assessed PD 
will be submitted for verification by BICR. Treatment beyond centrally-verified PD per 
RECIST 1.1 may be permitted at the discretion of the investigator after consultation with the 
Sponsor and receiving signed informed consent. 
Survival follow-up will begin after centrally-verified PD (or on completion of all efficacy 
assessments if the participant is receiving study intervention beyond centrally-verified PD) or 
the start of new anticancer treatment, whichever occurs first. On Sponsor request, 
participants may be contacted for survival status at any time during the study.
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the NCI CTCAE v5.0.
Treatment with pembrolizumab will continue for up to 35 treatment cycles, or until a 
discontinuation criterion (Section 7.1) is met. Participants who stop pembrolizumab after 
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35 cycles may continue to receive lenvatinib/placebo until a discontinuation criterion 
(Section 7.1) is met.
Participants who meet the criteria outlined in Section 6.7 may be considered for Second 
Course treatment with up to 17 cycles of pembrolizumab with or without lenvatinib/placebo.
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. An extension portion of the study will be identical to 
the global study, (eg, inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, and study procedures).
Note: At the time of writing Amendment 05, enrollment in the China extension has closed. 
Refer to Appendix 7 for country-specific requirements.
Three interim analyses are planned in this study (Section 9.7).
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use OS, ORR and PFS as primary endpoints. OS has been recognized as the 
gold standard for demonstration of superiority of a new antineoplastic therapy in randomized 
clinical trial. ORR and PFS are based on RECIST 1.1 criteria as assessed by BICR as the 
primary endpoints. ORR and PFS are acceptable measures of clinical benefit for a late-stage 
study that demonstrates superiority of a new antineoplastic therapy, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use 
of BICR and RECIST 1.1 to assess ORR and PFS is typically considered acceptable by 
regulatory authorities. Images will be submitted to an iCRO and read by an independent 
central review blinded to treatment assignment to minimize bias in the response assessments. 
In addition, the final determination of radiologic progression will be based on the central 
assessment of progression, rather than a local site investigator/radiology assessment. 
Expedited verification of radiologic progression as determined by central review will be 
communicated to the site.     
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.5 for additional 
detail.
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4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Exploratory Endpoints
4.2.1.3.1
Rationale for Patient-reported Outcomes Endpoints
Changes in HRQoL using PRO assessments can provide important information on clinical 
benefit and are accepted clinical endpoints by health authorities. Participants will provide 
information regarding their HRQoL using the EORTC QLQ-C30 and EORTC QLQ-H&N35 
PRO instruments. Health utilities will be evaluated using the EQ 5D-5L PRO instrument. 
These PROs assessments are not pure efficacy or safety endpoints because they are affected 
by both disease progression and treatment tolerability. 
The EORTC QLQ-C30 and EORTC QLQ-H&N35 are psychometrically and clinically 
validated instruments appropriate for assessing HRQoL in participants with HNSCC 
[Bjordal, K., et al 1994] [Bjordal, K., et al 2000]. These instruments have been widely used 
in Phase 3 studies of participants with R/M HNSCC [Mesia, R., et al 2010] [Machiels, J. P., 
et al 2015] [Harrington, K. J., et al 2017] [Cohen, E. E. W., et al 2018].
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, 
and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, 
sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global 
health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 is a 
psychometrically and clinically validated instrument appropriate for assessing QoL in 
oncology studies [Aaronson, N. K., et al 1993]. 
EORTC QLQ-H&N35
The EORTC QLQ-H&N35 is a disease-specific questionnaire developed to measure QoL in 
head and neck cancer. The EORTC QLQ-H&N35 consists of 7 multi-item scales (pain in the 
mouth, problems with swallowing, senses, speech, social eating, social contact, and 
sexuality), and 11 single-item scales (problems with teeth, mouth opening, dry mouth, sticky 
saliva, coughing, feeling ill, use of analgesics, use of nutritional supplements, use of feeding 
tube, weight gain, and weight loss) [Bjordal, K., et al 1994].
EuroQoL EQ-5D-5L
The EuroQoL EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
and will provide data to develop health utilities for use in health economic analyses [Rabin, 
R. and de Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the 
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following: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007] [Pickard, A. S., et al 
2007a].
4.2.1.4
Pharmacokinetic Endpoints
No PK endpoints are planned for this study.
4.2.1.5
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.1.6
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies, including novel 
combination with antiangiogenesis therapy, is not completely understood and much remains 
to be learned regarding how best to leverage these new drugs in treating patients. Thus, to aid 
future patients, it is important to investigate the determinants of response or resistance to 
cancer immunotherapy and other treatments administered, as well as determinants of AEs in 
the course of our clinical studies. These efforts may identify novel predictive/PD biomarkers 
and generate information that may better guide single-agent and combination therapy with 
immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include but are 
not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability) contributing towards the development/progression of cancer 
and/or driving response to therapy. Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
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mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Evaluation of molecular targets and signaling 
pathways including angiogenesis and/or growth factor related signaling pathways related to 
pembrolizumab and lenvatinib may also be explored. Thus, genome-wide approaches may be 
used for this effort. Note that in order to understand tumor-specific mutations, it is necessary 
to compare the tumor genome with the germline genome. Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system and growth factor signaling pathways (eg, VEGF and 
FGF) may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab and lenvatinib combination therapy. Therefore, tumor tissue 
may be subjected to proteomic analyses using a variety of platforms that could include but 
are not limited to immunoassays and liquid chromatography/mass spectrometry. This 
approach could identify novel protein biomarkers that could aid in patient selection for 
pembrolizumab (MK-3475) and lenvatinib combination therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1, circulating cytokines and angiogenic 
factors, and other tumor derived proteins can be shed from tumor and released into the blood. 
Assays such as enzyme-linked immunosorbent assay (ELISA) measure such proteins in 
serum. Correlation of expression with response to pembrolizumab and lenvatinib 
combination therapy may identify new approaches for predictive biomarkers in blood, 
representing a major advance from today’s reliance on assessing tumor biomarkers. This 
research would serve to develop such assays for future clinical use.
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Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Biomarker research using stool
Landmark studies have demonstrated that the gut microbiome can shape anti-tumor 
immunity and responses to immune checkpoint blockade in mouse models, and that 
modulation of the gut microbiome may enhance responses to immune checkpoint blockade. 
This has also been studied in patients on immune checkpoint blockade (anti-CTLA-4 and 
anti-PD-1), with evidence that differential bacterial signatures exist in responders versus non-
responders to therapy (with responders having higher diversity of the gut microbiome and 
differential composition compared with non-responders). Importantly, these differences in 
the gut microbiome are associated with differential immune signatures in the tumor 
microenvironment [Lynch, S. V. 2016].
4.2.2
Rationale for the Use of Comparator/Placebo
Based on results from the KEYNOTE-048 trial, which compared pembrolizumab 
monotherapy to current standard platinum-based chemotherapy plus cetuximab, 
pembrolizumab monotherapy showed clinical benefit and may be considered a standard-of-
care treatment in first-line R/M HNSCC participants whose tumors express PD-L1 (CPS ≥1) 
and is therefore being used as the comparator in this trial.
The use of a placebo in combination with pembrolizumab will ensure the objectivity of the 
local investigators’ treatment decisions and AE causality assessments.
4.3
Justification for Dose
4.3.1
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 an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W.
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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 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 
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
Lenvatinib
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
Phase 1b/2 Study 111/KEYNOTE-146, the primary endpoint of which was to determine the 
MTD and RP2D for lenvatinib in combination with pembrolizumab 200 mg Q3W. Thirteen 
participants (lenvatinib 24 mg/day + pembrolizumab 200 mg IV Q3W: n=3; lenvatinib 20 
mg/day + pembrolizumab 200 mg: n=10) were enrolled in the Phase 1b portion of the study. 
Eight of the participants had RCC, 2 had NSCLC, 2 had endometrial carcinoma, and 1 had 
melanoma. There were 2 DLTs at the dose of lenvatinib 24 mg/day + pembrolizumab 200 mg 
IV Q3W (1 participant had Grade 3 arthralgia, and another had Grade 3 fatigue); hence, this 
was defined as the toxic dose. No DLTs were reported in the next 10 participants (expansion 
part), all of whom received the lenvatinib 20 mg/day + pembrolizumab 200 mg Q3W dose.
Based on review of all of the clinical data from these 13 participants, the MTD and RP2D 
were determined to be 20 mg lenvatinib daily in combination with a fixed dose of 200 mg 
pembrolizumab given Q3W. Based on the promising anti-tumor efficacy and tolerable safety 
profile seen in both the endometrial carcinoma and RCC expansion cohorts from Study 
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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.
4.3.3
Starting Dose for This Study
The starting dose of lenvatinib/placebo is 20 mg/day. Dose reductions of lenvatinib occur in 
succession based on the previous dose level (14, 10, and 8 mg/day). See Section 6.6 for dose 
modification. All participants will receive pembrolizumab 200 mg IV Q3W. Pembrolizumab 
dose reductions are not permitted.
4.3.4
Maximum Dose Exposure for This Study
NOTE: In alignment with the study-specific investigator letter dated 25-AUG-2023, all study 
participants still receiving pembrolizumab should continue to receive pembrolizumab 
monotherapy on study and undergo modified protocol study procedures as specified in this 
amendment. Study participation should end after the 30-day Safety Follow-up Visit (last 
scheduled visit) with the following exceptions: participants who are potential candidates for 
Second Course treatment will continue in Efficacy Follow-up and all participants in China 
will continue in Efficacy Follow-up and Survival Follow-up. All participants should stop 
ongoing treatment with lenvatinib/placebo. 
Exceptions may be requested for lenvatinib for study participants who, in the assessment of 
their study physician, are benefiting from ongoing lenvatinib after consulting with the 
Sponsor. This applies to participants currently on pembrolizumab and lenvatinib and 
participants who have discontinued pembrolizumab and are currently continuing lenvatinib 
monotherapy. Participants who are considered by the investigator as candidates for continued 
monotherapy with lenvatinib after completion of 35 cycles of pembrolizumab and lenvatinib 
require a separate communication with the Sponsor. Participants who discontinue 
pembrolizumab prior to completion of Cycle 35 (eg, due to an AE) must discontinue 
lenvatinib at the same time.
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W for 
approximately 2 years (35 cycles). Participants meeting criteria for Second Course treatment 
with pembrolizumab (Section 6.7) may receive an additional 200 mg IV Q3W for up to 1 
year (17 cycles).
The maximum dose/exposure of lenvatinib allowed in this study is 20 mg QD until disease 
progression or unacceptable toxicity.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). 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.
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If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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 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 as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has histologically confirmed diagnosis of R/M HNSCC that is considered incurable by 
local therapies. 
Note:  Participants with newly-diagnosed HNSCC must have distant metastases and be 
Stage M1 at study entry.
2. Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx. 
Note:  Other primary tumor sites of HNSCC, including nasopharynx (any histology) or 
unknown primary tumor (including p16+ unknown primary) are not eligible.
Demographics
3. Is male or female, and at least 18 years of age at the time of documented informed 
consent.
Male Participants
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.
4. 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/placebo 
•
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
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•
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.
Please note that 7 days after lenvatinib is stopped, if the participant is on pembrolizumab 
only, no male contraception measures are needed.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than the 
requirements above, the local label requirements are to be followed.
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 120 days 
post pembrolizumab or 30 days post lenvatinib/placebo 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. 
-
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. 
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Informed Consent
6. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. 
Additional Categories
7. Has measurable disease per RECIST 1.1 as assessed by BICR.
Note: Lesions situated in a previously irradiated area are considered measurable if 
progression has been shown in such lesions.
8. Has provided an archival tumor tissue sample or newly obtained core, excisional, or 
incisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are 
preferred to slides. Newly obtained biopsies are preferred to archived tissue. 
Note: Details pertaining to tumor tissue submission can be found in the Procedures 
Manual.
9. Has a PD-L1 positive (CPS ≥1) tumor as determined by the central laboratory. 
10. Participants with oropharyngeal cancer must have results from testing of HPV status 
defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point. If 
HPV status was previously tested using this method, no additional testing is required.
Note:  If local p16 testing results are not available or cannot be assessed using this 
method, a tumor tissue sample must be submitted for p16 testing at the designated central 
laboratory, and results must be received before randomization.
11. Has an ECOG performance score of 0 to 1.
12. Have adequately controlled BP with or without antihypertensive medications, defined as 
BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior 
to randomization.
13. Has adequate organ function as defined in the following table (Table 3). Specimens must 
be collected within 7 days before the start of study intervention.
