Clinical trial NCT02720068
Conditions: Neoplasms
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2) Lymphocyte-activation gene 3 (LAG3, LAG-3, CD223)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-05-02; Completion date: 2024-03-15
Enrollment: 481 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a safety and pharmacokinetics study of favezelimab as monotherapy and in combination with pembrolizumab AND favezelimab/pembrolizumab as monotherapy in adults with metastatic solid tumors for which there is no available therapy which may convey clinical benefit. Part A of this study is a dose escalation design in which participants receive favezelimab as monotherapy or favezelimab in combination with pembrolizumab. Part B is a dose confirmation design to estimate the recommended Phase 2 dose (RP2D), as determined by dose-limiting toxicity, for favezelimab in combination with pembrolizumab or pembrolizumab and lenvatinib in participants with advanced solid tumors. Part B will also assess the efficacy of favezelimab as monotherapy; favezelimab in combination with pembrolizumab with and without chemotherapy; favezelimab in combination with pembrolizumab and lenvatinib; and favezelimab/pembrolizumab as monotherapy in expansion cohorts. Participants who have completed the initial course of treatment and have investigator-determined progressive disease may be eligible for a second course of an additional 17 cycles of study treatment.

Detailed description:
All participants who completed the first course were eligible for second course treatment after Sponsor consultation if there was investigator-determined progressive disease after initial treatment had been been completed.

Arms: arm 1: Participants received favezelimab 7 mg intravenous (IV) infusion on Day 1 of each 21-day cycle. arm 2: Participants received favezelimab 21 mg IV infusion on Day 1 of each 21-day cycle. arm 3: Participants received favezelimab 70 mg IV infusion on Day 1 of each 21-day cycle. arm 4: Participants received favezelimab 210 mg IV infusion on Day 1 of each 21-day cycle. arm 5: Participants received favezelimab 700 mg IV infusion on Day 1 of each 21-day cycle. arm 6: Participants received favezelimab 7 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 7: Participants received favezelimab 21 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 8: Participants received favezelimab 70 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 9: Participants received favezelimab 210 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 10: Participants received favezelimab 700 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 11: Participants received favezelimab 800 mg monotherapy IV infusion on Day 1 of each 21-day cycle. arm 12: Participants received favezelimab 200 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 13: Participants received favezelimab 700 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 14: Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle. arm 15: Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle PLUS mFOLFOX7 (oxaliplatin 85 mg/m\^2 IV, leucovorin \[calcium folinate\] 400 mg/m\^2 IV, and fluorouracil \[5-FU\] 2400 mg/m\^2 IV over 46 to 48 hours, every 2 weeks \[Q2W\]). arm 16: Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle PLUS FOLFIRI (irinotecan 180 mg/m\^2 IV, leucovorin \[calcium folinate\] 400 mg/m\^2 IV and 5-FU 2400 mg/m\^2 IV over 46 to 48 hours, Q2W). arm 17: Participants received MK-4280A, a coformulation of favezelimab 800 mg + pembrolizumab 200 mg IV infusion on Day 1 of each 21-day cycle. arm 18: Participants received favezelimab 800 mg IV infusion on Day 1 of each 21-day cycle PLUS pembrolizumab 200 mg IV infusion administered sequentially on Day 1 of each 21-day cycle PLUS oral lenvatinib 20 mg once daily.
Interventions: intervention 1: Favezelimab intervention 2: Pembrolizumab intervention 3: Oxaliplatin intervention 4: Irinotecan intervention 5: Leucovorin (Calcium Folinate) intervention 6: Fluorouracil [5-FU] intervention 7: Favezelimab/Pembrolizumab intervention 8: Lenvatinib
Intervention descriptions: intervention 1: IV infusion intervention 2: IV infusion intervention 3: IV infusion intervention 4: IV infusion intervention 5: IV infusion intervention 6: IV infusion intervention 7: IV infusion intervention 8: Oral