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Table 3
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/La
Renal
Creatinine OR
Measured or calculatedb 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)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)c
≤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.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
b
Creatinine 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.
c
PTT may be performed if the local lab is unable to perform aPTT.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has any evidence of symptoms or signs of active tumor bleeding within 6 months before 
randomization. 
2. Has radiographic evidence of major blood vessel invasion/infiltration or tumor 
demonstrates >90 degree abutment or encasement of a major blood vessel. 
Note: The degree of proximity to major blood vessels should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after 
lenvatinib therapy.
3. Has a history of re-irradiation to any head and neck sites of disease including the cervical, 
infraclavicular or supraclavicular lymph nodes for head and neck cancer. 
4. Has ulceration and/or fungation of disease onto the skin surface. 
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5.
Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, 
uncontrolled tumor pain) in the opinion of the treating investigator.
6. Has a history of any contraindication or has a severe hypersensitivity to any components 
of pembrolizumab (≥Grade 3) or lenvatinib. 
7. Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula. 
8. Has a history of a gastrointestinal condition or procedure that, in the opinion of the 
investigator, may affect oral study drug absorption. 
9. Has clinically significant cardiovascular impairment within 12 months of the first dose of 
study intervention, such as history of congestive heart failure greater than NYHA Class 
II, unstable angina, myocardial infarction or cerebrovascular accident/TIA/stroke, cardiac 
revascularization, or cardiac arrhythmia associated with hemodynamic instability. 
Note:  Medically controlled arrhythmia that is stable with medication is permitted.
10. Has disease that is suitable for local therapy administered with curative intent. 
11. Had PD within 6 months of completion of curatively intended systemic treatment for 
locoregionally advanced HNSCC. 
Note:  Prior systemic therapy administered in the recurrent or metastatic setting is not 
permitted unless it was given as part of a multimodal treatment for locally advanced 
disease.
12. Has had major surgery within 3 weeks before first dose of study interventions. 
Note:  Adequate wound healing after major surgery must be assessed clinically, 
independent of time elapsed for eligibility.
13. Has difficulty swallowing capsules or ingesting a suspension orally or by a feeding tube. 
Prior/Concomitant Therapy
14. Has received prior therapy with lenvatinib or pembrolizumab. 
15. Received last dose of systemic therapy for locoregionally advanced disease less than 6 
months before signing consent.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
17. Has received prior systemic anticancer therapy including investigational agents within 4 
weeks before randomization.
Note:  Participants must have recovered from all AEs due to previous therapies to ≤Grade 
1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
18. Has received prior radiotherapy within 2 weeks of start of study intervention.
Note:  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.
19. Has received a live vaccine within 30 days before the first dose of study intervention. 
Administration of killed vaccines is allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
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Prior/Concurrent Clinical Study Experience
20. Has Received an investigational agent or has used an investigational device within 
4 weeks prior to study intervention administration.
Diagnostic Assessments
21. Has urine protein ≥1 g/24 hours. 
Note:  Participants with proteinuria ≥2+ (≥100mg/dL) on urine dipstick testing 
(urinalysis) will undergo 24-hour urine collection for quantitative assessment of 
proteinuria.
22. Has prolongation of QTc interval (calculated using Fridericia’s formula) to >480 msec. 
23. Has a LVEF below the institutional (or local laboratory) normal range, as determined by 
MUGA or ECHO. 
24. 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. 
25. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
26. 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) 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 prior to first dose of study 
intervention.
27. Has an active autoimmune disease that has required systemic treatment in past 2 years 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed. 
28. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
29. Has an active infection requiring systemic therapy (eg, tuberculosis, known viral or 
bacterial infections, etc.). 
30. Has a known history of HIV infection. 
Note: No HIV testing is required unless mandated by local health authority.
31. Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis 
C virus (defined as HCV RNA [qualitative] is detected) infection. 
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority. 
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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 the 
participant’s ability to cooperate 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.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (pembrolizumab and lenvatinib/matching placebo) 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
NOTE: In alignment with the study-specific investigator letter dated 25-AUG-2023, all study 
participants still receiving pembrolizumab should continue to receive pembrolizumab 
monotherapy on study and undergo modified protocol study procedures as specified in this 
amendment. Study participation should end after the 30-day Safety Follow-up Visit (last 
scheduled visit) with the following exceptions: participants who are potential candidates for 
Second Course treatment will continue in Efficacy Follow-up and all participants in China 
will continue in Efficacy Follow-up and Survival Follow-up. All participants should stop 
ongoing treatment with lenvatinib/placebo. 
Exceptions may be requested for lenvatinib for study participants who, in the assessment of 
their study physician, are benefiting from ongoing lenvatinib after consulting with the 
Sponsor. This applies to participants currently on pembrolizumab and lenvatinib and 
participants who have discontinued pembrolizumab and are currently continuing lenvatinib 
monotherapy. Participants who are considered by the investigator as candidates for continued 
monotherapy with lenvatinib after completion of 35 cycles of pembrolizumab and lenvatinib 
require a separate communication with the Sponsor. Participants who discontinue 
pembrolizumab prior to completion of Cycle 35 (eg, due to an AE) must discontinue 
lenvatinib at the same time.
The study intervention(s) to be used in this study are outlined in Table 4.
Country-specific requirements are noted in Appendix 7.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP 
or 
NIMP/
AxMP
Sourcing
Arm 1 Experimental Lenvatinib
Drug
Capsule
10 mg
4 mg
20 mg
Oral
QD, no 
treatment 
duration 
limit
Test 
Product
IMP
Central
Arm 1 Experimental Pembrolizumab Biological/Vaccine Solution
25 mg/mL
200 mg
IV Infusion
Day 1 of 
each 21-day 
cycle
Test 
Product
IMP
Central
Arm 2 Experimental Matching 
placebo
Drug
Capsule
N/A
N/A
Oral
QD, no 
treatment 
duration 
limit
Placebo IMP
Central
Arm 2
Experimental Pembrolizumab Biological/Vaccine Solution
25 mg/mL
200 mg
IV Infusion
Day 1 of 
each 21-day 
cycle
Test 
Product
IMP
Central
EEA = European Economic Area; IMP = investigational medicinal product; IV = intravenous; N/A = not applicable; NIMP/AxMP = noninvestigational/auxiliary medicinal 
product; 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.
4 mg capsules provided for successive dose reduction of lenvatinib, if needed, as described in Section 6.6.2.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The initial treatment or first course of pembrolizumab Q3W consists of 35 treatments. Note: 
The number of treatments is calculated starting with the first dose.
These participants may be eligible for Second Course described in Section 6.7.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab and lenvatinib/matching 
placebo are provided in the Pharmacy Manual. 
Lenvatinib is provided as capsules for oral administration and does not require preparation. 
For participants unable to swallow capsules, a suspension can be prepared. Refer to 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).
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For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to pembrolizumab + 
lenvatinib (Arm 1) or pembrolizumab + placebo (Arm 2) study interventions.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (TPS <50% vs. 
≥50%).
2. HPV status for oropharynx cancer as determined by p16 immunohistochemistry (positive 
vs. negative); HPV status for participants without oropharynx cancer (eg, cancers of the 
oral cavity, hypopharynx and larynx) is considered HPV negative.
3. ECOG performance status (0 vs. 1).
6.3.3
Blinding
After IA2, the study was unblinded on 16-AUG-2023. Original protocol text that is contained 
in this section has been retained for reference.
A double-blinding technique with in-house blinding will be used. Lenvatinib/matching 
placebo will be packaged identically for Arms 1 and 2 so that blind is maintained. The 
participant, the investigator, and Sponsor personnel or delegate(s) who are involved in the 
study intervention administration or clinical evaluation of the participants are unaware of the 
intervention assignments.
The treatment identity of pembrolizumab will be open-label; therefore, the Sponsor, 
investigator, and participant will know the intervention administered.
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See Section 8.1.10 for the description of unblinding if a medical emergency occurs during the 
study.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Interruptions from the protocol-specified treatment plan for ≥28 days for lenvatinib/placebo
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
Lenvatinib/placebo:  On Day 1 of each cycle lenvatinib/placebo will be dosed in the clinic, 0 
to 4 hours after pembrolizumab. Lenvatinib/placebo will be taken at home on all other days.
6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor.
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab and lenvatinib
•
Radiation therapy
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study.
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.
•
Refer to Appendix 7 for country-specific requirements.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
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-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention 
pembrolizumab+lenvatinib/placebo must be discontinued:
•
Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not 
specified in this protocol
•
Investigational agents other than those specified in this protocol
•
Radiation therapy
•
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 6.6.2 for 
guidelines for lenvatinib/placebo dose modification and supportive care.
6.5.2
Drug Interactions
There are no DDI-related concomitant medication prohibitions or restrictions. Lenvatinib is 
not expected to clinically meaningfully alter exposure to CYP3A4/ P-glycoprotein (Pgp) 
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substrates based on results from a lenvatinib DDI study with midazolam (a sensitive CYP3A 
and Pgp substrate). Clinical studies also showed that co-administration of lenvatinib with 
either inducers or inhibitors of CYP3A4/Pgp are not of clinical concern.
No drug interaction is expected between pembrolizumab and lenvatinib because of their 
divergent metabolic pathways. Pembrolizumab is a mAb and is primarily catabolized like 
other proteins, while lenvatinib is metabolized by enzymatic (CYP3A and aldehyde oxidase) 
and nonenzymatic processes (LENVIMA® product information).
6.6
Dose Modification (Escalation/Titration/Other)
NOTE: In alignment with the study-specific investigator letter dated 25-AUG-2023, all study 
participants still receiving pembrolizumab should continue to receive pembrolizumab 
monotherapy on study and undergo modified protocol study procedures as specified in this 
amendment. Study participation should end after the 30-day Safety Follow-up Visit (last 
scheduled visit) with the following exceptions: participants who are potential candidates for 
Second Course treatment will continue in Efficacy Follow-up and all participants in China 
will continue in Efficacy Follow-up and Survival Follow-up. All participants should stop 
ongoing treatment with lenvatinib/placebo.
Exceptions may be requested for lenvatinib for study participants who, in the assessment of 
their study physician, are benefiting from ongoing lenvatinib after consulting with the 
Sponsor. This applies to participants currently on pembrolizumab and lenvatinib and 
participants who have discontinued pembrolizumab and are currently continuing lenvatinib 
monotherapy. Participants who are considered by the investigator as candidates for continued 
monotherapy with lenvatinib after completion of 35 cycles of pembrolizumab and lenvatinib 
require a separate communication with the Sponsor. Participants who discontinue 
pembrolizumab prior to completion of Cycle 35 (eg, due to an AE) must discontinue
lenvatinib at the same time.
Adverse events will be graded using NCI CTCAE Version v5.0. Investigators will decide the 
probability of the event being related to one or both drugs as to whether dose modification of 
one or both drugs is required.
Participants 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.
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6.6.1
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.
Dose Modification and Toxicity Management Guidelines for irAEs Associated With 
Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 5.
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated With Pembrolizumab Monotherapy, Coformulations, or IO 
Combinations
General instructions:
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. 
Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.
2. Pembrolizumab monotherapy, coformulations, or IO combinations must be permanently discontinued if 
the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last 
treatment.
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4. If pembrolizumab monotherapy, coformulations, or IO combinations have been withheld, treatment may 
resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE 
v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and Follow-
up
Pneumonitis 
Grade 2
Withhold 
Administer 
corticosteroids 
(initial dose of 1 
to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Add prophylactic 
antibiotics for 
opportunistic 
infections
Monitor participants for 
signs and symptoms of 
pneumonitis
Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment
Recurrent 
Grade 2, or 
Grade 3 or 4
Permanently 
discontinue
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irAEs
Toxicity 
Grade 
(CTCAE 
v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and Follow-
up
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 1 
to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (ie, 
peritoneal signs and 
ileus)
Participants with 
≥Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing endoscopy 
to rule out colitis
Participants with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids. If sufficient 
oral fluid intake is not 
feasible, fluid and 
electrolytes should be 
substituted via IV 
infusion
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2a
Withhold
Administer 
corticosteroids 
(initial dose of 0.5 
to 1 mg/kg 
prednisone or 
equivalent) 
followed by taper
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable)
Grade 3b or 4c
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 1 
to 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
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irAEs
Toxicity 
Grade 
(CTCAE 
v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and Follow-
up
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold d
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM
Administer 
antihyperglycemic 
in participants 
with 
hyperglycemia
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hyperthyroidism
Grade 2
Continue
Treat with 
nonselective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hypothyroidism
Grade 2, 3, or 
4
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 1 to 
2 mg/kg or 
equivalent) 
followed by taper
Monitor changes of 
renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
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irAEs
Toxicity 
Grade 
(CTCAE 
v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, 
or IO 
Combinations
Corticosteroid 
and/or Other 
Therapies
Monitoring and Follow-
up
Myocarditis
Asymptomatic 
cardiac 
enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(which was 
previously 
myocarditis 
Grade 1 using 
CTCAE v4.0)
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes
Grade 2, 3 or 
4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected 
SJS, TEN, or 
DRESS
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Confirmed 
SJS, TEN, or 
DRESS
Permanently 
discontinue
All Other irAEs
Persistent
Grade2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes
Grade 3
Withhold or 
discontinue 
based on the 
evente
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common 
Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; 
GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal; bilirubin:>3.0 to 
10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline if baseline abnormal
c
AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal; 
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations, or IO 
combinations is at the discretion of the investigator or treating physician. If control achieved or ≤Grade 2, 
pembrolizumab monotherapy, coformulations, or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to encephalitis and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis)
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reactions are provided in Table 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 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 intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: 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 v5.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
6.6.2
Dose Modification with Lenvatinib
Lenvatinib dose reduction and interruption for participants who experience lenvatinib-
pembrolizumab combination therapy-related toxicity will be in accordance with the dose 
modification guidelines described in Table 7. An interruption of study intervention for more 
than 28 days will require Sponsor approval before treatment can be resumed.
The starting dose of lenvatinib is [20 mg/day] in combination with pembrolizumab . Dose 
reductions of lenvatinib occur in succession based on the previous dose level (20, 14, 10, and 
8 mg/day). Any dose reduction below 8 mg/day must be discussed with the Sponsor. Once 
the lenvatinib placebo 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.
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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 7). For overlapping toxicities of pembrolizumab and lenvatinib/matching placebo, 
please refer to Section 6.6.3.
Table 7
Dose Modification Guidelines for Lenvatinib-Related Adverse Events
Treatment-Related 
Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d or Grade 3e,f
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
14 mg once a day (1-level 
reduction)
Second occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
10 mg once a day (1-level 
reduction)
Third occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 8 mg 
orally once a day (1-level 
reduction)
Fourth occurrence (same 
toxicity or new toxicity)
Interrupt lenvatinib
Discuss with Sponsor
Grade 4g: Discontinue Study Treatment
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for 
Adverse Events.
Note: For grading see CTCAE version 5.0. Collect all AE grades (ie, decreasing and increasing CTCAE 
grade).
a
An interruption of study treatment for more than 28 days will require Sponsor approval before treatment 
can be resumed. 
b
Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or 
diarrhea prior to any lenvatinib interruption or dose reduction. 
c
Applicable only to Grade 2 toxicities judged by the participant and/or physician to be intolerable.
d
Obese participants (BMI ≥30) with weight loss do not need to return to their baseline weight or within 
10% of their baseline weight (ie, Grade 1 weight loss). These participants may restart study intervention 
at a lower dose once their weight remains stable for at least 1 week and they have a minimum BMI of 
25. The new stable weight should be used as the new baseline for further dose reductions.
e
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are 
not considered clinically relevant by the investigator, continuation of treatment should be discussed with 
Sponsor. 
f
For Grade 3 thromboembolic event, permanently discontinue lenvatinib/matching placebo. See Section 
6.6.2.5.
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 1.3.1 and Section 1.3.2). 
Hypertension will be graded using NCI CTCAE v5.0, based on BP measurements only (and 
not on the number of antihypertensive medications).
If the participant’s first BP measurement of the current assessment is elevated (ie, systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP measurement should be repeated at least 5 
minutes later. One BP assessment is defined as the mean value of 2 measurements at least 5 
minutes apart. If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 
5 minutes apart) is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a 
confirmatory assessment should be obtained at least 30 minutes later by performing 2 
measurements (at least 5 minutes apart) to yield a mean value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. The 
choice of antihypertensive treatment should be individualized to the participant’s clinical 
circumstances and follow standard medical practice. For previously normotensive 
participants, appropriate antihypertensive therapy should be started when systolic BP ≥140 
mm Hg or diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 30 minutes 
apart. For those participants already on antihypertensive medication, treatment modification 
may be necessary if hypertension persists.
Lenvatinib should be withheld in any instance where a participant is at imminent risk to 
develop a hypertensive crisis or has uncontrolled hypertension (eg, BP ≥160/100 mm Hg) 
with significant risk factors for severe complications, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant co-morbidities.  Once the participant 
has been on the same antihypertensive medications for at least 48 hours and the BP is 
controlled, lenvatinib should be resumed as described below.
Participants who have had systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have 
their BP monitored on Day 15 (or more frequently as clinically indicated) until systolic BP 
has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment 
cycles. If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the 
participant must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles.
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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.
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at an additional dose reduction only when systolic BP ≤150 mm Hg and diastolic BP 
≤95 mm Hg and the participant has been on a stable dose of antihypertensive 
medication for at least 48 hours. 
-
If systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a third dose reduction only when systolic BP ≤150 mm Hg and diastolic BP ≤95 
mm Hg and the participant has been on a stable dose of antihypertensive medication 
for at least 48 hours.
-
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life threatening consequences):
4. Institute appropriate medical management
5. Discontinue study drug
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:
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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 UPCR test) is required in the following situations:
-
The first (initial) occurrence of ≥2+(≥100 mg/dL) proteinuria on urine dipstick (or 
urinalysis) while the participant is receiving lenvatinib.
-
A subsequent increase in severity of urine dipstick or urinalysis proteinuria occurring 
on the same lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+ (≥100 mg/dL).
3. A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.
Grading of Proteinuria
-
Grading according to NCI CTCAE v5.0 will be based on the 24-hour urinary protein 
result if one has been obtained. If the participant has 4+ proteinuria by dipstick 
(≥1000 mg/dL by urinalysis), a 24-hour urinary protein result is required to confirm 
Grade 3 proteinuria. Management of lenvatinib administration will be based on the 
grade of proteinuria according to Table 7.
Monitoring
-
Urine dipstick or urinalysis testing for participants with proteinuria ≥2+ (≥100 
mg/dL) should be performed on Day 15 (or more frequently as clinically indicated) 
until the results have been 1+ (30 mg/dL) or negative for 2 consecutive treatment 
cycles.
-
Proteinuria monitoring can be performed at the local laboratory or investigator site, 
but must be managed by the site physician.
-
In the event of nephrotic syndrome, lenvatinib must be discontinued.
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 7 should be followed.
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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 1.3.1 and Section 1.3.2) and as 
clinically indicated. If signs/symptoms indicating liver injury occur, instructions contained in 
Table 7 should be followed. Appropriate supportive care should be provided together with 
close monitoring. If hepatic failure (any grade per CTCAE v5) occurs, lenvatinib must be 
discontinued.
6.6.2.5
Management of Thromboembolic Events
Participants should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events which include acute onset of shortness of breath, dyspnea, chest pain, 
cough, hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity 
swelling, and warmth to touch or tenderness. In case any of these symptoms appear, 
participants should be instructed to report such symptoms promptly to the treating physician.  
If a thromboembolic event is confirmed, instructions contained in Table 7 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/placebo 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 7 should be followed.
6.6.2.7
Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 1.3.1 and Section 1.3.2). Corrected 
serum calcium should be used to assess the grade of hypocalcemia per CTCAE v5.0, using 
the following formula:
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
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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 7 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.
Refer to 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).
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 
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interrupted to assess whether an AE improves/resolves with dechallenge (ie, interruption 
of treatment) based on the following two scenarios:
-
If an AE is identified during a treatment cycle (ie, between 2 pembrolizumab doses), 
only lenvatinib dose interruption is needed. 
-
If an AE is identified at the beginning of a treatment cycle, lenvatinib can be 
interrupted and dosing of pembrolizumab should be held.
If the participant recovers from an AE in response to lenvatinib interruption (ie, positive 
dechallenge), the event is more likely to be related to lenvatinib. Otherwise, after 
excluding other alternative explanations, an immune-related AE should be considered. 
2. Severity of AE
If an AE is suspected to be treatment related and is severe/life threatening at the time of 
onset or is rapidly worsened, action including interrupting both drugs and initiating 
treatment with a corticosteroid (with exception of hypothyroidism, 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 5, but 
lenvatinib may be administered at a reduced dose by the time this criterion is met and 
must be permanently discontinued immediately.
-
ALT or AST >3 X ULN and (TBL >2 X ULN or INR >1.5).
Although Table 5 advises pembrolizumab to be withheld (interrupted), and Table 7
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.
6.7
Second Course
All participants who stopped study intervention with SD or better may be eligible for up to an 
additional 17 cycles of pembrolizumab (approximately 1 year) if they progress after initial 
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treatment. This retreatment is the Second Course of this study, and a participant is eligible if 
the following conditions are met: 
Either
•
Stopped initial study intervention after attaining an investigator determined confirmed 
CR based on RECIST 1.1, and
-
Was treated with at least 8 cycles of study intervention before discontinuing 
treatment, and
-
Received at least 2 treatments with pembrolizumab beyond the date when the initial 
CR was declared
OR
•
Had SD, PR, or CR and stopped study intervention after completion of 35 administrations 
(approximately 2 years) of study intervention for reasons other than disease progression 
or intolerability
AND
•
Experienced centrally-verified radiographic disease progression by RECIST 1.1 after 
stopping initial treatment, and
-
No new anticancer treatment was administered after the last dose of study 
intervention, and
-
The participant meets all of the safety parameters listed in the inclusion criteria and 
none of the safety parameters listed in the exclusion criteria, and
-
The study is ongoing
As of Amendment 05: Participants will be considered for Second Course treatment upon 
investigator-assessed radiographic disease progression by RECIST 1.1.  (Note: participants in 
China will be considered for Second Course after experiencing centrally-verified 
radiographic disease progression by RECIST 1.1.).
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
study.
Participants who discontinue pembrolizumab after attaining CR or who complete treatment 
with pembrolizumab after 35 cycles will continue to receive lenvatinib/placebo alone until 
disease progression is verified by BICR, development of unacceptable toxicity, or 
withdrawal of consent. Participants who are receiving lenvatinib/placebo at the time disease 
progression is verified may continue to receive lenvatinib/placebo during Second Course 
treatment at the discretion of the investigator. Participants who discontinue 
lenvatinib/placebo before initiation of Second Course treatment will not restart 
lenvatinib/placebo.
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6.8
Intervention After the End of the Study
Upon study termination, participants are to be discontinued and may be enrolled in an 
extension study using pembrolizumab in combination with compound (eg, lenvatinib) if 
available.
6.9
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity of lenvatinib or 
matching placebo. The emergency unblinding call center should only be used in cases of 
emergency (see Section 8.1.10). If the emergency unblinding call center is not available for a 
given site in this study, the central electronic intervention randomization system (IRT) should 
be used to unblind participants and to unmask study intervention identity. The Sponsor will 
not provide random code/disclosure envelopes or lists with the clinical supplies.
6.10
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Original protocol text that is contained in this section and the following sections has been 
retained for reference.
Discontinuation of study intervention does not represent withdrawal from the study. 
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.5 and 8.11.6 unless the participant 
has withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
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 Section 6.6.1, 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 confirmed positive serum pregnancy test.
•
The participant has a positive urine drug screen at any time during the course of the 
study.
•
Centrally-verified radiographic disease progression as outlined in Sections 8.2.1 and
8.2.1.5. Treatment beyond centrally-verified PD per RECIST 1.1 may be permitted at the 
discretion of the investigator and after consultation with the Sponsor and receiving signed 
informed consent. 
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-
As of Amendment 05: Central tumor response assessments will no longer be 
performed.  Participants who are receiving study intervention will be assessed locally by 
the investigator for disease progression per the protocol schedule.  Scans will not be sent 
to the iCRO.  (Note: participants in China will continue to have BICR tumor response 
assessments and will continue to submit scans to the iCRO.)
-
Participants with RECIST 1.1 disease progression per local investigator assessment 
may continue pembrolizumab monotherapy at the discretion of the investigator and after 
consultation with the Sponsor and receiving signed informed consent.
-
Participants with RECIST 1.1 disease progression must discontinue lenvatinib.
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Recurrent Grade 2 pneumonitis
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in Table 5, 
Table 6, or Table 7.