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1 Trial of MK-4280 as Monotherapy
and in Combination with Pembrolizumab with or
without Chemotherapy or Lenvatinib
(E7080/MK-7902) in Subjects with Advanced
Solid Tumors
NCT02720068
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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 1 Trial of MK-4280 as Monotherapy and in Combination with Pembrolizumab with 
or without Chemotherapy or Lenvatinib (E7080/MK-7902) in Subjects with Advanced Solid 
Tumors
IND NUMBER:  128624
EudraCT NUMBER:  2017-001464-38
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 13
SUMMARY OF CHANGES................................................................................................ 15
1.0
TRIAL SUMMARY.................................................................................................. 19
2.0
TRIAL DESIGN........................................................................................................ 21
Trial Design ........................................................................................................... 21
Part A .................................................................................................................. 21
Part B .................................................................................................................. 22
Trial Diagram........................................................................................................ 24
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 26
Primary Objective(s) & Hypothesis(es).............................................................. 26
Secondary Objective(s) & Hypothesis(es)........................................................... 26
Exploratory Objectives......................................................................................... 27
4.0
BACKGROUND & RATIONALE.......................................................................... 29
Background ........................................................................................................... 29
Pharmaceutical and Therapeutic Background .................................................... 29
MK-4280 Background ................................................................................. 29
Pembrolizumab (MK-3475) Background .................................................... 29
Lenvatinib Background................................................................................ 30
Pembrolizumab Plus Lenvatinib Background ............................................. 31
Rationale................................................................................................................ 32
Rationale for the Trial and Selected Subject Population .................................... 32
Rationale for Arm 3 and Arm 4 – Combining MK-4280 and 
Pembrolizumab With Either mFOLFOX7 or FOLFIRI .............................. 33
Rationale 
for 
MK-4280A 
–
Co-formulated 
MK-4280 
and 
Pembrolizumab............................................................................................ 35
Rationale for Arm 6 – Combining MK-4280 and Pembrolizumab With 
Lenvatinib in CRC....................................................................................... 35
Rationale for Dose Selection/Regimen/Modification......................................... 36
Starting Dose for This Trial......................................................................... 36
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4.2.2.1.1
Rationale for MK-4280 Dose ............................................................... 36
4.2.2.1.2
Rationale for Preliminary RP2D (200 mg) and Additional MK-
4280 Dose (800 mg) ............................................................................. 38
4.2.2.1.3
Rationale for Pembrolizumab Dose...................................................... 39
4.2.2.1.4
Rationale for MK-4280A Dose and Biocomparability Study .............. 40
4.2.2.1.5
Rationale for mFOLFOX7 and FOLFIRI Doses .................................. 40
4.2.2.1.6
Rationale for Lenvatinib Dose.............................................................. 40
DLTs and AEs for Part A............................................................................. 41
DLTs for the Combination of Pembrolizumab With mFOLFOX7 or 
FOLFIRI ...................................................................................................... 41
Maximum Dose/Exposure for This Trial..................................................... 41
Rationale for Endpoints ...................................................................................... 41
Efficacy Endpoints....................................................................................... 41
Safety Endpoints.......................................................................................... 43
Pharmacokinetic Endpoints ......................................................................... 43
4.2.3.3.1
Biocomparability Endpoints ................................................................. 44
Pharmacodynamic Endpoints....................................................................... 44
4.2.3.4.1
Target Engagement: Receptor Availability of Cell Surface LAG-3..... 44
4.2.3.4.2
Antidrug Antibodies ............................................................................. 44
Serum Cytokines.......................................................................................... 44
Planned Exploratory Biomarker Research................................................... 45
Planned Genetic Analysis ............................................................................ 46
Future Biomedical Research........................................................................ 47
Benefit/Risk ........................................................................................................... 47
5.0
METHODOLOGY ................................................................................................... 47
Entry Criteria........................................................................................................ 47
Diagnosis/Condition for Entry into the Trial...................................................... 47
Subject Inclusion Criteria.................................................................................... 48
Subject Exclusion Criteria .................................................................................. 53
Trial Treatment(s) ................................................................................................ 56
Part A – Dose Escalation of Arm 1 (MK-4280 Monotherapy) and Arm 2 
(MK-4280 + Pembrolizumab)............................................................................. 59
Part B – Dose Confirmation and Efficacy Expansion Cohorts........................... 60
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Arm 1 MK-4280 Monotherapy.................................................................... 60
Arm 2 – MK-4280 + Pembrolizumab.......................................................... 60
5.2.2.2.1
Dose Confirmation Using TPI in Subjects With HNSCC or CRC 
(Arm 2A)............................................................................................... 60
5.2.2.2.2
Adaptive Efficacy Expansion Cohorts (Arm 2A)................................. 60
5.2.2.2.3
PD-1/PD-L1-treatment-failure HNSCC Cohort (Arm 2A) .................. 61
5.2.2.2.4
Dose Finding in Subjects With Gastric Cancer (Arm 2A and 2B)....... 61
5.2.2.2.5
Additional MK-4280 Dose in Part B (Arm 2C) ................................... 61
Arm 
3 
and 
Arm 
4 
–
MK-4280 
+ 
Pembrolizumab 
+ 
mFOLFOX7/FOLFIRI................................................................................. 61
Arm 5 – MK-4280A..................................................................................... 61
Arm 6 – MK-4280 + Pembrolizumab + Lenvatinib .................................... 62
Dose Selection/Escalation................................................................................... 62
Dose Selection (Preparation) ....................................................................... 62
3+3 Dose Escalation Design........................................................................ 62
Dose Confirmation – Arm 2A...................................................................... 64
Dose Confirmation – Arm 3 and Arm 4 ...................................................... 65
Dose Confirmation – Arm 6 ........................................................................ 65
Definition of Dose Limiting Toxicity................................................................. 66
Timing of Dose Administration.......................................................................... 67
Dose Modification (Escalation/Titration/Other)................................................. 67
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 68
Dose Modification and Toxicity Management of AEs Related to 
mFOLFOX7 or FOLFIRI ............................................................................ 74
Dose Modification with Lenvatinib............................................................. 75
5.2.6.3.1
Management of Hypertension............................................................... 76
5.2.6.3.2
Management of Proteinuria .................................................................. 78
5.2.6.3.3
Management of Diarrhea ...................................................................... 79
5.2.6.3.4
Management of Hepatotoxicity ............................................................ 79
5.2.6.3.5
Management of Thromboembolic Events............................................. 79
5.2.6.3.6
Management 
of 
Posterior 
Reversible 
Encephalopathy 
Syndrome/Reversible 
Encephalopathy 
Syndrome/ 
Reversible 
Posterior Leukoencephalopathy Syndrome .......................................... 79
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5.2.6.3.7
Management of Hypocalcemia ............................................................. 80
5.2.6.3.8
Management of Hemorrhage ................................................................ 80
5.2.6.3.9
Management of Gastrointestinal Perforation or Fistula Formation...... 80
5.2.6.3.10 Management of QT Prolongation ......................................................... 80
5.2.6.3.11 Management of Osteonecrosis of the Jaw ............................................ 80
Dose Modifications for Overlapping Toxicities .......................................... 80
Other Allowed Dose Interruptions............................................................... 82
Crossover Criteria ............................................................................................... 82
Second Course of Study Treatment .................................................................... 82
Trial Blinding...................................................................................................... 83
Randomization or Treatment Allocation............................................................ 83
Stratification.......................................................................................................... 83
Concomitant Medications/Vaccinations (Acceptable & Prohibited)............... 83
Acceptable Concomitant Medications/Procedures ............................................. 83
Prohibited Concomitant Medications/Procedures............................................... 84
Lenvatinib Drug Interactions .............................................................................. 85
Rescue Medications & Supportive Care............................................................. 85
Supportive Care Guidelines ................................................................................ 85
Diet/Activity/Other Considerations..................................................................... 86
Diet...................................................................................................................... 86
Lifestyle Restrictions .......................................................................................... 86
Contraception...................................................................................................... 86
Use in Pregnant Women ..................................................................................... 86
Use in Nursing Women....................................................................................... 86
Subject Withdrawal/Discontinuation Criteria................................................... 87
Subject Replacement Strategy............................................................................. 88
Beginning and End of the Trial ........................................................................... 88
Clinical Criteria for Early Trial Termination ................................................... 89
6.0
TRIAL FLOW CHART ........................................................................................... 90
Part A - Arm 1 and Arm 2; Part B - Arm 1, Arm 2A, Arm 2B, Arm 2C, 
and Arm 5 Flow Chart ......................................................................................... 90
Part B - Arm 3 and Arm 4 Flow Chart............................................................... 96
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Part B – Arm 6 Flow Chart................................................................................ 103
Crossover Flow Chart ........................................................................................ 109
Second Course - Part A - Arm 1 and Arm 2; Part B - Arm 1, Arm 2A , 
Arm 2B, Arm 2C, and Arm 5 Flow Chart........................................................ 112
Second Course - Part B - Arm 3 and Arm 4 Flow Chart................................ 115
Second Course - Part B – Arm 6 Flow Chart................................................... 119
7.0
TRIAL PROCEDURES ......................................................................................... 123
Trial Procedures ................................................................................................. 123
Administrative Procedures................................................................................ 123
Informed Consent....................................................................................... 123
7.1.1.1.1
General Informed Consent.................................................................. 123
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................. 124
Inclusion/Exclusion Criteria ...................................................................... 124
Subject Identification Card ........................................................................ 124
Medical History ......................................................................................... 124
Prior and Concomitant Medications Review............................................. 124
7.1.1.5.1
Prior Medications................................................................................ 124
7.1.1.5.2
Concomitant Medications................................................................... 125
Assignment of Screening Number............................................................. 125
Assignment of Treatment/Randomization Number................................... 125
Trial Compliance (Medication/Diet/Activity/Other)................................. 125
Administration of Study Treatments.......................................................... 126
Disease Details and Treatments................................................................. 127
7.1.1.10.1 Disease Details.................................................................................... 127
7.1.1.10.2 Prior Oncology Treatment History ..................................................... 127
Clinical Procedures/Assessments...................................................................... 127
Adverse Event Monitoring......................................................................... 127
Full Physical Exam .................................................................................... 127
Vital Signs, Height, and Weight ................................................................ 128
Eastern Cooperative Oncology Group (ECOG) Performance Status ........ 128
Electrocardiogram...................................................................................... 128
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Echocardiogram or Multiple Gated Acquisition Scan............................... 129
Pregnancy Testing...................................................................................... 129
Disease Assessments.................................................................................. 130
Tumor Tissue Collection and Biomarker Assessment............................... 131
Laboratory Procedures/Assessments ................................................................ 131
Laboratory Evaluations (Hematology, Chemistry, and Urinalysis)........... 131
Pharmacokinetic/Pharmacodynamic Evaluations...................................... 133
7.1.3.2.1
Blood Collection for Analysis ............................................................ 133
Planned Genetic Analysis Sample Collection............................................ 133
Future Biomedical Research Sample Collection ....................................... 133
Other Procedures............................................................................................... 133
Withdrawal/Discontinuation...................................................................... 133
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................. 134
Blinding/Unblinding .................................................................................. 134
Calibration of Equipment........................................................................... 134
Visit Requirements............................................................................................ 134
Screening.................................................................................................... 134
Treatment Visit Period............................................................................... 135
Post-Trial.................................................................................................... 135
7.1.5.3.1
Safety Follow-up Visit........................................................................ 135
7.1.5.3.2
Survival Follow-up ............................................................................. 135
Survival Status ........................................................................................... 136
Assessing and Recording Adverse Events ........................................................ 136
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor........................................................................................................ 137
Definitions of Medication Error, Misuse, and Abuse................................ 138
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 138
Immediate Reporting of Adverse Events to the Sponsor.................................. 138
Serious Adverse Events ............................................................................. 138
Events of Clinical Interest.......................................................................... 139
Evaluating Adverse Events............................................................................... 140
Sponsor Responsibility for Reporting Adverse Events .................................... 143
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TRIAL GOVERNANCE AND OVERSIGHT................................................. 143
Scientific Advisory Committee......................................................................... 143
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 143
Statistical Analysis Plan Summary ................................................................... 143
Responsibility for Analyses/In-House Blinding ............................................... 145
Hypotheses/Estimation....................................................................................... 145
Analysis Endpoints ............................................................................................. 145
Efficacy/Immunogenicity/Pharmacokinetics Endpoints................................... 145
Safety Endpoints ............................................................................................... 146
Derivations of Safety Endpoints ....................................................................... 146
Analysis Populations........................................................................................... 146
Safety Analysis Populations ............................................................................. 146
Pharmacokinetic Analysis Populations............................................................. 146
Efficacy Analysis Populations .......................................................................... 146
Statistical Methods.............................................................................................. 147
Statistical Methods for Safety Analyses ........................................................... 147
Statistical Methods for Efficacy Analyses........................................................ 147
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 148
Demographic and Baseline Characteristics ............................................... 148
Pharmacokinetics and Pharmacodynamics Modeling Analysis ................ 148
Statistical Methods for Biocomparability Analyses ......................................... 148
Interim Analyses ................................................................................................. 149
Multiplicity .......................................................................................................... 150
Sample Size and Power Calculations ................................................................ 150
Dose Escalation and Dose Confirmation .......................................................... 150
Precision of the DLT Rate at Preliminary RP2D.............................................. 151
Efficacy Expansion ........................................................................................... 152
Pharmacokinetic Comparison Between MK-4280A (Co-formulated Product) 
and MK-4280 and Pembrolizumab Administered Sequentially ....................... 154
Subgroup Analyses ............................................................................................. 154
Compliance (Medication Adherence)................................................................ 154
Extent of Exposure.............................................................................................. 155
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9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 155
Investigational Product ...................................................................................... 155
Packaging and Labeling Information ............................................................... 156
Clinical Supplies Disclosure............................................................................... 156
Storage and Handling Requirements................................................................ 156
Discard/Destruction/Returns and Reconciliation ............................................ 156
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 156
Confidentiality..................................................................................................... 156
Confidentiality of Data ..................................................................................... 156
Confidentiality of Subject Records................................................................... 157
Confidentiality of Investigator Information...................................................... 157
Confidentiality of IRB/IEC Information........................................................... 157
Compliance with Financial Disclosure Requirements..................................... 157
Compliance with Law, Audit and Debarment ................................................. 158
Compliance with Trial Registration and Results Posting Requirements...... 160
Quality Management System............................................................................. 160
Data Management............................................................................................... 160
Publications ......................................................................................................... 160
11.0
LIST OF REFERENCES....................................................................................... 162
12.0
APPENDICES......................................................................................................... 167
Code of Conduct for Clinical Trials.................................................................. 167
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 169
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 173
ECOG Performance Status................................................................................ 184
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 185
List of Abbreviations and Definitions of Terms............................................... 186
Country-specific Requirements......................................................................... 190
China................................................................................................................. 190
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Japan ................................................................................................................. 190
Germany............................................................................................................ 192
Section 6.3  Part B – Arm 6 Flow Chart........................................................... 193
Canada............................................................................................................... 193
Contraceptive Guidance..................................................................................... 194
Definitions......................................................................................................... 194
Contraception Requirements............................................................................. 195
13.0
SIGNATURES......................................................................................................... 196
Sponsor's Representative ................................................................................... 196
Investigator.......................................................................................................... 196
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LIST OF TABLES
Table 1
Pharmacokinetic Parameter Estimates Obtained in Cynomolgus Monkeys and 
Parameter Estimates Used in Prediction of Human Exposure to MK-4280 .......... 37
Table 2
Adequate Organ Function Laboratory Values........................................................ 51
Table 3
Trial Treatments ..................................................................................................... 57
Table 4
Dose Confirmation Rules ....................................................................................... 64
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations...................................................................... 70
Table 6
Pembrolizumab and MK-4280 (or MK-4280A) Infusion Reaction Dose 
Modification and Treatment Guidelines................................................................. 73
Table 7
Dose Modification Guidelines for Lenvatinib-Related Adverse Events................ 75
Table 8
Laboratory Tests................................................................................................... 132
Table 9
Evaluating Adverse Events .................................................................................. 141
Table 10 Operating Characteristics of Interim Analysis Rule for Each Tumor Type......... 149
Table 11 Operating Characteristics of Interim Analysis Rule for Determining Conduct 
of Gastric Cancer Monotherapy Cohort ............................................................... 150
Table 12 Precision of the Estimated DLT Rates at MK-4280 Plus Pembrolizumab 
RP2D .................................................................................................................... 152
Table 13 Precision of the Estimated DLT Rates at MK-4280 Plus Pembrolizumab Plus 
Either mFOLFOX7 or FOLFIRI RP2D ............................................................... 152
Table 14 Estimate and 95% CI of ORR (N=40).................................................................. 152
Table 15 Estimate and 95% CI of ORR (N=60).................................................................. 153
Table 16 Estimate and 95% CI of ORR (N=100)................................................................ 153
Table 17 Product Descriptions ............................................................................................ 155
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LIST OF FIGURES
Figure 1
Study Design....................................................................................................... 25
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DOCUMENT HISTORY
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
CCI
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
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1.0 TRIAL SUMMARY
Abbreviated 
Title
Phase 1 Trial of MK-4280 as Monotherapy and in Combination with Pembrolizumab
with or without Chemotherapy or Lenvatinib (E7080/MK-7902) in Subjects with 
Advanced Solid Tumors
Sponsor Product 
Identifiers
MK-4280
Pembrolizumab
MK-4280A
Lenvatinib
Trial Phase
Phase 1b
Clinical 
Indication
Treatment of subjects with advanced solid tumors
Trial Type
Interventional
Type of control
None
Route 
of 
administration
Intravenous (MK-4280, pembrolizumab, and MK-4280A)
Oral (lenvatinib)
Trial Blinding
Unblinded Open-label
Treatment 
Groups
During Part A of the study, subjects will be allocated by nonrandom assignment to 1
of 2 treatment arms:
Arm 1: MK-4280 (escalating doses) as monotherapy
Arm 2: MK-4280 (escalating doses) in combination with pembrolizumab (200 mg 
fixed dose every 3 weeks [Q3W])
Part B will be a dose confirmation of MK-4280 in combination with pembrolizumab. 
Additionally, expansion cohorts will assess the antitumor efficacy of MK-4280 as 
monotherapy and in combination with pembrolizumab with or without chemotherapy
or lenvatinib. Part B will consist of 6 treatment arms and 7 cohorts:
Arm 1: MK-4280 (800 mg Q3W) as monotherapy
Arm 2A: MK-4280 (200 mg Q3W) in combination with pembrolizumab (200 mg 
Q3W)
Arm 2B: MK-4280 (700 mg Q3W) in combination with pembrolizumab (200 mg 
Q3W)
Arm 2C: MK-4280 (800 mg Q3W) in combination with pembrolizumab (200 mg 
Q3W)
Arm 3: MK-4280 (800 mg Q3W) + pembrolizumab (200 mg Q3W) + mFOLFOX7
(oxaliplatin [85 mg/m2], leucovorin [calcium folinate, 400 mg/m2], fluorouracil 
[5-FU, 2400 mg/m2 over 46 to 48 hours] every 2 weeks [Q2W])
Arm 4: MK-4280 (800 mg Q3W) + pembrolizumab (200 mg Q3W) + FOLFIRI
(irinotecan [180 mg/m2], leucovorin [calcium folinate, 400 mg/m2], 5-FU 
[2400 mg/m2 over 46 to 48 hours] Q2W)
Arm 5: MK-4280A (800 mg MK-4280 + 200 mg pembrolizumab Q3W)
Arm 6: MK-4280 (800 mg Q3W) + pembrolizumab (200 mg Q3W) + lenvatinib 
(20 mg QD)
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Cohort A: 3L+ CRC (PD-1-treatment naïve)
Cohort B: 1L or 2L CRC (PD-1-treatment naïve)
Cohort C: HNSCC (PD-1-treatment naïve)
Cohort D: HNSCC (PD-1-treatment failure)
Cohort E: Gastric Cancer (PD-1-treatment naïve)
Cohort F: Chinese subjects from mainland China with advanced solid tumors
Note: Chinese subjects from mainland China (Cohort F) will not enroll in Cohorts 
A through E or Cohort G.
Cohort G: 3L CRC (PD-1-treatment naïve)
Number of trial 
subjects
Approximately 576 subjects will be enrolled.
Estimated 
duration of trial
The Sponsor estimates that the trial will require approximately 7 years from the time 
the first subject (or their legally acceptable representative) provides documented 
informed consent until the last subject’s last study-related contact.
Duration 
of 
Participation
Each subject will participate in the study from the time the subject provides 
documented informed consent through the final contact. After a screening phase of up 
to 28 days, study treatment will begin on Day 1 of each 3-week cycle and will
continue for up to 35 cycles. Treatment in all parts and arms of the study will continue 
until disease progression, unacceptable adverse event(s) (AEs), intercurrent illness 
that prevents further administration of treatment, the investigator’s decision to 
withdraw treatment, subject withdrawal of consent, pregnancy of the subject, subject 
completion of 35 cycles of treatment, or administrative reasons requiring cessation of 
treatment. Subjects in Arm 1 of Part B may be allowed to crossover to Arm 2C
following confirmed disease progression per irRECIST 1.1. Treatment with the 
combination therapy will then continue until further disease progression, unacceptable 
AEs, intercurrent illness that prevents further administration of treatment, the 
investigator’s decision to withdraw treatment, subject withdrawal of consent, 
pregnancy of the subject, subject completion of 35 cycles of treatment, or 
administrative reasons requiring cessation of treatment. For subjects in Arm 6, 
pembrolizumab and MK-4280 treatment will be discontinued once the subject has 
received 35 cycles (approximately 2 years). Subjects experiencing clinical benefit, 
according to the PI, may continue treatment with lenvatinib beyond 2 years with 
Sponsor consultation and approval. After the end of treatment (EOT), subjects in 
Arm 1 of both parts will be followed for 30 days for recording of AEs and serious 
adverse events (SAEs). Subjects in Arms 2 (both parts), 3, 4, 5, or 6 will be followed 
for 30 days after the EOT for recording of AEs and 90 days for the recording of SAEs 
(or 30 days if the subject initiates new anticancer therapy). After documented disease 
progression, subjects will be contacted approximately every 12 weeks for survival 
until withdrawal of consent to participate in the trial, becoming lost to follow-up, 
death, or the end of the study, whichever occurs first.
Randomization 
Ratio
In Part A and all cohorts of Part B besides the gastric cancer cohort (Cohort E), 
subjects are allocated to their particular treatment arm without randomization. In 
Cohort E of Part B, subjects are randomized at a 1:1 ratio to 1 of 2 doses of MK-4280
(200 mg [Arm 2A] or 700 mg [Arm 2B]) in combination with a fixed dose of 
pembrolizumab.
Allocation to Arm 3 or Arm 4 will be guided by a subject’s 
eligibility for one arm or the other or, if eligible for both arms, will be determined by 
investigator choice.  If Arms 1, 2C and 5 for 3L+ CRC subjects are enrolling at the 
same time, subjects will be assigned in an alternating fashion across the open arms at 
the study level through IVRS. Cohort F of Part B is only open to sites in China and 
these subjects will be assigned to Arm 5 only.
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A list of abbreviations used in this document can be found in Appendix 12.6.
2.0 TRIAL DESIGN
Trial Design
This is a multisite, open-label, dose-escalation study of MK-4280 monotherapy (Part A, 
Arm 1) and MK-4280 in combination with pembrolizumab (Part A, Arm 2) followed by both 
nonrandomized and randomized dose confirmation of MK-4280 in combination with
pembrolizumab along with efficacy evaluations of MK-4280 as monotherapy and in 
combination with pembrolizumab with or without chemotherapy or lenvatinib (also known as 
E7080 or MK-7902; hereafter referred to as lenvatinib) (Part B) in subjects with a 
histologically or cytologically confirmed diagnosis of advanced solid tumors.
This trial will use an adaptive design based on the pre-specified criteria of dose limiting 
toxicity (DLT). For dose escalation (Part A, Arm 1 and Arm 2), a 3+3 dose escalation design 
will be utilized (see Section 5.2 – Trial Treatments). For dose confirmation (Part B), the 
toxicity probability interval (TPI) design [1] will be utilized to refine the estimate of a 
preliminary RP2D from Part A, Arm 2. Additionally, Part B will compare the safety and 
antitumor efficacy of multiple doses of MK4280 in combination with pembrolizumab, the 
safety and efficacy of MK-4280 in combination with pembrolizumab and chemotherapy, and 
the safety and efficacy of MK-4280 in combination with pembrolizumab and lenvatinib.
Part A
In Part A, Arm 1 (MK-4280 monotherapy), the study will begin with a 3+3 design to identify 
a preliminary maximum tolerated dose (MTD) or maximum administered dose (MAD), as 
described in Section 5.2.1. During 3+3 dose escalation in both arms of Part A, an initial 
cohort of 3 subjects will be enrolled to a dose level. If none of the 3 subjects experiences a 
DLT during the first 21 day cycle, escalation to the next dose will occur. If 1 of the 3 subjects 
experiences a DLT, another 3 subjects will be enrolled at this dose level. If 1 DLT is 
observed among the 6 subjects, the dose escalation will continue. If more than 1 of 3 or more 
than 1 of 6 subjects at a dose level develop DLTs, dose escalation will be terminated, and the 
study will proceed at the previous dose level. At least 2 days of observation will occur 
between each of the first 3 subjects in the first 2 dose levels.
Treatment in Part A, Arm 2 (MK-4280 in combination with pembrolizumab) will begin with 
a 3+3 design to identify a preliminary RP2D for Part B. The starting dose of MK-4280 will 
be at least 1 dose level below that being tested in Part A, Arm 1. A fixed dose of 200 mg 
pembrolizumab will be used in Part A, Arm 2. During 3+3 dose escalation, at least 2 days of 
observation will occur between each of the first 3 subjects at the first 2 dose levels. Please 
note that intrasubject dose escalation is not allowed for any part of this study.
Enrollment to both arms of Part A will occur sequentially. The higher dose level cohort of 
Part A, Arm 1 must be fully enrolled and all subjects must begin dosing before Part A, Arm 2
is dosed. For example, the 70 mg MK-4280 monotherapy cohort must be fully enrolled and 
all subjects must have begun dosing before the 21 mg MK-4280 + 200 mg pembrolizumab 
cohort initiates recruitment and dosing. Doses of MK-4280
in combination
with 
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pembrolizumab will be at least 1 dose level behind the monotherapy dose, and would not 
exceed the MTD or MAD of Part A, Arm 1. However, once the MTD or MAD for Part A, 
Arm 1 is established, the dose of MK-4280 in Part A, Arm 2 may continue escalation up to 
that dose. For enrollment to the last 2 dose levels of Arm 2, all 3 (or 6) subjects in the second 
highest dose level must complete 1 cycle of treatment and DLT evaluation before the highest 
dose level may begin enrollment.
Part B
In Part B, dose confirmation and preliminary antitumor efficacy will be assessed in subjects 
with colorectal cancer (CRC) that have progressed on all available standard-of-care therapies
(Cohort A), that have received 1 or fewer lines of treatment (Cohort B), or that have received 
2 lines of treatment (Cohort G), PD-1-treatment-naïve head and neck squamous cell cancer 
(HNSCC, Cohort C), PD-1-treatment-failure HNSCC (Cohort D), and gastric cancer (Cohort 
E). A TPI design will be used to refine the estimate of tolerability of the preliminary RP2D of 
MK-4280 administered in combination with pembrolizumab identified in Part A (Arm 2A, 
200 mg), using the first 14 subjects enrolled in Arm 2A (Cohorts A, C or D). The safety, PK, 
and preliminary efficacy of MK-4280A, a co-formulated product of 800 mg MK-4280 and 
200 mg pembrolizumab, will be assessed in subjects with CRC in the US (Cohort A) and 
Chinese subjects with advanced solid tumors in mainland China (Cohort F) enrolled in Arm 
5. The combination of MK-4280, pembrolizumab, and lenvatinib will be evaluated in 
subjects with 3L CRC (Cohort G) in Arm 6.
Cohort A will enroll subjects with microsatellite stable (MSS) CRC that are naïve to prior 
PD-1/PD-L1 therapy and that have progressed on all available standard-of-care therapies. 
MK-4280 antitumor efficacy will be tested as monotherapy (Arm 1), in combination with 
pembrolizumab (Arm 2A and 2C), and as a coformulation (MK-4280A, Arm 5). 
Monotherapy MK-4280 (Arm 1) will be administered at a dose of 800 mg in up to 20 
subjects. In Arm 2, up to 100 subjects may be treated with the combination of 200 mg MK-
4280 plus pembrolizumab (Arm 2A), and approximately 40 subjects will be treated with the 
combination of 800 mg MK-4280 plus pembrolizumab (Arm 2C). Forty subjects in Cohort A 
will also be enrolled to assess the safety, PK, and preliminary efficacy of MK-4280A, a co-
formulated product of 800 mg MK-4280 and pembrolizumab (Arm 5). The biocomparability 
of MK-4280A to the sequential administration of MK-4280 and pembrolizumab will also be 
assessed.
Cohort B will enroll subjects with MSS CRC naïve to prior PD-1/PD-L1 therapy that have 
progressed on ≤ 1 prior line of therapy. Cohort B will test the antitumor efficacy of MK-4280 
(800 mg) administered in combination with pembrolizumab and mFOLFOX7 (up to 20 
subjects, Arm 3) or FOLFIRI (up to 20 subjects, Arm 4). A TPI design will be used to assess 
the safety and tolerability of these triplet combinations in the first 14 subjects treated with 
each combination. If a de-escalation is called for by TPI, the dose of mFOLFOX7 or 
FOLFIRI will be reduced—the doses of MK-4280 and pembrolizumab will remain fixed.
Cohort C will enroll up to 40 subjects with HNSCC that are naïve to prior PD-1/PD-L1 
therapy and have progressed after ≥1 prior line of chemotherapy. Subjects will receive 200
mg MK-4280 in combination with pembrolizumab (Arm 2A) to evaluate antitumor efficacy.
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Cohort D will enroll up to 20 subjects with HNSCC that have progressed (defined in 
Section 5.1.2 – Subject Inclusion Criteria) following prior anti-PD-1/PD-L1 therapy. 
Subjects will receive 200 mg MK-4280 in combination with pembrolizumab (Arm 2A) to 
evaluate antitumor efficacy.
Cohort E will enroll up to 80 subjects with gastric adenocarcinoma that are naïve to prior 
PD-1/PD-L1 therapy and that have progressed on ≥1 prior line of chemotherapy. Cohort E
will employ a randomized comparison of 2 doses of MK-4280 (200 mg [Arm 2A] and 700
mg [Arm 2B]) in combination with a fixed dose of pembrolizumab. This cohort will initiate 
enrollment only after the dose confirmation of the first 14 subjects in Cohorts A, C and D
have completed. Additionally, if antitumor activity is observed in Arm 2 of Cohort E (≥8 of 
40 subjects with an objective response, irrespective of dose) an additional 20 subjects with 
gastric cancer will be enrolled to receive MK-4280 (800 mg) monotherapy (Arm 1). If this 
predetermined ORR is not observed, the Sponsor will evaluate all available data before 
deciding whether to enroll these additional gastric cancer subjects in Arm 1 of Part B.
Cohort F will enroll up to 20 Chinese subjects from mainland China with advanced solid 
tumors for which there is no available therapy that may convey clinical benefit. Subjects will 
receive MK-4280A, a co-formulated product of 800 mg MK-4280 and 200 mg 
pembrolizumab, on Arm 5 to evaluate its safety and PK profile in Chinese subjects. Cohort F 
is only open to sites in China and these subjects will be assigned to Arm 5 only. Chinese 
subjects from mainland China will not enroll in Cohorts A through E or Cohort G.
Cohort G will enroll subjects with MSS CRC naïve to prior PD-1/PD-L1 therapy that have 
progressed on 2 prior lines of therapy. Cohort G will test the antitumor efficacy of MK-4280 
(800 mg) administered in combination with pembrolizumab and lenvatinib (up to 40 subjects, 
Arm 6). A TPI design will be used to assess the safety and tolerability of this triplet 
combination in the first 14 subjects treated. If a de-escalation is called for by TPI, the dose of 
lenvatinib will be reduced; the doses of MK-4280 and pembrolizumab will remain fixed.
For Part B Cohorts A and C (MSS CRC and PD-1/PD-L1 naïve HNSCC), the antitumor 
efficacy of 200 mg MK-4280 in combination with pembrolizumab (Arm 2A) will be 
examined using an adaptive expansion design. If an individual cohort experiences an 
objective response rate (ORR) of at least 20% in the first 10 subjects enrolled in Arm 2A (ie, 
at least 2 of 10 subjects) as assessed by response evaluation criteria in solid tumors 
(RECIST) 1.1 criteria, these cohorts will be expanded to enroll additional subjects. Arm 2A 
of Cohort A (MSS CRC) cohort may enroll a maximum of 90 additional subjects, for a 
maximum total of 100 subjects. Arm 2A of Cohort C (PD-1 naïve HNSCC cohort) may 
enroll a maximum of 30 additional subjects, for a maximum total of 40 subjects. 
Subjects with confirmed disease progression per irRECIST 1.1 in Arm 1 of Part B will be 
allowed to crossover to Arm 2C (Part B) and receive MK-4280 in combination with 
pembrolizumab. More details on crossover can be found in Section 5.2.7.
Specific details regarding the eligibility criteria for these tumor types can be found in Section 
5.1 – Entry Criteria.
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The final number of subjects enrolled in both parts of the study will depend on the DLT 
observations and, in particular, at what dose the 3+3 design is triggered and what dose is 
identified as the preliminary RP2D, and on which cohorts (if any) undergo expansion in 
Part B. For example, in Part A, the maximum sample size across Arm 1 and Arm 2 is 
60 subjects (30 subjects each). In Part B, the sample size for the dose confirmation and 
expansion phase of the study will be a maximum of 516 subjects assuming both the 
PD-1-treatment-naïve HNSCC and CRC adaptive cohorts are expanded, the gastric cancer 
cohort (Cohort E) of Arm 1 is opened, and if a de-escalation is needed for the mFOLFOX7,
FOLFIRI, and lenvatinib treatment arms. Therefore, the maximum total sample size across 
Part A and Part B is 576 subjects. See Section 8.9 – Sample Size and Power Calculations for 
alternate scenarios.
The trial will be conducted in conformance with Good Clinical Practices and the MSD Code 
of Conduct (Appendix 12.1). Adverse events will be evaluated according to criteria outlined 
in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Experiences (CTCAE), Version 4 (Appendix 12.5).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
The trial design is depicted in Figure 1.
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Figure 1
Study Design
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male/female subjects of at least 18 years-of-age with:
Part A, Arm 1 and Arm 2 - histologically or cytologically confirmed metastatic solid 
tumor for which there is no available therapy that may convey clinical benefit, or
Part B – histologically or cytologically confirmed diagnosis of 1 of the tumor types 
described in Section 5.1 – Entry Criteria.
Primary Objective(s) & Hypothesis(es)
1) Objective: To determine the safety and tolerability of MK-4280 monotherapy (for 
subjects in Part A, Arm 1 and Part B, Arm 1) and to establish a maximum tolerated 
dose (MTD) or maximum administered dose (MAD)
2) Objective: To determine the safety and tolerability of MK-4280 in combination with 
pembrolizumab (for subjects in Part A, Arm 2 and Part B, Arm 2A, 2B and 2C) and 
to establish a preliminary recommended Phase 2 dose (RP2D) for combination 
therapy
3) Objective: To determine the safety and tolerability and to establish a preliminary 
RP2D of MK-4280 in combination with pembrolizumab and mFOLFOX7 (Arm 3)
and of MK-4280 in combination with pembrolizumab and FOLFIRI (Arm 4) in 
subjects with MSS PD-1-treatment-naïve CRC that have received ≤1 line of prior 
therapy (Cohort B)
4) Objective: To determine the safety and tolerability of MK-4280 and pembrolizumab 
when administered as a co-formulated product (MK-4280A, Arm 5) and compare to 
the safety and tolerability of MK-4280 and pembrolizumab when administered 
sequentially (Part B subjects receiving MK-4280 800 mg plus pembrolizumab 200 
mg Q3W, Arm 2C) (Cohort A)
5) Objective: To determine the safety and tolerability of MK-4280 and pembrolizumab 
when administered as a co-formulated product in subjects in China (MK-4280A, Arm 
5, Cohort F)
6) Objective: To determine the safety and tolerability and to establish a preliminary 
RP2D of MK-4280 in combination with pembrolizumab and lenvatinib (Arm 6) in 
subjects with MSS PD-1-treatment-naïve CRC that have received 2 lines of prior 
therapy (Cohort G)
Secondary Objective(s) & Hypothesis(es)
1) Objective: To characterize the pharmacokinetic (PK) profile of MK-4280 in all 
subjects receiving MK-4280 alone, in combination with pembrolizumab, in 
combination with pembrolizumab and mFOLFOX7, in combination with 
pembrolizumab and FOLFIRI, and in combination with pembrolizumab and 
lenvatinib.
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2) Objective: To characterize the PK profile of pembrolizumab in all subjects receiving 
pembrolizumab in combination with MK-4280 with or without mFOLFOX7,
FOLFIRI, or lenvatinib
3) Objective: To characterize the PK profile of lenvatinib in subjects receiving 
lenvatinib in combination with MK-4280 and pembrolizumab
4) Objective: To evaluate the objective response rate (ORR) as determined by 
RECIST 1.1 as assessed by investigator review of MK-4280 alone and in 
combination with pembrolizumab for each tumor cohort in Part B separately