•
Discontinuation of pembrolizumab 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 
at least 2 doses of pembrolizumab beyond the date when the initial CR was declared. 
These participants may be eligible for Second Course treatment described in Section 6.7.  
Participants who stop pembrolizumab due to CR will continue to receive 
lenvatinib/placebo until PD verified by BICR or until a discontinuation criterion is met, if 
lenvatinib/placebo was not previously discontinued.
As of Amendment 05: Participants who are considered by the investigator as candidates 
for continued monotherapy with lenvatinib after stopping pembrolizumab due to CR 
require a separate communication with the Sponsor.
•
Completion of 35 treatments (approximately 2 years) with pembrolizumab
Note: The number of treatments is calculated starting with the first dose. Participants who 
stop the combination or pembrolizumab after receiving 35 doses may be eligible for 
retreatment if they progress after stopping study intervention provided they meet the 
requirements detailed in Section 6.7. Participants receiving lenvatinib/placebo may 
continue to receive lenvatinib/placebo after completion of 35 treatments with 
pembrolizumab. Participants may be retreated in the Second Course Phase (Retreatment) 
for up to an additional 17 cycles (approximately 1 year) of pembrolizumab.
As of Amendment 05:  Participants who are considered by the investigator as candidates 
for continued monotherapy with lenvatinib after completion of 35 cycles of 
pembrolizumab and lenvatinib require a separate communication with the Sponsor.
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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 5, 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 5 advises pembrolizumab to be withheld (interrupted), and Table 7
advises lenvatinib to have no dose modification or a reduction, if this criterion is met, 
both drugs must be permanently discontinued immediately.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (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 providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study 
will be provided in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study. If there are changes to 
the participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate documented 
informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study intervention. Treatment for the disease for which 
the participant has enrolled in this study will be recorded separately and will not be listed as a 
prior medication.
Medications taken 28 days before the first dose of Second Course study intervention will be 
recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. Concomitant medications will be 
recorded for 30 days after the last dose of study intervention.
In addition, concomitant medications will be recorded during Second Course treatment, and 
for 30 days after the last dose of Second Course study intervention.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
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randomization. Once a randomization number is assigned to a participant, it can never be 
reassigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
It is strongly preferred that participants receive the first dose of study intervention on the day 
of randomization. Study intervention should begin within 3 days of randomization.
Pembrolizumab: Study intervention(s) will be administered by the investigator and/or study 
staff according to the specifications within the pharmacy manual.
Lenvatinib/placebo:  Lenvatinib/placebo will be administered by the investigator and/or 
study staff in the clinic on Day 1 of each cycle, 0 to 4 hours after pembrolizumab. All other 
lenvatinib/placebo doses will be taken at home. Lenvatinib/placebo will be administered 
according to the specifications in the Pharmacy Manual. An extemporaneous suspension of 
lenvatinib capsules should be used for participants unable to swallow capsules, as detailed in 
the Pharmacy Manual. Please refer to Section 8.1.8.1 for further details.
8.1.8.1
Timing of Dose Administration
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 to +10 minutes is permitted (ie, infusion time is 30 minutes: –5 
min/+10 min).
After Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle due to administrative reasons.
Lenvatinib/placebo: Lenvatinib 20 mg (two 10-mg capsules) or matching placebo will be 
taken orally with water (with or without food) once daily at approximately the same time 
each day in each 21-day cycle. Day 1 of each cycle will be dosed in the clinic, 0-4 hours after 
pembrolizumab.
If a lenvatinib/placebo dose is missed and cannot be taken within 12 hours, then that dose 
will be skipped, and the next dose will be taken at the usual time of administration.
Lenvatinib capsules should be swallowed whole. Alternatively, the capsules can be dissolved 
in a small glass of liquid (ie, water or apple juice) if a participant is unable to swallow or has 
a feeding tube. See the Pharmacy Manual for additional information.
8.1.8.2
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% 
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compliance and investigators and their staff should evaluate compliance at each visit and take 
appropriate steps to optimize compliance.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End-of-Treatment visit at the time of withdrawal. Any AEs that 
are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
After efficacy IA2, the study was unblinded on 16-AUG-2023. Original protocol text that is 
contained in this section has been retained for reference.
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Nonemergency Unblinding
After Sponsor consultation, participants may be unblinded if knowledge of treatment arm is 
required to guide future treatment decisions for the participant. Participants must have
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centrally-verified PD and study intervention must be permanently discontinued for 
nonemergency unblinding to be considered.
For nonemergency unblinding (eg, after cases of centrally-verified PD and treatment 
discontinuation) IRT should be used to unblind the participant’s treatment assignment. The 
emergency unblinding call center should not be used for this purpose.
Participants whose treatment assignment has been unblinded for any reason will continue to 
be monitored in the study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:
•
A newly obtained core or incisional biopsy of a tumor lesion, which was not previously 
irradiated
Or
•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx diagnostic kit except it is labeled IUO. 
The PD-L1 IHC 22C3 pharmDx assay kit is currently approved to select participants with 
HNSCC for treatment with pembrolizumab.
The PD-L1 CPS1 result will be unmasked to the site.
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8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
As of Amendment 05: Central tumor response assessments will be discontinued. Imaging 
scans will no longer be submitted to the iCRO nor read by BICR. Participants still on study 
intervention and participants in Efficacy Follow-up should continue tumor imaging and 
investigator assessments of imaging per protocol. (Note: participants in China will continue 
to have BICR tumor response assessments and will continue to submit scans to the iCRO.) 
Original protocol text that is contained in this section has been retained for reference.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment based on scans.
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility. 
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
Expedited confirmation of measurable disease based on RECIST 1.1 by BICR at Screening 
will be used to determine participant eligibility. Confirmation by the BICR that the 
participant’s imaging shows at least 1 lesion that is appropriate for selection as a target lesion 
per RECIST 1.1 is required before participant randomization.
All scheduled scans for participants will be submitted to the iCRO. In addition, a scan that is 
obtained at an unscheduled time point, for any reason (including suspicion of progression or 
other clinical reason), should also be submitted to the iCRO if it shows disease progression, 
or if it is used to support a response assessment. All scans acquired within the protocol-
specified window of time around a scheduled scan visit are to be classified as pertaining to 
that visit.
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When the investigator identifies radiographic progression per RECIST 1.1, the iCRO will 
verify this progression and email the results to the study site and Sponsor. In clinically stable 
participants, imaging should continue until PD has been verified by BICR (if initial site-
assessed PD was not verified by BICR, each subsequent scan must be submitted to iCRO 
with verification of PD request until PD has been verified by BICR).
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days before the date of 
randomization. Any scan obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review the screening scans to confirm the participant has 
measurable disease per RECIST 1.1.
The Screening scans must be submitted to the iCRO for confirmation of measurable disease 
per RECIST 1.1 for eligibility before randomization.
Tumor scan performed as part of routine clinical management is acceptable for use as 
screening tumor scan if it is of diagnostic quality and performed within 28 days before the 
date of randomization and can be assessed by the iCRO for confirmation of measurable 
disease.
If brain scans are required to document the stability of existing metastases, the brain scan 
should be acquired during screening. The specific methods permitted for this study are 
described in the SIM.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at Week 6 (42 to 49 days window) from the date 
of randomization. Subsequent tumor scans should be performed every 6 weeks (42 days ± 7 
days) or more frequently if clinically indicated. After 48 weeks, participants who remain on 
treatment will have scans performed every 9 weeks (63 days ± 7 days). Scan timing should 
follow calendar days and should not be adjusted for delays in cycle starts. Scans should 
continue to be performed until disease progression is identified by the investigator and 
verified by the BICR, the start of new anticancer treatment, withdrawal of consent, or death, 
whichever occurs first.
Treatment beyond centrally-verified PD per RECIST 1.1 may be permitted at the discretion 
of the investigator after consultation with the Sponsor and receiving signed informed 
consent. Participants who continue treatment beyond centrally-verified PD must continue 
tumor assessments as described in the SoA (Section 1.3.1). Investigator assessments are to be 
documented on the eCRF, but scans are not to be submitted to the iCRO. Further progression 
and discontinuation of study intervention are to be determined by the investigator.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular schedule 
scans, starting with the next scheduled scan time point. Participants who receive additional 
scan for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point. 
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On-study brain scan should be performed if clinically indicated or to confirm CR (if other 
lesions indicate CR and brain lesions existed at baseline).
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
As of Amendment 05: follow-up tumor imaging is only required for participants who are 
candidates for Second Course treatment. Imaging scans will no longer be submitted to the 
iCRO nor read by BICR. Original protocol text that is contained in this section has been 
retained for reference. (Note: participants in China will continue to have BICR tumor 
response assessments and will continue to submit scans to the iCRO.)
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 verified by BICR
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
8.2.1.4
Second Course (Retreatment) Tumor Scans
Tumor scans must be performed within 28 days before restarting study intervention with 
pembrolizumab.
If disease progression has been verified by BICR for the First Course, the Second Course 
may be initiated. The disease progression scan may be used as the Second Course baseline 
scan if performed within 4 weeks prior to dosing and meets scan standards.
The first scan should be performed at 6 weeks (42-49 days) after restarting study 
intervention. Subsequent tumor scans are to be performed every 6 weeks (42 days ±7 days) 
or more frequently, if clinically indicated. After 48 weeks, scans are to be performed every 9 
weeks (±7 days) or more frequently, if clinically indicated.
Scans are to be performed until:
•
disease progression
•
the start of a new anticancer treatment
•
withdrawal of consent
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•
death
•
completion of Second Course
•
or notification by the Sponsor, whichever occurs first
If participants discontinue study intervention, tumor scans are to be performed at 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans every 6 weeks (42 
days [±7 days]) until the start of a new anticancer treatment, disease progression, death, or 
the end of the study, whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
As of Amendment 05: Central tumor response assessments will be discontinued. Imaging 
scans will no longer be submitted to the iCRO nor read by BICR. However, participants in 
China will continue to have BICR tumor response assessments and will continue to submit 
scans to the iCRO.
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scan(s) is/are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
continue scans per protocol schedule (the next scheduled scan should be ≥4 weeks 
from most recent scan acquired)
-
send scans to iCRO
-
continue local assessment
-
do not change investigator assessment of progression
-
if subsequent scan(s) indicate progression, request verification from iCRO
•
If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
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If disease progression is verified, the process continues as follows:
•
investigator judgment will determine action
•
if the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent addendum must be signed
•
obtain scans locally per original protocol schedule
•
do not send scans to iCRO
Figure 5 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
unacceptable toxicity
-
clinical signs or symptoms indicating clinically significant disease progression
-
decline in performance status
-
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
Figure 5
Study Intervention Decision Making Process When Progression per RECIST 
1.1 is Observed by Investigator (PFS endpoint)
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8.2.2
Patient-reported Outcomes
As of Amendment 05: ePRO assessments will be discontinued.  Original protocol text that is 
contained in this section has been retained for reference. 
It is a best practice and strongly recommended that ePROs are administered before any other 
visit procedures and in the order listed in the SoA, starting with EuroQoL EQ-5D-5L. 
Collection begins at C1 and continues until C35 or treatment discontinuation, whichever 
occurs first. 
The PRO questionnaires will be administered:
•
Before dosing at Day1, Cycle 1, and then  
•
Day 1 of every cycle from Cycle 1 through Cycle 9, then 
•
Day 1 of every other cycle through Cycle 17 (C11, C13, C15, C17), then 
•
Every 3 cycles through Cycle 35 (C20, C23, C26, C29, C32, C35). 
•
Obtain at EOT and Safety FU (if EOT and Safety FU occur before C35).
If the EOT visit happens before the end of the study, PROs will be administered at EOT visit.
PROs will also be administered at the 30-day Safety Follow-up visit. In the event the EOT 
visit is combined with the 30-day Safety Follow-up visit, only the PRO assessments for the 
EOT visit will be completed.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
The total amount of blood/tissue to be drawn/collected over the course of the study (from pre 
study to poststudy visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per participant, can be found in the laboratory or study procedures 
manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
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A brief directed physical 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 during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings and changes from 
Screening physical examination findings will be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at Screening, before the 
administration of each dose of trial treatment and during the Safety Follow-up visit, as 
specified in the SoA (Section 1.3). 
Vital signs include temperature, heart rate, respiratory rate, weight, and blood pressure. 
Height will be measured at Screening only.
•
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 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. 
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•
Under exceptional circumstances, participants will have the option of having BP 
measured between visits obtained locally by a health care professional. A diary will be 
provided as a tool to aid the participant in collecting BP evaluations between study visits. 
8.3.3
Electrocardiograms
Electrocardiograms will be obtained as designated in the SoA (Section 1.3). Complete, 
standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a single 
page with an accompanying lead II rhythm strip below the customary 3 × 4 lead format are to 
be used. In addition to a rhythm strip, a minimum of 3 full complexes should be recorded 
from each lead simultaneously. Participants must be in the recumbent position for a period of 
5 minutes prior to the ECG. The Fridericia correction method for calculating QTc will be 
used.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded on the appropriate CRF.
QTc prolongation has been seen in some lenvatinib studies. Monitor electrocardiograms 
every cycle (as specified in the Schedule of Assessments) in patients with congenital long QT 
syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known 
to prolong the QT interval, including Class Ia and III antiarrhythmics. Refer to the lenvatinib 
IB.
8.3.4
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan (using technetium-based tracer) or an echocardiogram will be performed to 
assess LVEF as designated in the SoA (Section 1.3). MUGA or echocardiogram scans should 
be performed locally in accordance with the institution’s standard practice. MUGA scans are 
the preferred modality; however, whichever modality is used for an individual participant at 
baseline should be repeated for all subsequent LVEF assessments for that participant. LVEFs 
as assessed by the institution will be entered onto the CRF. Investigator assessment will be 
based upon institutional reports.
Refer to Appendix 7 for country-specific requirements.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the 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 or study procedures 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.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Procedures 
Manual.
Refer to the SoA (Section 1.3) for the timing of laboratory assessments
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2. Refer 
to Section 6.6 for required dose modifications for drug-related laboratory AEs.
8.3.5.1.1
Hematology and Clinical Chemistry
Hematology (CBC with differential) and clinical chemistry will be performed within 7 days 
before the first dose of study intervention. Results from Screening laboratory tests must be 
reviewed before randomization to confirm eligibility. Labs obtained and reviewed on C1D1 
before randomization may also be used as the screening value to determine eligibility.
In subsequent cycles, hematology and clinical chemistry will be performed within 3 days 
before dosing, and results must be reviewed before administration of study intervention.
For sites not able to test lipase locally, lipase testing will be performed using central 
laboratory and within 3 days of each subsequent cycle. Participants may be dosed while 
lipase test results are pending, however the results must be reviewed by the investigator when 
available.
8.3.5.1.2
Urine Dipstick Testing/Urinalysis
Urine dipstick testing and urinalysis will be performed locally within 7 days before the start 
of study intervention. Results must be reviewed before randomization to confirm eligibility.
Urinalysis obtained and reviewed on C1D1 before randomization may also be used as the 
screening value to determine eligibility. If 24-hour urine collection for quantitative 
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assessment of proteinuria is required, randomization and C1D1 is postponed to after 
proteinuria result is available.
After Screening, urine dipstick testing will be performed within 3 days before Day 1 of every 
cycle while participants are taking lenvatinib/placebo. Refer to Section 6.6.2.2 for additional 
testing and monitoring requirements if proteinuria is detected. 
Urinalysis will be performed for all participants according to the SoA. For cycles where 
urinalysis is required, urinalysis will be performed within 3 days before dosing, and results 
must be reviewed before administration of study intervention.
8.3.5.1.3
Thyroid Function Testing
The screening blood sample for thyroid function testing will be obtained within 7 days before 
the first dose of study intervention. Labs obtained and reviewed on C1D1 before 
randomization may also be used as the screening value to determine eligibility.
Thyroid function testing will be performed within 3 days of each subsequent cycle. 
Participants may be dosed while thyroid function test results are pending, however the results 
must be reviewed by the investigator when available.
8.3.5.2
Pregnancy Testing
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at every protocol treatment 
cycle , as per SoA.
-
Pregnancy testing (urine or serum) should be conducted for the time required to 
eliminate systemic exposure after the last dose of each study intervention and should 
correspond with the time frame for the participant’s contraception, as noted in Section
5.1. The length of time required to continue pregnancy testing for each study 
intervention is:
◦
120 days after the last dose of pembrolizumab
◦
30 days after the last dose of lenvatinib/placebo
-
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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8.3.6
Performance Assessments
8.3.6.1
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 (see Appendix 9) at 
screening, before the administration of each dose of study intervention and during the 
follow-up period as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
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protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days following cessation 
of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention 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/placebo, 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.
•
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 the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in 
Table 8.
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 8
Reporting 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
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
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. SAEs and other reportable safety events, including 
pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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 (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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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.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results. 
Lenvatinib overdose without an associated adverse event is not considered an ECI.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for:
•
Pembrolizumab: ≥5 times the protocol-specified dose.
•
Lenvatinib: any dose above the protocol-prescribed dose if associated with an adverse 
event
There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
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receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer, RCC, and HCC.
No specific information is available on the treatment of overdose of pembrolizumab or 
lenvatinib.
All reports of pembrolizumab overdose with and without an AE and all reports of lenvatinib 
overdose with an AE must be reported by the investigator within 24 hours to the Sponsor 
either by electronic media or paper.
Reports of pembrolizumab overdose without any associated clinical symptoms or abnormal 
laboratory results, should be reported using the terminology “accidental or intentional 
overdose without adverse effect.”
8.6
Pharmacokinetics
Pharmacokinetic parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
As of Amendment 05: Biomarker sample collections are discontinued.  Original protocol text 
that is contained in this section has been retained for reference.
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 genetic analysis
•
Blood for RNA analysis
•
Blood for serum biomarkers
•
Blood for plasma biomarkers
•
Blood for circulating tumor nucleic acids 
•
Tumor tissue
•
Stool analysis (optional)
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the operations/laboratory manual.
Refer to Appendix 7 for country-specific requirements.
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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.
8.9
Future Biomedical Research Sample Collection
FBR samples will not be collected in this study.
8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department 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.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Initial Treatment Phase
Visit requirements for the Initial Treatment Phase are outlined in the SoA (Section 1.3.1). 
Specific procedure-related details are provided in Section 8.1.
8.11.2.1
Telephone or Contact Visit
A telephone contact or visit will be conducted by the investigator or medically qualified 
designee (consistent with local requirements) on Cycle 1 Day 8 to assess participants for 
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development of early toxicity, as outlined in the SoA (Section 1.3.1). An unscheduled visit 
can occur before C1D15 if necessary for safety.
8.11.3
Second Course Treatment Phase
Participants who meet the criteria outlined in Section 6.7 may be considered for Second 
Course treatment with pembrolizumab. Visit requirements for the Second Course Treatment 
Phase are outlined in the SoA (Section 1.3.2). Specific procedure-related details are provided 
in Section 8.1.
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
The End-of-Treatment visit will take place at the time study intervention is discontinued for 
any reason. 
If the End-of-Treatment visit takes place approximately 30 days from the last dose of study 
intervention, a separate Safety Follow-up visit is not required. All procedures required at the 
End-of-Treatment visit and at the Safety Follow-up visit will be performed as a single visit.
8.11.5
Posttreatment Visit
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits: 1 after the Initial Treatment or First Course and 1 after the Second Course.
8.11.5.2
Efficacy Follow-up Visits
As of Amendment 05: Efficacy Follow-up Visits will be discontinued except for participants 
who are candidates for Second Course treatment and participants in China.  Imaging scans 
will no longer be submitted to the iCRO nor read by BICR. Participants who are eligible to 
receive retreatment with pembrolizumab according to the criteria in Section 6.7 will move 
from Efficacy Follow-up to Second Course when they experience investigator-assessed 
disease progression.  Original protocol text that is contained in this section has been retained 
for reference. (Note: participants in China will continue to have BICR tumor response 
assessments and will continue to submit scans to the iCRO. Participants in China who are 
eligible to receive retreatment with pembrolizumab according to the criteria in Section 6.7 
will move from Efficacy Follow-up to Second Course when they experience 
centrally-verified disease progression.) 
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than centrally-verified radiographic disease 
progression will move into  Efficacy Follow-up  and will be assessed as outlined in the SoA 
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(Section 1.3) to monitor disease status. Every effort should be made to collect information 
regarding disease status until centrally-verified disease progression, the start of new 
anticancer therapy, death, or the end of the study, whichever occurs first. Information 
regarding poststudy anticancer treatment will be collected if new treatment is initiated. 
Participants who completed all efficacy assessments and/or will not have further efficacy 
assessments must enter Survival Follow-up.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.7 will move from Efficacy Follow-up to Second Course when they 
experience centrally-verified disease progression. Second Course study procedure 
requirements are provided in the SoA (Section 1.3.2).
8.11.5.3
Survival Follow-up Contacts
As of Amendment 05: Survival Follow-up Visits will be discontinued except for participants 
in China. Those participants remaining on study treatment at the time of Amendment 05 
should continue to be monitored in the study through the AE reporting period (Section 8.4). 
Original protocol text that is contained in this section has been retained for reference.
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
•
For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.6
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
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9
STATISTICAL ANALYSIS PLAN
As of Amendment 05: The Statistical Analysis Plan is amended as follows.
NOTE: Based on the data from an interim safety and efficacy analysis for LEAP-010 (data 
cutoff 30-MAY-2023), the study will be discontinued due to lack of efficacy because 
pembrolizumab in combination with lenvatinib did not demonstrate an improvement in OS, 
one of the trial’s primary endpoints, compared to pembrolizumab plus placebo and appears 
unlikely to do so in a future analysis. Based upon these data and the recommendation of the 
eDMC, the study was unblinded on 16-AUG-2023. The prespecified interim analysis 3 (IA3) 
and final analysis of the study described in the SAP will not be performed. Safety analysis 
will be performed at the end of the study; there will be no further planned analyses for 
efficacy and ePRO endpoints.
This section outlines the statistical analysis strategy and procedures for the study. The study 
has been unblinded as of 16-AUG-2023. Changes made to primary and/or key secondary 
hypotheses, or the statistical methods related to those hypotheses that occurred prior to 
Amendment 05 were documented in previous protocol amendments(s) (consistent with 
International Conference on Harmonisation [ICH] Guideline E-9). Changes to exploratory or 
other nonconfirmatory analyses made after the protocol has been finalized, but before the 
conduct of any analysis, will be documented in an sSAP and referenced in the CSR for the 
study. The PRO analysis plan will also be included in the sSAP.
Details pertaining to the statistical analyses for participants enrolled in China will be 
provided in a separate sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Section 9.2 – Responsibility for Analyses/In-House Blinding through Section 9.12 – Extent 
of Exposure. As of Amendment 05, the prespecified IA3 and final analysis of the study
described in the SAP will not be performed. Safety analysis will be performed at the end of 
the study; there will be no further planned analyses of efficacy and ePRO endpoints. The 
SAP summary has been updated accordingly.
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Study Design 
Overview
A Phase 3 study of pembrolizumab (MK-3475) with or without 
lenvatinib (E7080/MK-7902) as 1L intervention in a PD-L1 
selected population with R/M HNSCC (LEAP-010)
Treatment 
Assignment
Approximately 500 participants will be randomized in a 1:1 
ratio treatment groups: (1) the pembrolizumab + lenvatinib arm 
and (2) the pembrolizumab + placebo arm. Stratification factors 
are: 
•
PD-L1 tumor expression as determined by PD-L1 
immunohistochemistry (TPS <50% vs. ≥50%)
•
HPV status for oropharynx cancer as determined by p16 
immunohistochemistry (positive vs. negative); HPV status 
for participants without oropharynx cancer (eg, cancers of 
the oral cavity, hypopharynx and larynx) is considered HPV 
negative.
•
ECOG performance status (0 vs. 1)
This is a randomized double-blind study.
Analysis Populations
Efficacy: Intent-to-Treat
Safety: All-Participants-as-Treated
Primary Endpoints
ORR, PFS, OS
Statistical Methods for 
Key Efficacy Analyses
The primary hypotheses addressing PFS and OS will be 
evaluated by comparing the experimental group to the control 
group using a stratified log-rank test. The hazard ratio will be 
estimated using a stratified Cox regression model. Event rates 
over time will be estimated within each treatment group using 
the Kaplan-Meier method. The stratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985] with 
strata weighted by sample size will be used for the analysis of 
the primary hypothesis addressing ORR. 
Statistical Methods for 
Key Safety Analyses
For analyses in which 95% CIs will be provided for between-
treatment differences in the percentage of participants with 
events, these analyses will be performed using the Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985].
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Interim Analyses
As of Amendment 05, the prespecified IA3 and final analysis of 
the study described in the SAP will not be performed.