5) Objective: To evaluate the ORR as determined by RECIST 1.1 as assessed by 
investigator review of 2 doses of MK-4280 in combination with pembrolizumab for 
subjects with gastric cancer (Cohort E)
6) Objective: To evaluate the ORR as determined by RECIST 1.1 as assessed by 
investigator review of MK-4280 in combination with pembrolizumab and 
mFOLFOX7, and in combination with pembrolizumab and FOLFIRI in subjects with 
MSS PD-1-treatment-naïve CRC that have received ≤1 line of prior therapy (Cohort 
B)
7) Objective: To evaluate the ORR as determined by RECIST 1.1 as assessed by 
investigator review of MK-4280 in combination with pembrolizumab and lenvatinib 
in subjects with MSS PD-1-treatment-naïve CRC that have received 2 lines of prior 
therapy (Cohort G)
8) Objective: To compare the PK profile of MK-4280 when administered as a co-
formulated product with pembrolizumab (MK-4280A, Arm 5, Cohort A) and that 
when administered sequentially with pembrolizumab (Part B subjects receiving MK-
4280 800 mg plus pembrolizumab 200 mg Q3W, Arm 2C) (Cohort A)
9) Objective: To compare the PK profile of pembrolizumab when administered as a co-
formulated product with MK-4280 (MK-4280A, Arm 5, Cohort A) and that when 
administered sequentially with MK-4280 (Part B subjects receiving MK-4280 800 mg 
plus pembrolizumab 200 mg Q3W, Arm 2C) (Cohort A)
10) Objective: To characterize the PK profile of MK-4280 when administered as a co-
formulated product with pembrolizumab in subjects in China (MK-4280A, Arm 5, 
Cohort F)
11) Objective: To characterize the PK profile of pembrolizumab when administered as a 
co-formulated product with MK-4280 in subjects in China (MK-4280A, Arm 5, 
Cohort F)
Exploratory Objectives
CCI
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CCI
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4.0 BACKGROUND & RATIONALE
Background
Detailed background information on MK-4280, MK-4280A, and pembrolizumab is available 
in the Investigator’s Brochures (IBs) for MK-4280 and pembrolizumab.
Refer to the IB/approved labeling for detailed background information on lenvatinib.
Pharmaceutical and Therapeutic Background
MK-4280 Background
Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immune modulatory receptor that 
regulates effector T-cell homeostasis, proliferation, and activation, and has a role in the 
suppressor activity of regulatory T cells (Tregs). MK-4280 is a humanized IgG4 monoclonal 
antibody that antagonizes LAG-3. LAG-3 is expressed on activated CD8+ and CD4+ T cells, 
Tregs and the Tr1 regulatory T-cell population, as well as on natural killer cells and a subset of 
tolerogenic plasmacytoid dendritic cells. Because of its proposed role on both effector T cells 
and Tregs, LAG-3 is one of several immune checkpoint molecules where simultaneous 
blockade of both cell populations has the potential to enhance antitumor immunity.  
LAG-3 is structurally related to cluster of differentiation (CD) 4 and a member of the 
immunoglobulin (Ig) superfamily. Like CD4, its ligand is major histocompatibility complex 
(MHC) Class II molecules. Interaction with its ligand leads to dimerization and signal 
transduction resulting in altered T-cell activation. Following T-cell activation, LAG-3 is 
transiently expressed on the cell surface. A large proportion of LAG-3 molecules are found 
in intracellular stores and can be rapidly translocated to the cell membrane upon T-cell
activation. LAG-3 expression is regulated at the cell surface by extracellular cleavage to 
yield a soluble form of LAG-3 (sLAG-3), which can be detected in serum. Expression of 
LAG-3 is tightly regulated and represents a self-limiting mechanism to counter uncontrolled 
T-cell activity.
LAG-3 is commonly co-expressed with PD-1 on anergic/exhausted T cells, and both in vitro
and in vivo data indicate that dual blockade of LAG-3 and PD-1 can have a synergistic 
impact on reversing tumor-specific anergy. Indeed LAG-3 was selected as an initial target of 
interest based on published data indicating that the addition of an anti-LAG-3 antibody could 
enhance the activity of an anti-PD-1 antibody in rodent, preclinical tumor models. In addition 
to the data from preclinical models using anti-mouse antibodies, data from double knock-out 
mice (LAG-3-/-PD-1-/-) show the ability to resist growth of various tumor implants, indicating
a clear synergy between these molecules.
Pembrolizumab (MK-3475) Background
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 
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T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4
(CTLA-4) and has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [2], [3].
The structure of murine PD-1 has been resolved [4]. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig-variable-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 (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ) and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade 
[2], [5], [6], [7]. 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 [8], [9]. As a consequence, the PD-1/PD-L1 pathway is an attractive target 
for therapeutic intervention.
Lenvatinib Background
Angiogenesis, the formation of new blood vessels from a pre-existing vascular network, is 
essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its 
family of receptors (VEGF receptors [VEGFRs] 1-3) play a major role in tumor angiogenesis 
[10] [11] [12]. Accumulated evidence suggests that fibroblast growth factor (FGF) and its 
receptor tyrosine kinase, fibroblast growth factor receptor (FGFR) also play important roles 
for tumor angiogenesis [13] [14] [15]. 
Lenvatinib is a potent multiple receptor tyrosine kinase (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 human umbilical vein endothelial cell 
(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 mitogen-activated protein 
kinase (MAPK) pathway and the mTOR-S6K-S6 pathway in HUVECs triggered by activated 
VEGFR and FGFR. Furthermore, lenvatinib (10, 30 mg/kg) significantly inhibited both 
VEGF- and FGF-driven angiogenesis in a murine in vivo model [16]. 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), renal cell carcinoma (RCC), hepatocellular 
carcinoma (HCC), melanoma, gastric cancer, non-small cell lung cancer (NSCLC), ovarian 
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cancer, Ewing’s sarcoma, and osteosarcoma. In addition, the antitumor activity of lenvatinib 
in combination with other anticancer agents in several xenograft models was greater than that 
of lenvatinib or the other agents alone.
In summary, lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in HUVEC models. Antitumor activity of lenvatinib in vivo 
has been shown in numerous xenograft animals.  These results suggest that lenvatinib may be 
a novel anticancer therapy through inhibition of angiogenesis and may be useful as either 
monotherapy or in combination with other anticancer drugs.
Pembrolizumab Plus Lenvatinib Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [17]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis 
in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and 
long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
HCC; malignant melanoma; and RCC. Tumor-infiltrating lymphocytes can be expanded ex 
vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma 
[18] [19].
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 [20]. 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 [21]. 
All treatments were well tolerated and severe body weight loss was not observed.
An open-label, Phase 1b/2 study (KEYNOTE-146/Study E7080-A001-111) to assess the 
safety and preliminary antitumor activity of the combination of lenvatinib plus 
pembrolizumab in participants with selected solid tumors is currently ongoing. Phase 1b of 
this study determined the MTD and RP2D as 20 mg lenvatinib QD in combination with 
200 mg of pembrolizumab Q3W. The safety and efficacy of the combination at the lenvatinib 
RP2D is being assessed in the Phase 2 portion of the study that includes 6 cohorts (ie, 
NSCLC, RCC, endometrial carcinoma, urothelial carcinoma, melanoma, and HNSCC).
Based on results from the endometrial carcinoma cohort in KEYNOTE-146, pembrolizumab 
in combination with lenvatinib is indicated for the treatment of patients with advanced 
endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair 
deficient (dMMR), who have disease progression following prior systemic therapy and are 
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not candidates for curative surgery or radiation. This indication is approved under accelerated 
approval based on tumor response rate and durability of response [22].
Rationale
Rationale for the Trial and Selected Subject Population
MK-4280
is being developed for treatment of solid tumors. This trial is the 
first-in-human (FIH) trial designed to assess the safety, tolerability, antitumor efficacy, PK,
and pharmacodynamics of escalating doses of MK-4280 alone and in combination with 
pembrolizumab with or without chemotherapy or lenvatinib in subjects with advanced solid 
tumors. The specific tumor types for Part B were selected based on the expression of LAG-3,
the known response rates to anti-PD-1/PD-L1 monotherapy in these tumor types, unmet 
medical need, and preliminary efficacy data observed in Part A of the study.
HNSCC was chosen based on high expression of LAG-3, and known response to PD-1 
therapy. Both PD-1/PD-L1 inhibitor treatment-refractory (Cohort D) and naïve (Cohort C)
populations are being assessed. There is scientific evidence that the expression of alternate 
immune checkpoints including LAG-3 may increase after PD-1 blockade, promoting 
resistance to PD-1 therapy [23]. Co-blockade with LAG-3 and PD-1 may overcome 
resistance in some tumors. The intention of the PD-1 refractory cohort (Cohort D) is to 
determine if MK-4280 and pembrolizumab therapy can benefit patients that have progressed 
on prior PD-1 therapy. The intention of the PD-1 naïve HNSCC cohort (Cohort C) is to 
determine if MK-4280 and pembrolizumab therapy improves upon the response rates 
observed with pembrolizumab monotherapy in this population. Results from Keynote-055 
demonstrated an objective response rate of 18% in PD-1 naïve HNSCC patients that had 
progressed on at least 2 prior lines of therapy [24].
MSS CRC was chosen based on high expression of LAG-3, little to no responsiveness to 
PD-1 monotherapy, and high unmet medical need [25]. Response rates for regorafenib and 
TAS-102, approved agents in 3L CRC, have an OS benefit of 2 months compared to best 
supportive care and ~1-2% ORR. Regorafenib improved median OS to 6.4 months from 5.0 
months, and TAS-102 improved median OS to 7.1 months from 5.3 months [26] [27]. The 
intention of this cohort is to determine if MK-4280 plus pembrolizumab improves on the 
response rates observed for 3L standard of care therapies. 
Gastric cancer was chosen based on LAG-3 expression and intermediate responsiveness to 
PD-1 blockade with an ORR 11.2% in PD-L1 positive gastric cancer patients that had 
received at least 2 prior lines of therapy. 
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and ICF documents.
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Rationale for Arm 3 and Arm 4 – Combining MK-4280 and Pembrolizumab 
With Either mFOLFOX7 or FOLFIRI
Rationale for FOLFOX in CRC
FOLFOX have been established as SOC first-line and second-line chemotherapy options for 
mCRC; however, FOLFOX is more frequently used in the first-line setting.  Oxaliplatin 
combined with infusional 5-FU and leucovorin administered Q2W (FOLFOX) has been 
shown to be effective [28], and the mFOLFOX7 regimen is considered one of the SOC 
regimens for first-line line treatment of mCRC [29]. The most common AE overall was 
peripheral sensory neuropathy (PSN) (76.0%), followed by fatigue (70.9%), nausea (63.7%), 
diarrhea (53.6%), constipation (39.7%), and vomiting (31.3%); other AEs occurred in <30% 
of subjects. The most common SAE was neutropenia (16.7%), PSN (11.1%), diarrhea (8.3%), 
lymphopenia (2.8%), hypertension (2.8%), vomiting (2.8%), and fatigue (2.8%) [30]. 
Neutropenia/neutropenic fever is a known toxicity associated with mFOLFOX6 
chemotherapy and may be related to the 5-FU bolus for this regimen, which is known to be 
associated with myelosuppression. Hochster et al. reported 18.2% Grade 3/4 neutropenia with 
mFOLFOX7 (without 5-FU bolus), while FOLFOX regimens that contain 5-FU bolus 
reported significantly higher frequency of approximately 44% to 47% [30] [31] [32].  For this 
reason in KN651 and MK-4280-001, the Sponsor elected to use the mFOLFOX7 regimen, 
which lacks a 5-FU bolus and is associated with less neutropenia than mFOLFOX6.  
Rationale for FOLFIRI in CRC
FOLFIRI have been established as SOC first-line and second-line chemotherapy options for 
mCRC.  However, FOLFIRI is more frequently used in the second-line setting after 
oxaliplatin-based first-line therapies. Irinotecan combined with infusional 5-FU and 
leucovorin administered Q2W (FOLFIRI) has been shown to be more effective than when 
irinotecan is combined with bolus 5FU [33]. The regimen is considered one of the SOC 
regimens in second-line mCRC [29] and has also been shown to be effective in previously 
untreated patients [34]. For example, in the randomized Phase II/III FIRIS study comparing 
FOLFIRI vs irinotecan/S-1 (IRIS) in second-line treatment of mCRC, FOLFIRI was 
associated with ORR of 16.7% and median PFS of 5.1 months. The incidence of Grade 3 or 4 
neutropenia was 52.1%. The most common non-hematological toxicities were diarrhea 
(4.7%), anorexia (5.2%), nausea (4.3%), fatigue (3.3%), and febrile neutropenia (0.9%), all at 
Grade 3. One treatment-related death from hypotension due to shock was reported in the 
FOLFIRI group within 28 days after the end of treatment [35].
Rationale for MK-4280 Plus Pembrolizumab Plus FOLFOX/FOLFIRI in CRC
There is accumulating evidence demonstrating that chemotherapy agents including 5-FU and 
oxaliplatin that are commonly used to treat CRC may modulate the intrinsic immunogenicity 
of tumor and sensitize tumors to immunotherapy agents [36] [37]. Preclinical and clinical 
evidence suggest that conventional chemotherapies reactivate antitumor immune responses 
by increasing immunogenic cell death and antigen release, and/or by inhibiting 
immunosuppressive factors in the tumor microenvironment [38] [39] [40]. Further, 
chemotherapies can enhance tumor antigen presentation by upregulating the expression of 
tumor T-cell receptor (TCR) themselves, or of the MHC1 molecules to which the TCRs bind
[38]. A substantial body of scientific evidence has emerged to suggest that the efficacy of 
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immunotherapy can be enhanced by chemotherapy such as fluorouracil (5-FU) and 
oxaliplatin. Therefore, Arm 3 will combine MK-4280 and pembrolizumab with mFOLFOX7, 
a commonly-used treatment regimen for advanced CRC. Although evidence of similar 
immune-modulating effect and synergy from clinical studies is scant for irinotecan, FOLFIRI 
may potentially sensitize tumors to checkpoint inhibitors similarly to mFOLFOX7 and 
therefore Arm 4 will combine MK-4280 and pembrolizumab with FOLFIRI, another 
commonly used chemotherapy for the treatment of advanced CRC. Given the preliminary 
clinical efficacy observed with the combination of MK-4280 plus pembrolizumab in MSS 
CRC, the Sponsor seeks to test whether the combination of MK-4280 plus pembrolizumab 
plus chemotherapy (mFOLFOX7 or FOLFIRI) could augment antitumor activity compared to 
chemotherapy alone. 
There is preliminary clinical safety and efficacy data for the combination of pembrolizumab 
plus mFOLFOX6 in CRC. Modified FOLFOX6 + pembrolizumab has been previously tested
in an investigator-initiated study in unresectable CRC (NCT02375672). The study employed 
a 3+3 design for dose confirmation. In the initial 6 patients tested with the combination of 
mFOLFOX6 ([OX 85 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2, 5FU infusion 
2400 mg/m2 over 46 hours] and pembrolizumab 200 mg Q3W), 3 DLTs were observed, 2 
patients with G3 neutropenia, and 1 patient with G4 neutropenia. As a result, mFOLFOX6 
was dose reduced to oxaliplatin 68 mg/m2, leucovorin 400 mg/m2, 5-FU of 320 mg/m2, 5-FU 
infusion of 1920 mg/m2over 46 hours. Pembrolizumab remained at 200 mg IV Q3W. This 
dose was used for the remaining 24 subjects on the study. Rate of G3/4 toxicity associated 
with FOLFOX + pembrolizumab and pembrolizumab alone was 36.7% and 13.2%, 
respectively. No Grade 5 toxicity was seen on study. Best response was recorded as: 1 
complete response, 15 partial response (CR + PR = 53%), and 14 stable disease, with 100% 
DCR at 8 weeks. By comparison, FOLFOX and FOLFIRI have both demonstrated an ORR 
of ~55% in 1L metastatic CRC, with PFS ~8 months.
The Sponsor is also currently conducting a study to determine the safety and efficacy of 
pembrolizumab + mFOLFOX7 or FOLFIRI in subjects with advanced CRC (KEYNOTE-
651, NCT03374254). Notably, this study utilizes mFOLFOX7, which in comparison to 
mFOLFOX6, lacks a 5-FU bolus, resulting in a lower incidence of neutropenia. The study 
design employs a mTPI dose confirmation phase followed by expansion phase at the RP2D. 
As of 05-NOV-2018, 15 subjects have completed the DLT period in the mFOLFOX7 + 
pembrolizumab arm, and 0 subjects experienced a DLT. Sixteen subjects have completed the 
DLT period in the FOLFIRI + pembrolizumab arm, and 1 subject experienced a DLT (small 
bowel obstruction). The dose finding portion of the study has completed. The starting dose of 
200 mg pembrolizumab with full dose mFOLFOX7 and 200 mg pembrolizumab with full 
dose FOLFIRI will be used to treat patients in the expansion phase of the study. For more
information on the safety and tolerability of pembrolizumab when administered in 
combination with chemotherapy, refer to the pembrolizumab IB.
In summary, available clinical data suggests that immuno-oncology therapies given with 
FOLFOX and FOLFIRI may be well tolerated. Preliminary data suggest that the combination 
of MK-4280 plus pembrolizumab is well tolerated with a side effect profile similar to 
pembrolizumab monotherapy. There is no clinical safety data for the combination of 
MK-4280, pembrolizumab, and chemotherapy to date. This study will test the safety and 
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tolerability of MK-4280 plus pembrolizumab in combination with mFOLFOX7 or FOLFIRI 
in CRC subjects. The safety and tolerability of 1. MK-4280 plus pembrolizumab plus 
standard dose mFOLFOX7 and 2. MK-4280 plus pembrolizumab plus standard dose 
FOLFIRI will be tested using a TPI design. In the event of unacceptable toxicity, dose 
reduction of chemotherapy will be performed, consistent with the standard dose modification 
guidelines for these regimens. Chemotherapy rather than MK-4280 or pembrolizumab dose 
modification will be implemented. The rationale for this strategy is that chemotherapy 
regimens are defined by MTD, with dose limited by rate of DLTs. Biologics often do not 
reach MTD, since off-target toxicity rates are usually low. This was true in the case of 
pembrolizumab and MK-4280. On this study, no DLTs were observed during dose escalation 
at any dose of MK-4280, either alone or in combination with pembrolizumab. Therefore,
chemotherapy is the most likely agent to cause DLT on this study, and therefore dose 
reduction of chemotherapy is planned in the event of toxicity.
Rationale for MK-4280A – Co-formulated MK-4280 and Pembrolizumab
MK-4280A is a single drug product containing a fixed dose combination of 800 mg MK-
4280 and 200 mg pembrolizumab antibodies. The single formulation vial could provide 
significant benefit to subjects and providers, including simplified preparation and reduced 
infusion times compared to separate formulations. Data from Cohort A subjects enrolled in 
Part B, Arm 5 will be used to compare PK and safety parameters between sequentially 
administered (Part B, Arm 2C) and co-formulated (Part B, Arm 5) MK-4280 and 
pembrolizumab.
Rationale for MK-4280A in Chinese Subjects
MK-4280A will also be evaluated in Chinese subjects from mainland China with advanced 
solid tumors (Arm 5, Cohort F). The purpose of this cohort is to characterize the PK and 
safety profile of MK-4280A in subjects in China. Data from this evaluation will be used to 
demonstrate acceptable safety and PK of MK-4280A in Chinese subjects and will be 
leveraged to support use of MK-4280A in China in future studies.
Rationale for Arm 6 – Combining MK-4280 and Pembrolizumab With 
Lenvatinib in CRC
While PD-1/PD-L1 blocking antibodies have not demonstrated clear monotherapy activity in 
MSS CRC, combinations of anti-PD-1 antibodies with either an anti-LAG3 blocking 
antibody or a TKI have demonstrated promising clinical activity in this patient population.
Modest but reproducible activity has been observed in 3L+ MSS CRC subjects treated with 
MK-4280 in combination with pembrolizumab in study MK-4280-001. Further, the 
combination of an anti-PD-1 antibody and a TKI has demonstrated improved efficacy over 
TKI alone. In CRC patients treated with both regorafenib plus nivolumab, objective tumor 
response was observed in 9 out of 25 patients (36%) and the median PFS was 7.9 months 
(95% CI, 2.9 months to not reached) [41]. In CRC patients treated with regorafenib 
monotherapy, by comparison, 5 out of 505 patients (1%) experienced an objective response 
and the median PFS was 1.9 months (IQR 1.6-3.9) [26].
CCI
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Based on these data, the triplet combination of MK-4280, pembrolizumab, and lenvatinib 
may further improve the activity seen in the doublet combinations in CRC patients. Available 
clinical data also suggest that this combination will be well tolerated. The AE profile of MK-
4280 plus pembrolizumab is similar to pembrolizumab monotherapy. Given the distinct 
mechanism of action and safety profile of lenvatinib, as well as the tolerable safety profile 
seen with the combination of lenvatinib and pembrolizumab, no safety issues are anticipated 
with this triplet combination.
Rationale for Dose Selection/Regimen/Modification
The FIH dose selection for MK-4280 will be guided by PK, pharmacodynamics, and safety 
studies in cynomolgus monkeys.
Starting Dose for This Trial
4.2.2.1.1
Rationale for MK-4280 Dose
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4.2.2.1.2 Rationale for Preliminary RP2D (200 mg) and Additional MK-4280 Dose (800
mg)
CCI
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4.2.2.1.3 Rationale for Pembrolizumab Dose
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab across all indications and regardless of tumor type. As 
outlined below, this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects 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 vs. 10 mg/kg 
Q3W/Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 3 studies compared 10 
mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5 to 7.5 fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-/exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These 
findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, 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 subject 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.
No dose reduction is allowed for pembrolizumab in this study.
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4.2.2.1.4 Rationale for MK-4280A Dose and Biocomparability Study
The dose of MK-4280A will be comprised of 800 mg of MK-4280 and 200 mg of
pembrolizumab. This dosing will allow for comparisons of Cohort A subjects in Arm 5 
against subjects in Arm 2C of Part B receiving the sequential administration of 800 mg of 
MK-4280 and 200 mg of pembrolizumab.
Data collected from Cohort A subjects receiving sequentially administered MK-4280 + 
pembrolizumab (Arm 2C) will serve as a comparator to subjects from Cohort A receiving
MK-4280A (Arm 5). Since 800 mg is a new dose of MK-4280 and no subjects on study that 
have yet received this dose, additional subjects in Cohort A to receive 800 mg MK-4280 and 
pembrolizumab (Arm 2C) were added to enable comparison. 
The dose of MK-4280A will also allow for comparisons within Arm 5 of subjects in China 
(Cohort F) against subjects in the US (Cohort A).
4.2.2.1.5 Rationale for mFOLFOX7 and FOLFIRI Doses
mFOLFOX7 Starting Dose
The starting dose of mFOLFOX7 is oxaliplatin 85 mg/m2 IV infusion, leucovorin 400 mg/m2
IV infusion, 5-FU 2400 mg/m2 IV infusion over 46 to 48-hour infusion Q2W, which is 
considered a globally accepted SOC.   
FOLFIRI Starting Dose
The starting dose of FOLFIRI is irinotecan 180 mg/m2 IV over 30-90 minutes, leucovorin 
400 mg/m2 IV infusion, 5-FU 2400 mg/m2 IV over 46 to 48-hour infusion) Q2W, which is 
considered a globally accepted SOC.
If the TPI design calls for a de-escalation, the doses of mFOLFOX7 and/or FOLFIRI may be 
reduced as follows:

mFOLFOX7: Oxaliplatin (65 mg/m2), leucovorin (calcium folinate, 400 mg/m2), and 
5-FU (2000 mg/m2) Q2W

FOLFIRI: Irinotecan (150 mg/m2), leucovorin (calcium folinate, 400 mg/m2), and 
5-FU (2000 mg/m2) Q2W
The dose levels of mFOLFOX7 and/or FOLFIRI will not be reduced below these. If the TPI 
design calls for an additional de-escalation, enrollment into that particular arm will be closed.
4.2.2.1.6 Rationale for Lenvatinib Dose
The dosing regimen of lenvatinib was selected based on the results of the Phase 1b portion of 
KEYNOTE-146, which determined the MTD and RP2D as lenvatinib 20 mg QD when 
administered in combination with pembrolizumab 200 mg Q3W [43].
If the TPI design calls for a de-escalation, reduced doses of lenvatinib (14 mg and 10 mg) 
will be used. If the TPI design calls for additional de-escalation, enrollment into Arm 6 will 
be closed.
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DLTs and AEs for Part A
As of 09-JUN-2017, Part A dose escalation has been fully enrolled and all subjects have 
completed the DLT period. No DLTs were observed in any subjects. After the DLT period, 
one subject in the 21 mg cohort of MK-4280 monotherapy experienced Grade 3 pneumonitis. 
For this reason, this cohort was expanded to enroll an additional 3 subjects. No DLTs were 
observed in these additional 3 subjects.
A total of 61.1% of subjects (11/18) receiving MK-4280 monotherapy and 53.3% (8/15) of 
subjects receiving MK-4280 in combination with pembrolizumab experienced one or more 
drug-related AEs. There have been no observed ECIs. There did not appear to be any dose-
dependency on the frequency or severity of AEs in Part A. For more information on expected 
AEs refer to the IBs for MK 4280 and pembrolizumab.
DLTs for the Combination of Pembrolizumab With mFOLFOX7 or FOLFIRI
Given the Sponsor’s observation in this study that pembrolizumab + MK-4280 is well 
tolerated (with no DLTs up to the 700 mg dose level) as well as the observation in 
KEYNOTE-651 that pembrolizumab + mFOLFOX7 and pembrolizumab + FOLFIRI were 
also well tolerated (with no DLTs at the same proposed starting doses in this study, see 
Section 4.2.1.1), the Sponsor considers it acceptably safe to begin the dose confirmation of 
the 2 triplet combination arms at the proposed starting doses.
Maximum Dose/Exposure for This Trial
Although dose escalation will depend on AEs observed, a potential dose up to 800 mg of 
MK-4280 is planned. Because current target engagement predictions are based on normal 
cynomolgus monkeys, doses higher than 7 mg are expected to account for LAG-3 target 
engagement in humans with tumors. Although the maximum clinical dose to be evaluated in 
this trial is 800 mg, studies in cynomolgus monkeys showed no AEs at doses at which the 
Cmax and AUC0-tau values were 22-fold and 14-fold higher respectively relative to the 
predicted human exposure at this maximum dose. Pembrolizumab will be administered at the 
approved fixed dose of 200 mg. mFOLFOX7 and FOLFIRI will be administered at their 
approved doses. Lenvatinib will be administered at the RP2D for combination therapy with 
pembrolizumab.
Rationale for Endpoints
Efficacy Endpoints
Secondary and exploratory objectives for this trial are to evaluate the antitumor activity of 
MK-4280 alone and in combination with pembrolizumab with or without chemotherapy or 
lenvatinib in subjects with several types of advanced solid malignancies, as detailed in 
Section 5.1 – Entry Criteria. Additionally, the antitumor activity of 2 different doses of 
MK-4280 in combination with a fixed dose of pembrolizumab will be evaluated as a 
secondary trial objective in subjects with gastric cancer. Tumor response will be assessed 
using both RECIST 1.1 and irRECIST 1.1 by investigator review. Antitumor activity will be 
measured through such endpoints as the ORR, DCR, DOR, BOR, Best Target Lesion 
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Response, and the Time to Confirmed Response, which are further described in Section 8.0 –
Statistical Analysis Plan.
irRECIST 1.1 is an exploratory assessment criteria, based on RECIST 1.1, and accounts for 
the unique tumor response characteristics seen following treatment with immunotherapeutic 
agents as described in [44]. With other immunotherapeutic agents, up to 7% of evaluable 
subjects experienced delayed or early tumor pseudoprogression. Of note, subjects who had
progressive disease (PD) by RECIST 1.1 but not by irRECIST 1.1 had longer overall survival
than subjects with PD by both criteria. These findings support the need to apply a 
modification to RECIST 1.1 that takes into account the unique patterns of atypical response 
in immunotherapy and enable treatment beyond initial radiographic progression. 
The assessment of unidimensional target lesions and response categories per irRECIST 1.1
are identical to RECIST 1.1. However, MSD has implemented an adaptation related to new 
lesions, non-target lesions,
and tumor burden assessment to confirm radiographic 
progression. irRECIST 1.1 will be used by local site investigators to assess tumor response 
and progression, and make treatment decisions. RECIST 1.1 will be used for the formal 
statistical analysis of the secondary trial objective.
Therefore, irRECIST 1.1 consists of RECIST 1.1 with the following adaptations:
Subjects who have initial evidence of radiological PD by RECIST 1.1 after starting study 
treatment should, at the discretion of the investigator, continue on study treatment per the 
conditions outlined in Section 7.1.2.6 until repeat imaging is obtained ≥4 weeks later to 
confirm PD.
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST 1.1):

Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the 
following occur (as assessed by irRECIST 1.1): 

Tumor burden is <20% or <5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No incremental new lesion(s) since last evaluation

No incremental new non-target progression since last evaluation
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If repeat imaging does not confirm PD by irRECIST 1.1 and the subject continues to be 
clinically stable, treatment may continue and follow the regular imaging schedule.
This allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response. Subjects that 
are deemed clinically unstable are not required to have repeat tumor imaging for 
confirmation of PD. Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
Additional details about irRECIST 1.1 are referenced in MSD TIP Sheet for RECIST 1.1 and 
irRECIST 1.1.
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of MK-4280
monotherapy and in combination with pembrolizumab (either administered sequentially or as 
a co-formulated product), in combination with pembrolizumab and chemotherapy, and in 
combination with pembrolizumab and lenvatinib in subjects with advanced solid tumors. The 
primary safety analysis will be based on subjects who experience toxicities as defined by 
CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades of toxicities 
experienced by subjects who have received MK-4280, including SAEs and events of clinical 
interest (ECIs).
Safety will be assessed by reported AEs using CTCAE, Version 4.0. The attribution to drug, 
time-of-onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded. Adverse events will be analyzed including, but not limited to,
all AEs, SAEs, fatal AEs, and laboratory changes. 
Pharmacokinetic Endpoints
A secondary objective of this trial is to characterize the PK profile of MK-4280 following 
administration as a single agent, and the profiles of both MK-4280 and pembrolizumab 
following administration of MK-4280 in combination with pembrolizumab (or administration 
of MK-4280A), the profiles of both MK-4280 and pembrolizumab when administered in 
combination with mFOLFOX7 or FOLFIRI, as well as the profiles of MK-4280, 
pembrolizumab, and lenvatinib when administered together. The serum concentrations of 
each antibody will serve as the primary readout for the PK, and these data will be used to 
assess PK profiles of the agents alone and in combination. Furthermore, the results of these 
analyses will be used in conjunction with the pharmacodynamics, safety and antidrug 
antibody endpoints to help assess future dosing strategies for MK-4280.
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4.2.3.3.1 Biocomparability Endpoints
An additional objective of the study is to demonstrate the biocomparability of MK-4280A, a 
co-formulated product of MK-4280 and pembrolizumab, to that of the sequential 
administration of MK-4280 and pembrolizumab. Endpoints such as the AUC0-21days and Cmax
will be used to demonstrate the biocomparability of MK-4280A. More details regarding the 
biocomparability analyses can be found in Section 8.6.4.
Pharmacodynamic Endpoints
4.2.3.4.1 Target Engagement: Receptor Availability of Cell Surface LAG-3
The active form of LAG-3 that mediates regulation of activated T cells is the cell-bound 
form, which forms a dimer and is the only form of LAG-3 that has high affinity for its ligand
MHC Class II [45], [46]. The expression of cell surface LAG-3 is tightly regulated, with a 
majority found stored in intracellular vesicles, which undergo rapid translocation to the 
membrane upon lymphocyte activation, and finally, regulation by cleavage with 
metalloproteases to release sLAG-3 as a waste product [47], [48]. This process allows for a 
tightly controlled modulation of the immune response. Both cell surface expression of 
LAG-3 and subsequent cleavage to form sLAG-3 increase upon immune activation. The 
actual level of cell surface LAG-3 expression has been found to be negligible by flow 
cytometric staining of both human, nonhuman primate (NHP), and mouse cell populations 
from peripheral blood, precluding the use of receptor binding or receptor availability assays
for measuring target engagement. The levels of sLAG-3 are easily detectable, and represent 
an alternative method to assess target engagement of MK-4280. An immunoassay has been 
developed up to assess levels of total sLAG-3, both free and bound to MK-4280. 
Administration of MK-4280 showed dose-dependent increases of total sLAG-3 following 
multiple-dose administration of MK-4280 in a cynomolgus monkey safety study.
4.2.3.4.2 Antidrug Antibodies
Formation of antidrug antibodies (ADAs) can potentially confound drug exposures at 
therapeutic doses, and prime for subsequent infusion-related toxicities. The presence of 
ADAs will be determined at the beginning of each cycle to understand drug metabolism, 
exposure and safety. Incidence of ADAs and neutralizing ADAs will be evaluated and 
summarized over time by dose. Correlations between the presence/absence in subjects of
ADAs with PK and pharmacodynamic markers, activity, and safety of MK-4280 will be 
explored.
Serum Cytokines
Because treatment with anti-LAG-3 and/or anti-PD-1 can result in immune stimulation and 
resulting potential for cytokine release, serum cytokines will be monitored to provide 
supplementary information to assist in the evaluation of any response outcomes (for example 
tumor necrosis factor-alpha [TNF-, interleukin [IL]-2, and IL-6).
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Planned Exploratory Biomarker Research
Mechanistic markers of anti-LAG-3/anti-PD-1 combination activity have been observed after 
administration of the surrogate monoclonal antibody (mAb) 28G10 in mouse syngeneic 
tumor models, including induction of gene expression changes of various immune mediators 
(eg, interferon gamma [IFN-γ], perforin, and granzymes). These changes in candidate 
pathway biomarkers are predominantly seen within the tumor, though some transient changes 
in gene expression in peripheral blood were observed. Immunophenotyping by 
immunohistochemistry (IHC) and gene expression profiling of tumor biopsies, and by whole 
blood flow cytometry will be performed to explore changes in lymphocyte populations. 
These include the expression of LAG-3, MHC Class II, and PD-L1 by IHC as well as levels 
of IFN-γ-pathway genes, effector T-cell response genes, T-cell immunomodulatory receptors 
(IMRs), and other related markers of immune response. Additional candidate biomarkers 
including positivity for human papillomavirus (HPV), Epstein-Barr virus (EBV), human 
epidermal growth factor receptor 2 (HER2/neu), and microsatellite instability (MSI) will also 
be assessed by appropriate tests.
Subjects will be required to provide an archival tumor tissue sample and/or a fresh biopsy of 
tumor before treatment for these biomarker analyses. Subjects will also be asked to agree to a 
biopsy of tumor after initiation of study treatment and to provide the acquired tissue for these 
biomarker analyses.
Immune modulatory agents may alter populations of circulating immune cells in blood. To 
assess the effect of MK-4280 on these cell populations, peripheral blood samples will be 
obtained at designated times before and after study treatment. Changes in immune cell 
populations will be evaluated by comparing changes in T-cell repertoire and expression of 
immune function genes or proteins from baseline to after treatment. 
The mechanism of action of many new therapeutics is not completely understood and much 
remains to be learned regarding how best to leverage new drugs in treating participants. 
Thus, to aid future participants, it is important to investigate the determinants of response or 
resistance to the treatments administered, as well as determinants of AEs during our clinical 
studies. These efforts may identify novel predictive/pharmacodynamic biomarkers and 
generate information that may better guide single-agent and combination therapies. To 
identify novel biomarkers, biospecimens (eg, blood components, tissue 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
This research may evaluate whether genetic variation within a clinical trial population 
correlates with response to the treatment(s) under evaluation. Genome and exome wide 
approaches may be used for this effort. In addition, epigenetic characterization techniques 
(ie, DNA methylation status, histone profiling) may be explored.  If genetic and/or epigenetic 
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 deoxyribonucleic 
acid (DNA) variation across the genome in order to interpret tumor-specific DNA mutations. 
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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, and microsatellite instability). Key molecular changes of interest to immune-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-
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. 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.  
Tumor and Blood Ribonucleic Acid (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 IFN-γ transcriptional 
pathways) may be evaluated and new signatures may be identified. Individual genes related 
to the immune system may also be evaluated (eg, IL-10). MicroRNA profiling may also be 
pursued.
Blood/Tissue Protein biomarker Analyses
Tissue and/or blood samples from this study may undergo protein-based biomarker analyses 
using a variety of platforms that could include, but are not limited to; immunoassays (e.g., 
ELISA) liquid chromatography/mass spectrometry, cytometry, and immunohistochemistry. 
These approaches may be used to quantify soluble, cell- and/or tissue-based analytes to 
further elucidate therapy mechanism of action and/or assess disease-related parameters. For 
immunohistochemical analyses information on spatial context and cellular distribution may 
also be included. Correlation of protein expression to response to therapy may be performed 
to identify novel predictive biomarkers that could aid in participant selection for therapy. 
This research would serve to develop such assays for future clinical use. 
Biomarker research using the human microbiome
The human microbiome plays a critical role in maintaining tissue homeostasis. Abnormal 
composition of the microbiome has been observed in several disease states. Furthermore, the 
composition of different bacterial signatures may be predictive of the efficacy of treatment 
and participant response. The microbiome may thus serve as a valuable diagnostic tool for 
properly assessing and managing disease states.
Planned Genetic Analysis
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
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where local regulations and institutional review board (IRB)/ independent ethics committee 
(IEC) allow, a sample will be collected for DNA analysis from consenting subjects.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome.
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of Future Biomedical Research are presented in Section 12.2 - Collection and Management 
of Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and ICF documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects of at least 18 years-of-age with advanced solid tumors will be enrolled 
in this trial.
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As stated in the Code of Conduct for Clinical Trials (Appendix 12.1) 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.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Part A - Have a histologically or cytologically confirmed metastatic solid tumor for 
which there is no available therapy that may convey clinical benefit.
Part B – Have 1 of the following histologically or cytologically confirmed tumor 
types:
a.
Cohort A - CRC for Arm 1, Arm 2A, Arm 2C, and Arm 5: CRC 
originating in either the colon or rectum that is locally advanced unresectable 
or metastatic (ie, Stage IV) and that has received, and progressed on, all 
available standard-of-care therapies including fluoropyrimidine, oxaliplatin, 
and irinotecan but has not been treated with prior anti-PD-1/PD-L1 therapy.
Note: Only subjects at sites in the US may be enrolled to Cohort A, Arm 5.
b. Cohort B - CRC for Arm 3 and Arm 4 : CRC originating in either the colon 
or rectum that is locally advanced unresectable or metastatic (ie, Stage IV) 
and has been treated with ≤1 line of systemic therapy but has not been treated 
with prior anti-PD-1/PD-L1 therapy.  Subjects eligible to receive EGFR-
targeted therapy must have previously received this treatment in order to be 
eligible for the study.
c.
Cohort G - CRC for Arm 6: CRC originating in either the colon or rectum 
that is locally advanced unresectable or metastatic (ie, Stage IV) and has been 
treated with 2 prior lines of therapy but has not been treated with prior anti-
PD-1/PD-L1 therapy. Study medication will treat 3L CRC.
Note: Subjects must have received oxaliplatin and irinotecan in separate lines 
of therapy, these are usually provided with fluoropyrimidine (eg, FOLFOX 
and FOLFIRI).
Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior 
therapy (XOLFOX, XOLFIRI)
Note: Subjects who have previously received fluoropyrimidine, oxaliplatin, 
and irinotecan as part of the same and only chemotherapy regimen, eg, 
FOLFOXIRI or FOLFIRINOX, will be considered 2L patients, and do not 
qualify for the study.
Note: Adjuvant chemotherapy counts as a first line of prior systemic therapy if 
there is documented disease progression within 6 months of chemotherapy 
completion.
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Note: All systemic cytotoxic chemotherapy, including antibody–drug 
conjugates with a cytotoxic warhead, are considered prior lines of therapy. 
Note: Definitive surgery with curative intent and radiation therapy or 
systemically administered radiopharmaceutical therapy are NOT considered 
prior lines of therapy.
Note: If a treatment regimen is discontinued for any reason and a different 
regimen is started, it should be considered a new line of therapy. Switching 
(eg, cisplatin to carboplatin) will NOT be considered a line of therapy change 
(unless a delay in treatment is required for ≥2 months). Switching for toxicity 
will be considered a line of therapy change if there is a change in mechanism 
of action between the therapies. Interruptions will NOT be considered a line 
of therapy change (unless the interruption is ≥2 months).
Note: Maintenance regimens administered with the purpose of maintaining 
response following treatment will not be considered lines of therapy.
Note: Hyperthermic intraperitoneal chemotherapy (HIPEC) or other 
locoregional therapies are allowed, but will not be counted as prior lines of 
therapies.
d. Cohort C and Cohort D- HNSCC that is considered incurable by local 
therapies. 
Subjects 
should 
have 
progressed 
after 
receiving 
platinum-containing systemic therapy. Systemic therapy given as part of 
multimodal treatment for locally advanced disease is allowed. The eligible 
primary tumor locations are oropharynx, oral cavity, hypopharynx, and 
larynx. Subjects may not have a primary tumor site of nasopharynx (any 
histology). Subjects enrolled in the PD-1-treatment-naïve HNSCC cohort
(Cohort C) may not have been treated with prior anti-PD-1/PD-L1 therapy.
Subjects enrolled in the PD-1-treatment-failure HNSCC cohort (Cohort D)
must be refractory to an FDA approved anti-PD-1/PD-L1 monoclonal 
antibody (mAb) as either monotherapy or in combination with other approved 
checkpoint inhibitors or other therapies according to their label, defined as 
(subjects must meet all of the following criteria):
i.
Have received at least 2 doses of anti-PD-1/PD-L1 mAb.
ii.
Have progressive disease after anti-PD-1/PD-L1 mAb defined 
according to RECIST 1.1. The initial evidence of PD is to be 
confirmed by a second assessment, no less than 4 weeks from the date
of the first documented PD, in the absence of rapid clinical 
progression. (Note, this determination is made by investigator. If PD is 
confirmed, the initial date of PD documentation will be considered the 
date of disease progression.)
iii.
Have documented PD within 24 weeks of the last dose of 
anti-PD-1/PD-L1 
mAb. 
Patients 
who 
were 
re-treated 
with 
anti-PD-1/PD-L1 mAb and patients who were on maintenance with 
anti-PD-1/PD-L1 mAb will be allowed to enter the trial as long as 
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there is documented PD within 24 weeks of the last treatment date 
(with anti-PD-1/PD-L1 mAb).
e.
Cohort E - Adenocarcinoma of the stomach and/or gastric-esophageal 
junction (GEJ) that is considered inoperable and that has received, and 
progressed on, at least 1 prior chemotherapy regimen or HER2/neu-targeted 
approved therapy (if HER2/neu-positive). In both cases, subjects must not 
have been treated with prior anti-PD-1/PD-L1 therapy.
Note – Subjects with known MSI high or MMR deficient gastric cancer or 
CRC (as determined by either PCR or IHC) are excluded from participating 
in this study. MSI high is defined as at least 2 allelic shifts occurring among 
the 5 analyzed microsatellite markers as detected by PCR. MMR deficient is 
defined as loss of expression of at least 1 of 4 proteins (MLH1, MSH2, MSH6, 
and/or PMS2) by IHC. If a subject’s MSI/MMR status is unknown, testing is 
not required to determine eligibility.
Note – Subjects with CRC enrolled into Arm 3 or Arm 4 are not eligible to be 
re-enrolled in the study on Arm 1 or Arm 2 following discontinuation.
Note – Subjects who have withdrawn from standard treatment due to 
unacceptable toxicity warranting discontinuation of that treatment and 
precluding retreatment with the same agent before progression of disease will 
also be eligible.
f.
Cohort F – Have a histologically or cytologically confirmed metastatic solid 
tumor for which no more than 2 prior lines of therapy were administered and 
there is no available therapy that may convey clinical benefit.
AND
Be a Chinese subject from mainland China. 
Note – Chinese subjects from mainland China are not eligible for Cohorts A 
through E or Cohort G.
2. Have measurable disease by irRECIST 1.1 criteria.
3. Be ≥18 years of age on the day of signing informed consent.
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale (Appendix 12.4).
5. Demonstrate adequate organ function as defined in Table 2 (labs to be obtained 
within 7 days of initiation of treatment).
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Table 2 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/mcL without growth factor dependency 
(including erythropoietin (EPO), granulocyte-
colony stimulating factor (G-CSF), or platelet 
derived growth factor (PDGF)
stimulating 
agents) within 7 days of assessment
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment)
Renal
Creatinine OR
Measured or calculated creatinine clearance
(glomerular filtration rate [GFR] can also be 
used in place of creatinine or creatinine 
clearance [CrCl])
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min 
for subject with creatinine levels >1.5 X 
institutional ULN
Note: Creatinine clearance should be calculated 
per institutional standard
Hepatic
Total Bilirubin
≤1.5 X ULN 
OR
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 ULN
Aspartate aminotransferase
(AST)
(serum 
glutamic oxaloacetic transaminase [SGOT]) 
and Alanine aminotransferase (ALT) (serum 
glutamic-pyruvic transaminase [SGPT])
≤2.5 X ULN OR
≤5 X ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or
Prothrombin Time (PT)
Activated Partial Thromboplastin Time
(aPTT) or Partial Thromboplastin Time
(PTT)
≤1.5 X ULN unless the subject is receiving 
anticoagulant therapy
≤1.5 X ULN unless the subject is receiving 
anticoagulant therapy
6. A female subject 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 Section 12.8 during the intervention 
period and for at least 180 days after the last dose of chemotherapy, 120 days after 
the last dose of pembrolizumab or MK-4280, or 30 days after the last dose of 
lenvatinib, whichever occurs last. The investigator should evaluate the potential 
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for contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention. 
•
Arm 3 and Arm 4 only: WOCBP must also agree not to donate eggs (ova, 
oocytes) to others or freeze/store for her own use for the purpose of reproduction 
during and for at least 180 days after the last dose of chemotherapy. 
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) within 72 hours before the first dose of study 
intervention.
Arm 6 only: 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.
•
Abstain from breastfeeding during the study intervention period and for at least 
180 days after the last dose of chemotherapy, 120 days after the last dose of 
pembrolizumab or MK-4280, or 30 days after the last dose of lenvatinib, 
whichever occurs last.
•
Additional requirements for pregnancy testing during and after study intervention 
are located in Section 7.1.2.7.
•
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
•
If the contraception requirements in the local label for any of the study drugs is 
more stringent than the requirements above, the local label requirements should 
be followed.
7. Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 95 days after the last dose of chemotherapy or 7
days after the last dose of lenvatinib, whichever occurs last:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause Section 12.8) 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 
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intercourse or use a male condom during each episode of penile-vaginal 
penetration.
•
Arm 3 and Arm 4 only: Male subjects must also refrain from donating sperm for 
at least 95 days after the last dose of chemotherapy.
•
Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
•
If the contraception requirements in the local label for any of the study drugs is 
more stringent than the requirements above, the local label requirements should 
be followed.
•
Note: For male participants who only receive pembrolizumab or MK-4280, or a 
combination of the aforementioned drugs, no contraception measures are needed.
8. Voluntarily agree to participate by the subject (or their legally acceptable 
representative) providing documented informed consent/assent for the trial. The 
subject (or their legally acceptable representative) may also provide consent/assent 
for Future Biomedical Research. However, the subject may participate in the main 
trial without participating in Future Biomedical Research.
The following criterion applies to all subjects except those being considered for enrollment 
into Cohort F:  
9. Submit an evaluable baseline tumor sample for PD-L1 analysis (either a newly 
obtained or archival tumor sample) as specified in the Procedures Manual.
The following criterion applies only to subjects being considered for treatment on Arm 6:
10. 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.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to 
the first dose of study therapy, or who has not recovered to CTCAE Grade 0 or 1 
from the AEs due to cancer therapeutics administered more than 4 weeks earlier (this 
includes subjects who received previous immunomodulatory therapy with residual 
immune-related adverse events [irAEs]). Subjects receiving ongoing replacement 
hormone therapy for endocrine irAEs will not be excluded from participation in this 
study.
Note: Subjects with Grade 2 neuropathy are excluded from Arm 3 of Part B but may 
be eligible for all other arms of Part B.
2. Is currently participating and receiving study therapy, or has participated in a study of 
an investigational agent and received study therapy, or used an investigational device
within 4 weeks of the first dose of study treatment.
3. Has received previous treatment with another agent targeting the LAG-3 receptor.
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4. Has
received previous treatment with an immunomodulatory therapy (eg,
anti-PD-1/PD-L1 or CTLA-4 agent) and was discontinued from that therapy due to a 
Grade 3 or higher irAE.
5. Is expected to require any other form of antineoplastic therapy while on study.
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
in excess of replacement doses, or on any other form of immunosuppressive 
medication.
Subjects (ie,
with asthma)
that require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections would not be excluded 
from the study.
7. Has a history of a previous, additional malignancy, unless potentially curative 
treatment has been completed, with no evidence of malignancy for 5 years.
a.
Note: The time requirement for no evidence of disease for 5 years does not 
apply to the tumor for which a subject is enrolled in the study. The time 
requirement does not apply to subjects who underwent successful definitive 
resection of basal cell carcinoma of the skin, superficial bladder cancer or in 
situ cervical cancer, or other in situ cancers.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects 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 trial treatment.
9. Has had a severe hypersensitivity reaction to treatment with another monoclonal 
antibody.
10. Has an active autoimmune disease or a documented history of autoimmune disease, 
except vitiligo or resolved childhood asthma/atopy.
Replacement therapy 
(eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