Efficacy
Three interim analyses are planned in this study. Results will be 
reviewed by an external DMC. Details are provided in Section 
9.7.
•
Interim Analysis 1 (IA1):
-
Timing: to be performed after 350 participants are 
randomized with 6 months of follow-up
-
Primary purpose: efficacy analysis for ORR and PFS
•
Interim Analysis 2 (IA2): 
-
Timing: to be performed after both ~432 PFS events 
have been observed and ~ 6 months after last participant 
randomized
-
Primary purpose: efficacy analysis for PFS and OS
•
Interim Analysis 3 (IA3): 
-
Timing: to be performed after both ~326 OS events have 
occurred and ~ 14 months after last participant 
randomized
-
Primary purpose: efficacy analysis for OS
•
Final Analysis (FA): 
-
Timing: to be performed after both ~361 OS events have 
occurred and ~ 20 months after last participant 
randomized
-
Primary purpose: efficacy analysis for OS
Note that for IA2, IA3 and the FA, if the events accrue more 
slowly than expected, the analysis can be delayed up to 3 
months after the projected timing.
Safety:
The first safety interim analysis will be performed and reviewed 
by the eDMC at 6 months after the first participant is 
randomized, or when the first 60 participants have been 
randomized, whichever is later. Afterwards, the eDMC will 
review safety data periodically in the study. Details will be 
included in the DMC charter.
Multiplicity
The overall Type I error over the primary hypotheses is strongly 
controlled at 2.5% (1-sided), with 0.25% initially allocated to 
ORR (H1), 0.1% to PFS (H2), and 2.15% to OS (H3).
By using the graphical approach of Maurer and Bretz [Maurer, 
W. and Bretz, F. 2013], if one hypothesis is rejected, the alpha 
will be shifted to other hypotheses as described in Section 9.8.
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Sample Size and 
Power
As of Amendment 05, the IA3 and final analysis of the study 
described in the SAP will not be performed.
The planned sample size is approximately 500 participants. 
There will be 350 participants randomized with at least 
6 months of follow-up at the ORR final analysis. The study has 
90.4% power for detecting a 20-percentage point difference 
between treatment arms with an underlying 20% response rate 
in the control arm at an initially assigned 0.0025 (1-sided) 
significance level.
It is estimated that there will be ~ 432 events at the PFS final 
analysis (ie, IA2 of the study). With 432 PFS events, the study 
has >99.9% power for detecting a hazard ratio of 0.5 at an 
initially assigned 0.001 (1-sided) significance level. 
There will be ~ 361 deaths at the OS final analysis. With 
361 deaths, the study has ~90.7% power for detecting a hazard 
ratio of 0.7 at an initially assigned 0.0215 (1-sided) significance 
level. 
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.
After efficacy IA2, the study was unblinded on 16-AUG-2023.
This study will be conducted as a double-blinded study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Sponsor will generate the randomized allocation schedule for study treatment 
assignment for this protocol and the randomization will be implemented in IVRS/IWRS.
The investigator and the study team at the Sponsor consisting of clinical, statistical, statistical 
programming and data management personnel will be blinded to participant-level PD-L1 
biomarker score. An unblinded Sponsor statistician and unblinded Sponsor statistical 
programmer will have access to the participant-level PD-L1 results for the purpose of data 
review and will have no other responsibilities associated with the study. A summary of PD 
L1 biomarker prevalence may be provided to the study team at the Sponsor by the unblinded 
Sponsor statistician. In addition, the independent radiologist(s) will perform the central 
imaging review without knowledge of treatment group assignment.  
Blinding issues related to the planned interim analyses are described in Section 9.7.  
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9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0 – Hypotheses, Objectives 
and Endpoints.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
Primary
•
Objective Response Rate
The ORR is defined as the percentage of participants who achieve a confirmed complete
response or partial response per RECIST 1.1 as assessed by BICR.
•
Progression-free Survival
PFS is defined as the time from randomization to the first documented disease progression 
per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. See Section 
9.6.1 – Statistical Methods for Efficacy Analyses for definition of censoring.
•
Overall Survival
OS is defined as the time from randomization to death due to any cause.
Secondary
•
Duration of Response
For participants who show confirmed CR or PR, duration of response is defined as the time 
from the first documented evidence of CR or PR until disease progression or death due to any 
cause, whichever occurs first.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2 – Safety Endpoints and Section 8 –
Study Assessments and Procedures. Safety and tolerability will be assessed by clinical 
review of all relevant parameters including AEs, laboratory tests and vital signs. Safety 
parameters to be analyzed include, but are not limited to, AEs, SAEs, fatal AEs, and 
laboratory changes.
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9.4.3
Patient-Reported Outcome Endpoints
Changes from baseline in the global health status/quality of life and physical functioning 
scores of the EORTC QLQ-C30 will be evaluated as overall measures of HRQoL. Additional 
details of the PRO endpoints, including analyses of the remaining functioning and symptom 
scores of the EORTC QLQ-C30 and EORTC QLQ-H&N35 and health status scores of the 
EQ-5D-5L, will be described in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The ITT population will serve as the population for the primary efficacy analyses. For the 
analyses of ORR, approximately the first 350 or more randomized participants will be 
included in the analysis population. For the analyses of PFS and OS, all randomized 
participants will be included in the ITT population. For the analyses of DOR, the subset of 
participants who show a confirmed complete response or partial response will be included in 
the analysis population. Participants will be included in the treatment group to which they are 
randomized.
9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study treatment. Participants will be included 
in the treatment group corresponding to the study treatment they actually received for the 
analysis of safety data using the APaT population. This will be the treatment group to which 
they are randomized except for participants who take incorrect study treatment for the entire 
treatment period; such participants will be included in the treatment group corresponding to 
the study treatment actually received.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
Patient-Reported Outcome Analysis Populations
The PRO analyses are based on the PRO FAS population, defined as participants who have at 
least 1 PRO assessment available for the specific endpoint and have received at least 1 dose 
of the study intervention.
9.5.4
Population Pharmacokinetic Analysis Set
No pharmacokinetic endpoints are planned for this study.
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9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
NOTE: As of Amendment 05, the prespecified IA3 and final analysis of the study described 
in the SAP will not be performed. Safety analysis will be performed at the end of the study; 
there will be no further planned analyses of efficacy and ePRO endpoints. Original protocol 
text that is contained in this section has been retained for reference.
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 9.8, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses but should be interpreted with caution due to 
potential issues of multiplicity and sample size.
The stratification factors used for randomization (see Section 6.3.2 - Stratification) will be 
applied to all stratified analyses, in particular, the stratified log-rank test, stratified Cox 
model, and stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 
1985]. If there are small strata, for the purpose of analysis, strata will be combined to ensure 
sufficient number of participants, responses or events in each stratum. Details regarding the 
pooling strategy will be prespecified in the sSAP before the database lock for the first 
efficacy interim analysis, and decisions regarding the pooling will be based on a blinded 
review of response and event counts by stratum.
9.6.1.1
Objective Response Rate
The stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] will 
be used for comparison of the ORR between two treatment groups. The difference in ORR 
and its 95% confidence interval from the stratified Miettinen and Nurminen method with 
strata weighting by sample size will be reported. The stratification factors used for 
randomization (See Section 6.3.2 - Stratification) will be applied to the analysis. The point 
estimate of ORR will be provided by treatment group, together with 95% CI using exact 
binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, E. S. 
1934]. Supportive analyses may be performed for comparison of ORR based on 
investigator’s assessment.
9.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, hazard ratio) between the 
treatment arms. The hazard ratio and its 95% confidence interval from the stratified Cox 
model with Efron’s method of tie handling and with a single treatment covariate will be 
reported. The stratification factors used for randomization (See Section 6.3.2 - Stratification) 
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will be applied to both the stratified log-rank test and the stratified Cox model. Supportive 
analyses may be performed for comparison of PFS based on investigator’s assessment.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is considered a PD event.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment before the missed visits. In addition, any participant who initiates new anticancer 
therapy will be censored at the last disease assessment before the initiation of new anticancer 
therapy. Participants who do not start new anticancer therapy and who do not experience an 
event will be censored at the last disease assessment. If a participant meets multiple criteria 
for censoring, the censoring criterion that occurs earliest will be applied.  
To evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 2 sensitivity 
analyses with different sets of censoring rules will be performed. The first sensitivity analysis 
follows the intention-to-treat principle. That is, PDs/deaths are counted as events regardless 
of missed study visits or initiation of new anticancer therapy. The second sensitivity analysis 
considers discontinuation of treatment due to reasons other than complete response or 
initiation of new anticancer treatment, whichever occurs later, to be a PD event for 
participants without documented PD or death. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied. The censoring rules for 
the primary and sensitivity analyses are summarized in Table 9.
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Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
PD or death documented 
immediately after 
≥2 consecutive missed 
disease assessments or 
after new anticancer 
therapy, if any
Censored at last 
disease assessment 
before the earlier date 
of ≥2 consecutive 
missed disease 
assessment and new 
anticancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last 
disease assessment 
Censored at last disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study treatment.
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last 
disease assessment 
before new anticancer 
treatment 
Censored at last disease 
assessment
Progressed at date of new 
anticancer treatment
Abbreviations: PD = disease progression; PFS = progression-free survival.
9.6.1.3
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The stratification factors used for randomization (See Section 6.3.2 - Stratification) 
will be applied to both the stratified log-rank test and the stratified Cox model. Participants 
without documented death at the time of analysis will be censored at the date the participant 
was last known to be alive.
9.6.1.4
Duration of Response
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed complete response or 
partial response will be included in this analysis. 
Censoring rules for DOR are summarized in Table 10. 
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For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer treatment, have not been determined to be lost to follow-up, 
and have had a disease assessment within ~5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.     
Table 10
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anticancer 
therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anticancer 
therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(non-event)
Death or progression immediately after ≥2 
consecutive missed disease assessments or 
after new anticancer therapy, if any
Earlier date of last adequate disease 
assessment before ≥2 missed 
adequate disease assessments and 
new anticancer therapy, if any
Censor
(non-event)
Death or progression after ≤ 1 missed disease 
assessments and before new anticancer 
therapy, if any
PD or death
End of response
(Event)
Abbreviations: DOR = duration of response; PD = disease progression.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation 
of response.  
9.6.1.5
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 11.
Table 11
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
ORR per RECIST 
1.1 by BICR
Testing and estimation:
stratified Miettinen and 
Nurminen method
ITT
Participants with missing data are 
considered nonresponders
PFS per RECIST 
1.1 by BICR
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling 
method 
ITT
Censored according to rules in 
Table 9
OS
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling 
method
ITT
Censored at participant’s last 
known alive date
Abbreviations: BICR = blinded independent central review; ITT = intent-to-treat; ORR = objective response rate; 
OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors.
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The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 9.7 (Interim Analyses) and Section 9.8 (Multiplicity).
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests and vital signs.
The analysis of safety results will follow a tiered approach (Table 12). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory and 
vital signs parameters are either prespecified as “Tier 1” endpoints or will be classified as 
belonging to “Tier 2” or “Tier 3” based on the observed proportions of participants with an 
event.
Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be participant to inferential testing for statistical 
significance. AEs that are immune-mediated or potentially immune-mediated are well 
documented and will be evaluated separately; however, these events have been characterized 
consistently throughout the pembrolizumab clinical development program, and determination 
of statistical significance is not expected to add value to the safety evaluation. Finally, there 
are no known AEs associated with participants with HNSCC for which determination of a p-
value is expected to impact the safety assessment. Thus, there are no AEs that warrant 
elevation to Tier 1 in this study.   
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group show 
the event; all other AEs will belong to Tier 3. The threshold of at least 10% of participants 
was chosen for Tier 2 events because the population enrolled in this study is in critical 
condition and usually experiences various AEs of similar types regardless of treatment; 
events reported less frequently than 10% of participants would obscure the assessment of the 
overall safety profile and add little to the interpretation of potentially meaningful treatment 
differences. In addition, Grade 3 to 5 AEs (≥5% of participants in 1 of the treatment groups), 
SAEs (5% of participants in 1 of the treatment groups) and tumor hemorrhage (incidence ≥4 
of participants in one of the treatment groups) will be considered Tier 2 endpoints. Because 
many 95% CIs may be provided without adjustment for multiplicity, the CIs should be 
regarded as a helpful descriptive measure to be used in safety review, not as a formal method 
for assessing the statistical significance of the between-group differences.
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Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, any drug-related AE, any 
Grade 3 to 5 AE, any serious AE, any AE which is both drug-related and Grade 3 to 5, any 
AE which is both serious and drug-related, discontinued due to an AE, and death that are not 
prespecified as Tier 1 endpoints will be classified as belong to “Tier 3”. Laboratory test 
toxicity grade shift from baseline will be considered Tier 3 event. Only point estimates by 
treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
Continuous measures such as changes from baseline in vital signs parameters will be 
considered Tier 3 event. Summary statistics for baseline, on-treatment, and change from 
baseline values will be provided by treatment group for vital signs parameters.
Table 12
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific Grade 3-5 AE (incidence ≥5% of 
participants in one of the treatment groups)
X
X
Specific serious AE (incidence ≥5% of participants 
in one of the treatment groups)
X
X
Specific AEs, SOCs (incidence ≥10% of 
participants in one of the treatment groups)
X
X
Tumor hemorrhage (incidence ≥ 4 of participants in 
one of the treatment groups) 
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence > 0% of participants 
in all of the treatment groups)
X
Change from Baseline Results (lab toxicity shift, 
vital signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class.
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses
Details of PRO analyses will be described in the sSAP.
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9.6.4
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
NOTE: As of Amendment 05, the prespecified IA3 and final analysis of the study described 
in the SAP will not be performed. This section is retained for reference.
Access to the allocation schedule for summaries or analyses for presentation to the eDMC 
will be restricted to an unblinded statistician and an unblinded scientific programmer 
performing the interim analysis, who will have no other responsibilities associated with the 
study.  
The eDMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or modification to the executive 
oversight committee of the Sponsor. If the eDMC recommends modifications to the design of 
the protocol or discontinuation of the study, this executive oversight committee and 
potentially other limited Sponsor personnel may be unblinded to results at the treatment level 
to act on these recommendations. The extent to which individuals are unblinded with respect 
to results of interim analyses will be documented by the unblinded team. Additional logistic 
details will be provided in the eDMC Charter.  
Treatment-level results of the interim analysis will be provided by the unblinded statistician 
to the eDMC. Before final study unblinding, the unblinded statistician will not be involved in 
any discussions regarding modifications to the protocol or statistical methods, identification 
of protocol deviations, or data validation efforts after the interim analyses.
9.7.1
Efficacy Interim Analyses
Three interim analyses are planned in addition to the final analysis for this study. Interim 
Analysis 1 will include at least 350 participants with 6 months of follow-up, and the other 
interim analyses and final analysis will include all randomized participants. Results of the 
interim analyses will be reviewed by the DMC. Details of the boundaries for establishing 
statistical significance with regards to efficacy are discussed further in Section 9.8.
The analyses planned, endpoints evaluated, and drivers of timing are summarized in Table 
13.
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Table 13
Summary of Interim and Final Analyses Strategy
Analyses 
Key 
Endpoints 
Timinga
Estimated Time 
after First 
Participant 
Randomized 
Primary Purpose of 
Analysis
IA1
ORR
PFS
At least 350 participants 
randomized with ~ 6 months 
of follow-up 
~ 24 months
Final ORR analysis
Interim PFS analysis
IA2
PFS
OS
Both ~ 432 PFS events have 
occurred and ~ 6 months after 
last participant randomized
~ 30 months
Final PFS analysis
Interim OS analysis
IA3
OS
Both ~ 326 deaths have 
occurred and ~ 14 months after 
last participant randomized
~ 38 months
Interim OS analysis
FA
OS
Both ~ 361 deaths have 
occurred and ~ 20 months after 
last participant randomized
~ 44 months
Final OS analysis
Abbreviations: FA = final analysis; IA1 = interim analysis 1; IA2 = interim analysis 2; IA3 = interim analysis 3; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
a
For IA2, IA3 and FA, if the events accrue slower than expected, the analysis can be delayed up to 3 months after the 
projected timing, ie, the Sponsor may conduct IA2, IA3 and FA when all participants have been followed up for 9, 
17 months and 23 months, respectively.
9.7.2
Safety Interim Analysis
The eDMC was responsible for periodic interim safety reviews as specified in the DMC 
charter. Details were included in the DMC charter. Safety monitoring will continue as per 
protocol. 
9.8
Multiplicity
NOTE: As of Amendment 05, the prespecified IA3 and final analysis of the study described 
in the SAP will not be performed. Original protocol text that is contained in this section has 
been retained for reference.
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
control multiplicity for multiple hypotheses as well as interim analyses. According to this 
approach, study hypotheses may be tested more than once, and when a particular null 
hypothesis is rejected, the α allocated to that hypothesis can be reallocated to other 
hypothesis tests. Figure 6 shows the initial 1-sided α allocation for each hypothesis in the 
ellipse representing the hypothesis. The weights for re-allocation from each hypothesis to the 
others are shown in the boxes on the lines connecting hypotheses.
The overall Type-I error is strongly controlled at 0.025 (1-sided) for the 3 primary endpoints 
ORR, PFS and OS. The initial α assigned to ORR, PFS, and OS will be 0.0025, 0.001 and 
0.0215, respectively. If the PFS hypothesis is rejected, the corresponding alpha can be 
reallocated to OS. If the OS hypothesis is rejected, the corresponding alpha can be 
reallocated to PFS. If ORR hypothesis is rejected, the corresponding alpha can be reallocated 
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to PFS. If both the OS and PFS hypotheses are rejected, the corresponding alpha can be 
reallocated to ORR.
Figure 6
Multiplicity Diagram for Type I Error Control
Abbreviations: ORR = objective response rate; OS = overall survival; PFS = progression-free survival.
9.8.1
Objective Response Rate
The study will test ORR only once at IA1, at an initial α level of 0.0025 (Figure 6). Note that 
if superiority for both the PFS and OS hypotheses is declared at a future planned analysis, 
α=0.0225 will be rolled over to the hypothesis for ORR, then the test statistics previously 
computed at IA1 for the ORR hypothesis will be used for inferential testing with an updated 
alpha level of 0.025.
Based on the first 350 randomized participants with at least 6 months of follow-up, power at 
the possible α-levels as well as the approximate treatment difference required to reach the 
bound (ΔORR) are shown in Table 14, assuming underlying 20% and 40% response rates in 
the control and experimental groups, respectively.
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Table 14
Possible α Levels (One-Sided) and Approximate ORR Difference Required to 
Show Efficacy for Objective Response at IA1
α (One-Sided)
~Δ ORR
Power
0.0025
0.1327
0.904
0.025
0.0901
0.985
Abbreviation: ORR = objective response rate.
9.8.2
Progression-free Survival
The study will test PFS at IA1 and IA2 only. After the multiplicity strategy as outline in 
Figure 6, the PFS hypothesis may be tested at α=0.001 (initially allocated α), at α=0.0035 (if 
the ORR null hypothesis is rejected but not the OS hypothesis), at α=0.0225 (if the OS null 
hypothesis is rejected but not the ORR hypothesis), or at α=0.025 (if both the OS and ORR 
null hypotheses are rejected). For the superiority hypothesis, a Lan-DeMets O’Brien-Fleming 
alpha spending function is used to construct group sequential boundaries to control the Type-
I error rate. Table 15 shows the boundary properties for each of these α levels for the PFS 
analysis. Note that the final row indicates the total power to reject the null hypothesis for PFS 
at each α level. Also, note that if the OS null hypothesis is rejected at IA3 or FA of the study, 
the previously computed PFS test statistics may be used for inferential testing with its 
updated bounds, considering the α reallocation from the OS hypothesis.
For the PFS hypothesis H2, IA2 will be the final PFS analysis with a target number of events 
of 432. The bounds provided in Table 15 are based on the assumption that the number of 
events at IA1 and IA2 are 350 and 432, respectively. At the time of an analysis, the observed 
number of events may differ substantially from the expected. To avoid overspending at IA1 
and keep reasonable alpha for the IA2, the minimum alpha spending strategy will be adopted. 
At IA1, the information fraction used in Lan-DeMets spending function to determine the 
alpha spending at the IA will be based on the minimum of the expected information fraction 
and the actual information fraction at the analysis.
•
In the scenario that the event accumulation is faster than expected, ie, if the number of 
observed events exceeds the expected number of events at IA1, then the information 
fraction will be calculated as the expected number of events at IA1 over the target 
number of events at IA2. 
•
In the scenario that the event accumulation is slower than expected and number of events 
is less than the expected number of events in the table when IA1 is conducted, the 
information fraction will be calculated as the actual number of events at IA1 over the 
target number of events at IA2. 
The final PFS analysis will use the remaining Type I error that was not spent at the earlier 
analysis. The p-value bound at the final PFS analysis will be calculated by considering the 
correlation between the test statistics as determined by the actual number of PFS events at 
IA1 and IA2 of the study.  
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Table 15
Efficacy Boundaries and Properties for Progression-free Survival Analyses
Analysis
Value
α=0.001
α=0.0035
α=0.0225
α=0.025
IA1: 81%*
N = 500 
Events: 350 
Month: 24
Z
3.4757
3.0428
2.2833
2.2344
p (1-sided) a
0.0003
0.0012
0.0112
0.0127
HR at boundb
0.6893
0.7221
0.7832
0.7873
P(Cross) if HR=1c
0.0003
0.0012
0.0112
0.0127
P(Cross) if HR=0.5d
0.9988
0.9997
1.0000
1.0000
IA2
N = 500
Events: 432
Month: 30
Z
3.1149
2.7327
2.0698
2.0276
p (1-sided) a
0.0009
0.0031
0.0192
0.0213
HR at boundb
0.7408
0.7686
0.8193
0.8226
P(Cross) if HR=1c
0.0010
0.0035
0.0225
0.0250
P(Cross) if HR=0.5d
1.0000
1.0000
1.0000
1.0000
Abbreviations: HR = hazard ratio; IA = interim analysis.
The number of events and timings are estimated approximately. 
*Percentage of the target number of events at final analysis anticipated at interim analysis
a
p (1-sided) is the nominal α for testing.
b
HR at bound is the approximate HR required to reach an efficacy bound.
c
P(Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
d
P(Cross if HR=0.5) is the probability of crossing a bound under the alternative hypothesis.
9.8.3
Overall Survival
The study will test OS at IA2, IA3 and FA. After the multiplicity strategy as outlined in 
Figure 6 the OS hypothesis may be tested at α=0.0215 (initially allocated α), or α=0.0225 (if 
the PFS null hypothesis is rejected but not the ORR hypothesis), or α=0.025 (if both the PFS 
and ORR null hypotheses are rejected). For the superiority hypothesis, a Lan-DeMets 
O’Brien-Fleming alpha spending function is used to construct group sequential boundaries to 
control the Type I error rate. Table 16 shows the boundary properties for each of these α 
levels for the OS analysis. The bounds provided in the table are based on the assumption that 
the number of events at IA2, IA3 and FA are 258, 326 and 361, respectively. At the time of 
an analysis, the observed number of events may differ substantially from the expected. To 
avoid overspending at an interim analysis and keep reasonable alpha for the final analysis, 
the minimum alpha spending strategy will be adopted. At an IA, the information fraction 
used in Lan-DeMets spending function to determine the alpha spending at the IA will be 
based on the minimum of the expected information fraction and the actual information 
fraction at each analysis.
•
In the scenario that the event accumulation is faster than expected, ie, if the number of 
observed events exceeds the expected number of events at an interim analysis, then the 
information fraction will be calculated as the expected number of events at the interim 
analysis over the target number of events at FA. 
•
In the scenario that the event accumulation is slower than expected and number of events 
is less than the expected number of events in the table when an interim analysis is 
conducted, the information fraction will be calculated as the actual number of events at 
the interim analysis over the target number of events at FA. 
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The final OS analysis will use the remaining Type I error that has not been spent at the earlier 
analyses. The event counts for all analyses will be used to compute correlations.
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at each analysis over the target 
number of events at FA.
Table 16
Efficacy Boundaries and Properties for Overall Survival Analyses
Analysis
Value
α=0.0215
α =0.0225
α =0.025
IA2: 71%* 
N = 500
Events: 258
Month: 30
Z 
2.4857
2.4636
2.4120
p (1-sided)a
0.0065
0.0069
0.0079
HR at boundb
0.7334
0.7355
0.7403
P(Cross) if HR=1c
0.0065
0.0069
0.0079
P(Cross) if HR=0.7d
0.6476
0.6557
0.6747
IA3: 90%* 
N: 500
Events: 326 
Month: 38
Z 
2.2091
2.1901
2.1457
p (1-sided)a
0.0136
0.0143
0.0159
HR at boundb
0.7828
0.7845
0.7884
P(Cross) if HR=1c
0.0155
0.0163
0.0183
P(Cross) if HR=0.7d
0.8509
0.8553
0.8655
FA 
N: 500
Events: 361 
Month: 44 
Z 
2.1297
2.1119
2.0702
p (1-sided)a
0.0166
0.0173
0.0192
HR at boundb
0.7991
0.8006
0.8042
P(Cross) if HR=1c
0.0215
0.0225
0.0250
P(Cross) if HR=0.7d
0.9070
0.9100
0.9169
Abbreviations: FA = final analysis; HR = hazard ratio; IA = interim analysis.
The number of events and timings are estimated approximately. 
*Percentage of the target number of events at final analysis anticipated at interim analysis.
a
p (1-sided) is the nominal α for testing.
b
HR at bound is the approximate HR required to reach an efficacy bound.
c
P(Cross if HR=1) is the probability of crossing a bound under the null hypothesis.
d
P(Cross if HR=0.7) is the probability of crossing a bound under the alternative hypothesis.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal. Given 
the probabilities derived with the proposed spending method, the correlations based on actual 
event counts are used to compute bounds that control the Type I error at the specified alpha 
level for a given hypothesis conditioned on the interim analysis timing. Since this is true 
regardless of what is conditioned on, the overall Type I error for a given hypothesis 
unconditionally is controlled at the specified level. By using more conservative spending 
early in the study, power can be retained to detect situations where the treatment effect may 
be delayed.
9.8.4
Safety Analyses
The DMC has responsibility for assessment of overall risk/benefit. When prompted by safety 
concerns, the DMC can request corresponding efficacy data. DMC review of efficacy data to 
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assess the overall risk/benefit to study participants will not require a multiplicity adjustment 
typically associated with a planned efficacy interim analysis. However, to account for any 
multiplicity concerns raised by the DMC review of unplanned efficacy data prompted by 
safety concerns, a sensitivity analysis for ORR, PFS and OS adopting a conservative 
multiplicity adjustment will be prespecified in the sSAP.
9.9
Sample Size and Power Calculations
NOTE: As of Amendment 05, the prespecified IA3 and final analysis of the study described 
in the SAP will not be performed. This section is retained for reference.
The study will randomize 500 participants in a 1:1 ratio into the pembrolizumab + lenvatinib 
arm and pembrolizumab + placebo arm. ORR, PFS and OS are primary endpoints for the 
study.
Based on the 350 participants with at least 6 months of follow-up, the power of the ORR 
testing at the initially allocated α=0.0025 (1-sided) is approximately 90.4% to detect a 20-
percentage point difference between an underlying 20% response rate in the control arm and 
a 40% response rate in the experimental arm.
For the PFS endpoint, based on a target number of 432 events at the final analysis and 1 
interim analysis at approximately 81% of the target number of events, the study has 
approximately >99.9% power to detect a hazard ratio of 0.5 at the initially allocated α=0.001 
(1-sided). 
For the OS endpoint, based on a target number of 361 events and 2 interim analyses at 
approximately 71% and 90% of the target number of events, the study has approximately 
90.7% power to detect a hazard ratio of 0.7 at the initially allocated α=0.0215 (1-sided).
Based on [Burtness, B., et al 2018], the above sample size and power calculations for PFS 
and OS assume the following:
•
PFS follows an exponential distribution with a median of 3 months for the control group. 
•
OS follows an exponential distribution with a median of 12 months for the control group. 
•
Enrollment period of 24 months with enrollment ramp-up over first 6 months. 
•
An annual dropout rate of 5% for PFS and OS.
•
A follow-up period of 6 and 20 months for PFS and OS, respectively, after the last 
participant is randomized. 
The sample size and power calculations were performed using R (“gsDesign” package) and 
SAS 9.4.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for ORR, PFS and OS (with a nominal 95% CI) will be 
estimated and plotted by treatment group within each category of the following subgroup 
variables:
•
Stratification factors 
-
PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (TPS <50% 
vs. ≥50%)
-
HPV status for oropharynx cancer as determined by p16 immunohistochemistry 
(positive vs. negative); HPV status for participants without oropharynx cancer (eg, 
cancers of the oral cavity, hypopharynx and larynx) is considered HPV negative.
-
ECOG performance status (0 vs. 1)
•
Age category (<65 years, ≥65 years)
•
Sex (female, male)
•
Race (white, all others)
•
Geographic region (North America, European Union, Asia, Rest of the World)
•
PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (CPS <50 vs. 
≥50)
A forest plot will be produced, which provides the estimated point estimates and confidence 
intervals for the treatment effect across the categories of subgroups listed above. If the 
number of participants in a category of a subgroup variable is less than 10% of the ITT 
population, the subgroup analysis will not be performed for this category of the subgroup 
variable, and this subgroup variable will not be displayed in the forest plot. The subgroup 
analyses for PFS and OS will be conducted using an unstratified Cox model, and the 
subgroup analyses for ORR will be conducted using the unstratified Miettinen and Nurminen 
method.
9.11
Compliance (Medication Adherence)
Drug accountability data for trial 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 the number of cycles and number of days in 
which the participant receives the study intervention. Summary statistics will be provided on 
the extent of exposure for the overall study intervention, and for pembrolizumab and 
lenvatinib separately for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the 
safety and effectiveness of our products. As such, we are committed to designing, 
implementing, conducting, analyzing, and reporting these trials in compliance with 
the highest ethical and scientific standards. Protection of participants in clinical trials 
is the overriding concern in the design and conduct of clinical trials. In all cases, 
MSD clinical trials will be conducted in compliance with local and/or national 
regulations (including all applicable data protection regulations), and International 
Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of 
Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial. Participants must meet 
protocol entry criteria to be enrolled in the trial.
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2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate 
participants, adequacy of facilities and staff, previous performance in clinical 
trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess 
the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
fraud, scientific/research misconduct or serious GCP-non-compliance is 
suspected, the issues are investigated. When necessary, the clinical site will be 
closed, the responsible regulatory authorities and ethics review committees 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations. Changes to the protocol that are required urgently to eliminate 
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an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible. Unless required by law, only the investigator, Sponsor (or individuals acting 
on behalf of MSD), ethics committee, and/or regulatory authorities will have access 
to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on chart review and medical evaluation to identify 
potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide 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, frequently 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
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be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
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
The following committees will have responsibilities regarding this protocol:
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with an 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.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
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way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 Interim 
Analysis) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical 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 trials 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.
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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, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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, 
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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.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 17 will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Table 17
Protocol-required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with differentiala:
   Neutrophils
   Lymphocytes
   Monocytes
   Eosinophils
   Basophils
RBC Indices:
   MCVb
   MCHb
   %Reticulocytesb
RBC Count
Hemoglobin
Hematocrit
Chemistry
Albumin
Blood Urea 
Nitrogen (BUN) c
Creatinine d
Potassium
Glucose
Calcium
Sodium
Magnesium
Amylase
Lipase
Total bilirubin 
(and direct 
bilirubin if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic 
Oxaloacetic 
Transaminase 
(SGOT)
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic Pyruvic 
Transaminase 
(SGPT)
Alkaline 
phosphatase
Total Proteinb
Bicarbonateb
Chlorideb
Phosphorousb
Thyroid Function 
Tests
Thyroid-
stimulating 
hormone (TSH)
Triiodothyronine 
(total T3)e
Free thyroxine 
(FT4)
Coagulation f
International normalized ratio (INR) or 
prothrombin time (PT)
Activated partial thromboplastin time 
(aPTT) g
Routine 
Urinalysis
Specific gravity
pH, glucose, proteinh, blood, ketones, by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
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) (if required by local health authority)
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Laboratory 
Assessments
Parameters
NOTES:
a
Absolute Neutrophil Count (ANC) is required at Screening to confirm eligibility. After Screening, absolute or % 
acceptable per institutional standard.  
b
Performed only if considered local standard of care.
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
Free T3 is acceptable where total T3 cannot be determined. 
f
Refer to Section 6.6.2.2 for additional testing/monitoring required for proteinuria.
g
PTT may be performed if the local laboratory is unable to perform aPTT 
h
Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulants
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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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.”
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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 the cancer under study).
•
Is associated with an overdose.
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Note: A semi-colon indicates ‘or’ within the description of the grade.
Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
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•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the 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
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb
IUSc
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
Male condom with cap, diaphragm, or sponge with spermicide.
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable 
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Canada
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.
Section 6.6.2.9
Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any participant who develops gastrointestinal 
perforation of any grade or ≥Grade 3 fistula.
10.7.2
China
Section 1.1 Synopsis and Section 1.2 Schema
Participants in China will continue participation this trial until all regulatory commitments 
have been met. Upon completion of all regulatory requirements, participants in China are to 
be discontinued and may be enrolled in an extension study using pembrolizumab in 
combination with compound (eg, lenvatinib) if available.
Section 4.1 Overall Design
After enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. 
Section 8.8 Biomarkers
Biomarker sample collection for participants enrolled in China will be dependent on approval 
by the Human Genetic Resources Administration of China
10.7.3
Germany
In Germany, the assessment that is in line with the standard of care is the ECHO scan. 
Therefore, in Germany, the participating sites will perform an ECHO scan as required per 
protocol. In the clinical study, the MUGA scan is not allowed in Germany as no German 
Federal Office for Radiation Protection BfS (Bundesamt für Strahlenschutz) approval has
been obtained for this assessment.
10.7.4
Japan
Section 6.1 Study Intervention(s) Administered
Table 4 – Study Interventions
Pembrolizumab IV used in this study is categorized as “product(s) used in the clinical trial 
other than test product(s)” in Japan local regulation.
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10.7.5
UK
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.
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.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable.
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10.9
Appendix 9: ECOG Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ACCP
American College of Chest Physicians
ADA
antidrug antibodies
ADL
activities of daily living
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
antiretroviral therapy
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
BICR
blinded independent central review
bid
twice daily
BMI
body mass index
BP
blood pressure
CAC
Clinical Adjudication Committee
CCU
Cardiac care unit
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CF
compact flash
CG
Cockcroft-Gault
CHS
cough hypersensitivity syndrome
CI
confidence interval
Cmax
maximum plasma concentration
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Abbreviation
Expanded Term
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CPS
combined positive score
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form
CRU
clinical research unit
CSD
Cough Severity Diary
C-SSRS
Columbia-Suicide Severity Rating Scale
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
CYP
cytochrome P450
DAIDS
Division of AIDS
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
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Abbreviation
Expanded Term
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
ePROs
electronic patient-reported outcomes
E-R
exposure response
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-Stimulating Factor
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HRQoL
health-related quality of life
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Abbreviation
Expanded Term
HRT
hormone replacement therapy
HSSB
Hepatic-specific Safety Board
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug
IO
Immune oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
ITP
idiopathic thrombocytopenic purpura
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWG
International Working Group
IWRS
integrated web response system
JRCT
Japan Registry of Clinical Trials
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Abbreviation
Expanded Term
KPS
Karnofsky performance status
LAM
lactational amenorrhea method
LCQ
Leicester Cough Questionnaire
LLN
lower limit of normal
LLOQ
lower limit of quantitation
mAb
monoclonal antibody
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NCS
not clinically significant
NEAB
noneosinophilic bronchitis
NDA
New Drug Application
NOAEL
no observed adverse effect level
OR
objective response
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over the counter
PBPK
physiologically based PK
PCL
Protocol Clarification Letter
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography
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Abbreviation
Expanded Term
PFS
progression free survival
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PP
per-protocol
PQC
product quality complaint
PR
partial response
PRO
patient-reported outcome
Q2W
every 2 weeks
Q3W
every 3 weeks
QoL
quality of life
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RCC
refractory chronic cough
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
rP2D
recommended Phase 2 dose
RR
respiratory rate
SAC
Scientific Advisory Committee
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transminase
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
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Abbreviation
Expanded Term
STING
stimulator of interferon genes
SUSAR
suspected unexpected serious adverse reaction
SVR12
sustained viral response
TEA
Treatment Eligibility Assessment (form)
Tmax
time to maximum plasma concentration
TMDD
target-mediated drug disposition
t½
half life
UACS
upper airway cough syndrome
UCC
unexplained chronic cough
UDS
urine drug screen
ULN
upper limit of normal
URTI
upper respiratory tract infection
UTN
Universal Trial Number
Vd
volume of distribution
VAS
Visual Analog Scale
VS
vital signs
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
ZAP70
zeta-chain-associated protein kinase
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11
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