11. Has an active infection requiring therapy.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
13. Has had a prior stem cell or bone marrow transplant.
14. Has a known history of or screens positive for Human Immunodeficiency Virus 
(HIV) (HIV 1/2 antibodies), or an active chronic or acute Hepatitis B (eg, hepatitis B 
surface antigen [HBsAg] reactive) or Hepatitis C infection (eg, hepatitis C virus
[HCV] RNA [qualitative] is detected).
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
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16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
17. Is a regular user as determined by investigator judgement (including “recreational 
use”) of any illicit drugs or has a recent history (within the last year) of substance 
abuse (including alcohol), at the time of signing informed consent.
18. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoraco-
or 
paracentesis) is eligible.
19. Has clinically significant heart disease that affects normal activities.
20. Has had major surgery in the past 4 weeks.
21. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Seasonal flu vaccines that do not contain live virus are permitted.
Refer to Section 5.5.2 for information on COVID-19 vaccines.
Subjects being considered for enrollment into Arm 4 with CRC in Part B are also excluded if 
any of the following additional criteria (22 through 24) apply:
22. Has plans to use, or is using, any herbal medications/supplements or any medications 
or foods that are strong inhibitors or inducers of cytochrome P450 3A 4/5 ≤1 week 
prior to the start of study treatment.
23. Has received previous treatment with irinotecan.
24. Has a known diagnosis of Gilbert’s Syndrome.
Subjects being considered for enrollment into Arm 6 in Part B are also excluded if any of the 
following additional criteria (25 through 36) apply:
25. Has received previous treatment with lenvatinib.
Note: Prior therapy with other kinase inhibitors that target VEGF are not 
exclusionary.
26. Has had major surgery within 3 weeks prior to first dose of study interventions. Note: 
Adequate wound healing after major surgery must be assessed clinically, independent 
of time elapsed for eligibility.
27. Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
28. Has urine protein ≥1 g/24 hours.
Note: Subjects with proteinuria >1+ on urine dipstick testing/urinalysis will undergo 
24-hour urine collection for quantitative assessment of proteinuria.
29. Has a left ventricular ejection fraction (LVEF) below the institutional (or local 
laboratory) normal range, as determined by multigated acquisition (MUGA) or 
echocardiogram (ECHO).
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30. Has radiographic evidence of encasement or invasion of a major blood vessel, or of 
intratumoral cavitation.
NOTE: The degree of proximity to major blood vessels should be considered because 
of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.
31. Prolongation of QTcF interval to >480 ms.
32. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention, including New York Heart Association Class III or IV congestive 
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or 
cardiac arrhythmia associated with hemodynamic instability. Note: Medically 
controlled arrhythmia would be permitted.
33. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid 
requiring drainage or diuretic drugs within 2 weeks prior to enrollment. The subject 
can receive diuretic drugs as needed per the treating physician, outside of the above 
mentioned conditions. Consult with the Sponsor if the subject has more than 
trivial/trace fluid accumulation.
34. Serious nonhealing wound, ulcer or bone fracture.
35. Has presence of gastrointestinal condition including malabsorption that might affect 
the absorption of lenvatinib.
36. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the 
first dose of study drug.
Trial Treatment(s)
The treatment(s) to be used in this trial are outlined below in Table 3.
Country-specific differences are noted in Appendix 12.7.
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Table 3 Trial Treatments
Drug
Dose/
Potency
Dose Fre-
quency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Part A, Arm 1
MK-4280
7 mg
21 mg
70 mg
210 mg
700 mg
Q3W
Intravenous (IV)
Infusion
Day 1 of 
each 21-day 
cycle
Test Product
Part A, Arm 2
MK-4280
7 mg
21 mg
70 mg
210 mg
700 mg
Q3W
Intravenous (IV) 
Infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
Part B, Arm 1
MK-4280
800 mga
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Part B, Arm 2A
MK-4280
200 mga
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
Part B, Arm 2B
MK-4280
700 mg
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
Part B, Arm 2C
MK-4280
800 mg
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
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Drug
Dose/
Potency
Dose Fre-
quency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Part B, Arm 3
MK-4280
800 mg
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
mFOLFO
X7
Oxali
platin
85 mg/m2
65 mg/m2 b
Q2W
IV infusion
Odd 
Number 
Cycles: Day 
1, Day 15
Even 
Number 
Cycles: Day 
8
Background 
Therapyd
Leuco
vorinc
(Calci
um 
Folina
te)
400 mg/m2
IV infusion
5-FU
2400 mg/m2
2000 mg/m2 
b
IV infusion
Part B, Arm 4
MK-4280
800 mg
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
FOLFIRI
Irinote
can
180 mg/m2
150 mg/m2 b
Q2W
IV infusion
Odd 
Number 
Cycles: Day 
1, Day 15
Even 
Number 
Cycles: Day 
8
Background 
Therapyd
Leuco
vorinc
(Calci
um 
Folina
te)
400 mg/m2
IV infusion
5-FU
2400 mg/m2
2000 mg/m2 
b
IV infusion
Part B, Arm 5
MK-4280A
800 mg MK-
4280 + 200 
mg pembro-
lizumab
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
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Drug
Dose/
Potency
Dose Fre-
quency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Part B, Arm 6
MK-4280
800 mg
Q3W
IV infusion
Day 1 of 
each 21-day 
cycle
Test Product
Pembrolizumab
200 mg
Q3W
IV Infusion
Day 1 of 
each 21-day 
cycle
Test Product
Lenvatinib
20 mg
14 mg
10 mg
8 mg
QD
Oral
QD of each 
21-day cycle
Test Product
a.
From a preliminary analysis of MK-4280 PK and pharmacodynamic biomarker data collected during 
Part A, the preliminary RP2D for MK-4280 to carry forward into Part B of the study was determined to be 
200 mg. Following the accumulation of more data, the Sponsor has elected to test the higher 800 mg dose of 
MK-4280 in Part B as well.
b.
Reduced doses for components of mFOLFOX7 and/or FOLFIRI will only be used if the TPI calls for a 
de-escalation.
c.
Depending on local practice guidelines, levofolinate calcium (200 mg/m2 Q2W) may be substituted for 
leucovorin.
d.
Every attempt should be made to source these supplies from a single lot/batch number. The trial 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.
Part A – Dose Escalation of Arm 1 (MK-4280 Monotherapy) and Arm 2 
(MK-4280 + Pembrolizumab)
In Part A, Arm 1 dose escalation will follow a 3+3 design and will begin with 7 mg of 
MK-4280 in cohorts of 3 to 6 subjects each (expansion to 6 subjects based on the occurrence 
of a DLT in the first 3 subjects), and may proceed based on safety events up to a dose of 
700 mg until an MTD or MAD is identified.
Enrollment to Part A, Arm 2, (MK-4280 in combination with pembrolizumab) will begin 
once all subjects complete 1 cycle of MK-4280 monotherapy at both the 7 mg and 21 mg 
dose levels in Arm 1, and will follow a 3+3 design to identify a preliminary RP2D for 
MK-4280. The higher dose level cohort of Arm 1 must be fully enrolled and all subjects must 
begin dosing before the next lower dose level of Arm 2 begins enrollment. However, once an 
MTD or MAD is identified in Arm 1, the dose of MK-4280 in Arm 2 may continue 
escalation up to that dose. For enrollment to the last 2 dose levels of Arm 2, all 3 (or 6) 
subjects in the second highest dose level must complete 1 cycle of treatment and DLT 
evaluation before the highest dose level may begin enrollment.
The starting dose of MK-4280 for both arms will be 7 mg and will be escalated as described 
in Table 3. The dose of pembrolizumab will be fixed at 200 mg. During the 3+3 dose 
escalation, at least 2 days of observation will occur between each of the first 3 subjects at 
each dose level.
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Enrollment to both arms will occur in parallel with treatment allocation accomplished by 
nonrandom assignment to Arm 1 or Arm 2 of Part A using an interactive voice response 
system/integrated web response system (IVRS/IWRS).
In Arm 2, pembrolizumab will be administered first and then, after a 30 minute observation 
period, MK-4280 will be administered.
Part B – Dose Confirmation and Efficacy Expansion Cohorts
Arm 1 MK-4280 Monotherapy
The 2 Arm 1 monotherapy cohorts of Part B (Cohort A in 3L+ CRC and Cohort E in PD-1 
treatment naïve gastric cancer) will each enroll 20 subjects at the 800 mg MK-4280 dose to 
assess the antitumor activity of MK-4280 monotherapy. Monotherapy subjects with 
confirmed disease progression per irRECIST 1.1 will be allowed to crossover to Arm 2C and 
receive 800 mg MK-4280 in combination with pembrolizumab (see Section 5.2.7). 
The gastric monotherapy cohort (Cohort E Arm 1) will be opened only if preliminary 
antitumor activity is observed (≥8 of 40 subjects with an objective response, irrespective of 
dose, Section 5.2.2.2.4) in the gastric cancer combination cohort (Cohort E Arm 2). 
Enrollment will not be paused in the Arm 2 gastric cancer cohort to make this determination. 
DLTs will also be evaluated in subjects enrolling at the 800 mg dose level after at least 10 
subjects have completed the DLT evaluation period. Enrollment will not be paused while 
this evaluation is performed.
Arm 2 – MK-4280 + Pembrolizumab
5.2.2.2.1 Dose Confirmation Using TPI in Subjects With HNSCC or CRC (Arm 2A)
Part B dose confirmation will refine the estimate of tolerability of the preliminary RP2D of 
MK-4280 in combination with 200 mg pembrolizumab identified in Part A, Arm 2 using a 
TPI design [1] for the first 14 subjects enrolled in Cohort A, Cohort C, and Cohort D. 
Enrollment of subjects into Cohort E should not begin until the TPI portion of this part has 
been completed.
5.2.2.2.2 Adaptive Efficacy Expansion Cohorts (Arm 2A)
The CRC and PD-1-treatment-naïve HNSCC cohorts (Cohort A and Cohort C) in Arm 2A
are designed to allow for expanded subject enrollment if a predefined ORR is observed in 
these cohorts. Specifically, these cohorts (see Section 5.1 – Entry Criteria) will each initially 
enroll 10 subjects. If, within an individual cohort, an ORR of 20% or greater is observed (ie, 
2 or more of 10 subjects experience an objective response), that specific cohort will be 
expanded to enroll additional subjects. The CRC cohort (Cohort A) may enroll a maximum 
of 90 additional subjects, for a maximum enrollment of 100 subjects. The HNSCC cohort 
(Cohort C) may enroll a maximum of 30 additional subjects, for a maximum enrollment of 
40 subjects. Enrollment will not be paused in the time period between when 10 subjects have 
been enrolled and when the interim analysis is completed. If a cohort does not reach this 
efficacy threshold, the Sponsor will evaluate all available data to determine whether or not to 
expand enrollment. For more details on how these adaptive cohorts will affect the total 
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number of trial subjects, see Section 8.9 - Sample Size and Power Calculations. Subject 
enrollment and the decision to expand these cohorts in Part B will be controlled using an 
IVRS/IWRS along with regular communication from the Sponsor.
5.2.2.2.3 PD-1/PD-L1-treatment-failure HNSCC Cohort (Arm 2A)
A cohort of 20 subjects with HNSCC that have progressed following anti-PD-1/PD-L1 
therapy (as defined in Section 5.1.2 – Subject Inclusion Criteria, Cohort D) will be enrolled 
in a nonadaptive fashion controlled using an IVRS/IWRS.
5.2.2.2.4 Dose Finding in Subjects With Gastric Cancer (Arm 2A and 2B)
Subjects with gastric cancer (Cohort E) of Part B will be randomized 1:1 via an IVRS/IWRS
to either the preliminary RP2D from Part A (200 mg, Arm 2A) or 700 mg (Arm 2B) dose
level of MK-4280 in combination with a fixed dose of pembrolizumab to more thoroughly 
assess differences in activity and safety/tolerability of these doses. However, if the TPI
portion of Part B calls for a de-escalation of the RP2D, these doses will be modified 
accordingly, and the decision to modify these doses will be communicated to sites via an 
administrative letter before enrollment into this cohort begins.
5.2.2.2.5 Additional MK-4280 Dose in Part B (Arm 2C)
Based on accumulating data from the study, the Sponsor has elected to test an 800 mg dose 
of MK-4280 in Part B (see Section 4.2.2.1.2 for rationale). An additional 40 subjects with 
CRC will be enrolled and receive 800 mg MK-4280 in combination with pembrolizumab
(Arm 2C). 
DLTs will be evaluated in the subjects enrolling at the 800 mg dose level in combination 
with pembrolizumab after at least 10 subjects have completed the DLT evaluation period.
Enrollment will not be paused while this evaluation is performed.
Arm 3 and Arm 4 – MK-4280 + Pembrolizumab + mFOLFOX7/FOLFIRI
Subjects with CRC that have received ≤1 line of prior systemic therapy in Part B (Cohort B)
will be assigned to receive MK-4280 (800 mg) in combination with pembrolizumab (200 
mg) and either mFOLFOX7 (Arm 3) or FOLFIRI (Arm 4). Arm 3 and 4 will not begin 
enrollment until 10 subjects have completed the DLT period in Arm 2C. A TPI design will 
be used to assess the safety and tolerability of Arms 3 and 4 in the first 14 subjects enrolled 
into each arm, independently. If the TPI calls for a de-escalation, the reduced doses of 
FOLFOX and/or FOLFIRI designated in Table 3 will be used. The doses of MK-4280 and 
pembrolizumab will not be adjusted.
Arm 5 – MK-4280A
Forty subjects with CRC from Cohort A and all subjects from Cohort F (up to 20 Chinese 
subjects with solid tumors) will be enrolled to receive MK-4280A, a co-formulated product 
of MK-4280 and pembrolizumab. Subjects will receive a dose of MK-4280A consisting of 
800 mg of MK-4280 and 200 mg pembrolizumab. The dose of MK-4280A will not be 
adjusted. Arm 5 will not begin enrollment until 10 subjects have completed the DLT period 
in Arm 2C. 
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In Arm 5, Cohort A, the Sponsor will evaluate DLTs when at least 10 subjects have 
completed the DLT period to confirm the safety of Arm 5. Only subjects at sites in the US 
may be enrolled to Arm 5, Cohort A. Only subjects at sites in China may be enrolled to Arm 
5, Cohort F.
Arm 6 – MK-4280 + Pembrolizumab + Lenvatinib
Subjects with CRC that have received 2 lines of prior systemic therapy in Part B (Cohort G) 
will be assigned to receive MK-4280 800 mg Q3W in combination with pembrolizumab 
200 mg Q3W and lenvatinib 20 mg QD. A TPI design will be used to assess the safety and 
tolerability of Arm 6 in the first 14 subjects enrolled. If the TPI calls for a de-escalation, 
reduced doses of lenvatinib (14 mg and 10 mg) will be used. The doses of MK-4280 and 
pembrolizumab will not be adjusted.
Trial treatment for all arms should begin on the day of treatment allocation/randomization or 
as close as possible to the date on which the subject is allocated/assigned.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Escalation
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.
Details on preparation of administration of MK-4280, pembrolizumab, mFOLFOX7, and 
FOLFIRI are provided in the Procedure Manual.
3+3 Dose Escalation Design
In Part A, Arm 1 (MK-4280 monotherapy), a 3+3 dose escalation design will be used to 
identify a preliminary MTD or MAD for MK-4280. Part A, Arm 2 (MK-4280 in combination 
with pembrolizumab) will also use a 3+3 dose escalation design to identify a preliminary 
RP2D for MK-4280 when given in combination with pembrolizumab. The starting dose of 
MK-4280 for both arms will be 7 mg and will be escalated as described in Table 3. The dose 
of pembrolizumab will be fixed at 200 mg Q3W.
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During Part A, Arm 1, the study will enroll 3 subjects at each dose level, with at least 2 days 
of observation occurring between each of the first 3 subjects at each of the first 2 dose levels.
The rules for the preliminary MK-4280 dose escalation using the 3+3 design are as follows 
(all dose adjustments are made only to MK-4280):
An initial cohort of 3 subjects is enrolled:
If 0 of 3 subjects develops a DLT, escalation to the next dose of MK-4280 will 
occur.
If 1 of 3 subjects develops a DLT, another 3 subjects will be enrolled at this dose 
level.
If 0 of the 3 new subjects develops a DLT (for a total of 1 of 6 subjects 
with a DLT at this dose level), escalation to the next dose level will 
occur.
If 1 or more of the 3 new subjects develop a DLT (for a total of at least 2
of 6 subjects with a DLT at this dose level), the dose escalation stage of 
the trial will be terminated. If the dose level directly below the current 
dose level had been studied in at least 3 subjects, the dose level directly 
below the current dose level will be considered the preliminary RP2D, and 
the study will proceed to the confirmation stage. If the dose level directly 
below the current dose level had been studied in less than 3 subjects, more 
subjects to a total of 3 will be enrolled at the dose level directly below the 
current dose level before proceeding to the confirmation stage.
If at least 2 of 3 subjects develop a DLT, the dose escalation stage of the trial will 
be terminated. If the dose level directly below the current dose level had been 
studied in at least 3 subjects, the dose level directly below the current dose level
will be considered the preliminary RP2D, and the study will proceed to the 
confirmation stage. If the dose level directly below the current dose level had been 
studied in less than 3 subjects, more subjects to a total of 3 will be enrolled at the 
dose level directly below the current dose level before proceeding to the 
confirmation stage.
It is conceptually acceptable to de-escalate to an intermediate, not predefined and not 
previously-studied dose of MK-4280, if evaluation of toxicity at such a dose level is desired 
in lieu of proceeding directly to the dose confirmation stage of the study. If this approach is 
taken, 3 new subjects should be enrolled at the new intermediate dose level, and the 
aforementioned rules should be used to determine further enrollment at this dose level. This 
would be communicated to sites via an administrative letter.
If the highest candidate dose of MK-4280 is studied during dose escalation of Part A, Arm 2, 
and 0 of 3, or less than 2 of 6, subjects develop a DLT at that dose, then dose escalation will 
terminate with this finding and this dose level may be taken to the confirmation stage
(Part B).
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Dose Confirmation – Arm 2A
The objective of dose confirmation in Part B is to refine the estimate of tolerability of the
MK-4280 preliminary RP2D (when delivered in combination with pembrolizumab) based on 
a TPI design [1] with a target toxicity rate less than or equal to 30%, utilizing the first 14 
subjects enrolled in this part in Cohort A, Cohort C, and Cohort D. Dose confirmation 
involves the expansion of at least 1 dose level studied in the dose-escalation stage of the 
study. After dosing of the first 14 subjects in Part B, dosing will continue as planned.
The 200 mg dose of pembrolizumab will not be adjusted.
Table 4 Dose Confirmation Rules
Number of Subjects Treated at Current Dose
Number 
of 
Toxicities
4
5
6
7
8
9
10
11
12
13
14
0
S
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
S
S
E
E
E
E
E
2
D
S
S
S
S
S
S
S
S
S
S
3
DU
D
D
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
D
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
D
S
S
S
6
DU
DU
DU
DU
DU
DU
D
D
D
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
E = Escalate to the next higher dose.
S = Stay at the current dose.
D = De-escalate to the next lower dose.
DU = The current dose is unacceptably toxic.
Target toxicity rate = 30%.
Noninformative prior is used: a=1; b=1; 
k1=1; k2=1.5; pow=1 per [1].
Subjects may be enrolled continuously (ie, without waiting for Cycle 1 completion of 
subjects who have received the first dose) unless a DLT is observed at the particular dose. 
Once a DLT is observed, the number of subjects who are enrolled at that dose but are not yet 
fully evaluable for DLT assessment may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic 
(denoted as DU in Table 4). For example, if 3 of 7 subjects have experienced a DLT at a 
given dose level, no more than an additional 2 subjects should be enrolled at this dose level
until additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 2 of the additional subjects experience a DLT (ie, 5 of 9 subjects 
with DLT in Table 4). To find out how many more subjects can be enrolled, one can count 
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steps in diagonal direction (down and to the right) from the cell (7 subjects, 3 toxicities) to 
the first cell marked DU.
If enrollment expands to 14 subjects for a dose level, and less than or equal to 5 of 14
subjects develop a DLT, then the dose confirmation will stop. If enrollment expands to 14
subjects for a dose level and greater than 5 of 14 subjects develop a DLT, then the next lower 
dose may be expanded to further explore the dose-response relationship. Even if less than or 
equal to 5 of 14 subjects develop a DLT for a dose level, the next lower dose level may be 
expanded if there is a potential safety concern. Note that although 30% has been the target 
toxicity rate used to generate the guidelines in Table 4, the observed rate of subjects with 
DLT at the MTD may be slightly above or below 30%.
Dose Confirmation – Arm 3 and Arm 4
A TPI design will be used to assess the safety and tolerability of MK-4280 and 
pembrolizumab when administered in combination with either mFOLFOX7 or FOLFIRI and 
to determine RP2Ds of the triplet combinations, with a target toxicity rate less than or equal 
to 30%, utilizing the first 14 subjects enrolled in each arm. At the start of each new dose, 3 
subjects will be enrolled (with at least 24 hours between each of these 3 subjects) and must 
complete their DLT evaluation period before additional subjects can be enrolled. Assuming 
no DLTs in the first 3 subjects have completed their DLT evaluation period, up to 6 subjects 
at a time can be enrolled and evaluated for DLTs following TPI rules, until 14 subjects are 
enrolled. If 1 or more DLTs are observed in the first 3 subjects on either cohort, 3 subjects at 
a time may enroll simultaneously for DLT assessment, until 14 subjects are treated.  All other
rules regarding the enrollment of subjects and de-escalation of doses are the same as in 
Section 5.2.3.3 and in Table 4. If the TPI calls for an initial de-escalation, the doses of 
mFOLFOX7 and/or FOLFIRI will be adjusted as described in Table 3. If this lower dose is 
still determined to be unacceptably toxic, enrollment into that Arm will be closed. If, after 
14 subjects are treated at a particular dose level, the TPI calls for “Stay” (or “Escalate” at the 
highest dose level), this dose will be considered the RP2D and an additional 6 subjects will 
be enrolled. Note that the TPI will operate independently for Arm 3 and Arm 4.
Dose Confirmation – Arm 6
A TPI design will be used to assess the safety and tolerability of MK-4280 and 
pembrolizumab when administered in combination with lenvatinib and to determine the 
RP2D of this triplet combination, with a target toxicity rate less than or equal to 30%, 
utilizing the first 14 subjects enrolled in this arm. At the start of each new dose, 3 subjects
will be enrolled (with at least 24 hours between each of these 3 subjects) and must complete 
their DLT evaluation period before additional subjects can be enrolled. Assuming no DLTs 
in the first 3 subjects after completing their DLT evaluation period, up to 6 subjects at a time 
can be enrolled and evaluated for DLTs following TPI rules, until 14 subjects are enrolled. If 
1 or more DLTs are observed in the first 3 subjects, 3 subjects at a time may enroll 
simultaneously for DLT assessment, until 14 subjects are treated.  All other rules regarding 
the enrollment of subjects and de-escalation of doses are the same as in Section 5.2.3.3 and in 
Table 4. If the TPI calls for de-escalation, the reduced doses of lenvatinib (14 mg and 10 mg)
will be used. If TPI calls for de-escalation to the lowest dose of lenvatinib, and this lower 
dose is still determined to be unacceptably toxic, enrollment into this Arm will be closed. If, 
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after 14 subjects are treated at a particular dose level, the TPI calls for “Stay” (or “Escalate”), 
this dose will be considered the RP2D and the remainder of the cohort will be enrolled. 
Definition of Dose Limiting Toxicity
Dose limiting toxicities will be defined from toxicities observed during the first cycle of 
treatment (21 days) for each dose level. See Section 5.9 for rules on replacement of subjects 
in the DLT period.
The occurrence of any of the following toxicities during Cycle 1, if assessed by the 
investigator to be unrelated to the underlying disease, will be considered a DLT:

Grade 4 non-hematologic toxicity (not laboratory)

Grade 4 hematologic toxicity lasting at least 7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia if associated with bleeding

Grade 3 nonhematologic toxicity (not laboratory) lasting more than 3 days despite 
optimal supportive care. Grade 3 nausea, vomiting, or diarrhea will be considered a 
DLT if lasting more than 3 days despite optimal supportive care.
Arm 6 only: Excluding Grade 3 hypertension able to be controlled by medication.

Any Grade 3 or Grade 4 nonhematologic laboratory abnormality, if

medical intervention is required, or

the abnormality leads to hospitalization, or

the abnormality persists for more than 1 week.

Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3°C (101°F) or a sustained temperature of ≥38°C 
(100.4°F) for more than 1 hour.

Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 
degrees F) for more than 1 hour, with life-threatening consequences and urgent 
intervention indicated.

Any drug-related AE that caused the subject to discontinue treatment during Cycle 1

Grade 5 toxicity

Any treatment-related toxicity that causes a greater than 2-week delay in initiation of 
Cycle 2
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Timing of Dose Administration
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 
of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after 
the scheduled Day 1. For Arm 6 only, trial treatment may be administered up to 3 days 
before or 3 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 
1 may be administered up to 3 days after the scheduled Day 1. In addition, dosing 
interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 2 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the subject's study record.
In Arm 2 of Part A and Part B, pembrolizumab will be administered first on Day 1 of each 
cycle, with administration of MK-4280 occurring approximately 30 minutes after completion 
of the pembrolizumab administration.
In Arm 3 and Arm 4 of Part B, pembrolizumab will be administered first, with administration 
of MK-4280 occurring approximately 30 minutes after completion of the pembrolizumab 
administration. On visits where MK-4280, pembrolizumab, and chemotherapy are to be 
administered, chemotherapy should be given according to local practice guidelines 30 
minutes after completion of the MK-4280 administration.
In Arm 6 of Part B, pembrolizumab will be administered first and then, following a 30-
minute interval, MK-4280 will be administered. Lenvatinib will be taken orally with water 
(with or without food) at approximately the same time each day in 21-day cycles. However, 
on visit days when pembrolizumab and MK-4280 are also administered, lenvatinib will be 
administered 0 to 4 hours after the MK-4280 infusion is complete.
Dose Modification (Escalation/Titration/Other)
CTCAE Version 4.0 must be used to grade the severity of adverse events. If appropriate,
the
investigator
may
attribute each
toxicity
event
to
MK-4280,
pembrolizumab, 
mFOLFOX7, FOLFIRI, or lenvatinib alone, or to any combination of these agents, and
follow the dose modification guidelines accordingly in Table 5, Section 5.2.6.2, and Table 
7. If a dose modification for toxicity occurs with any agent, the dose may not be re-escalated 
in that subject. Dose modifications are always based on the previous cycle.
For Part A, subjects may have 1 dose modification to MK-4280 throughout the course of
the study. If further toxicity occurs or the criteria for resuming treatment are not met, the
subject must be discontinued from the agent. If a subject experiences several toxicities and 
there are conflicting recommendations, following the most conservative dose adjustment is 
recommended (dose reduction appropriate to the most severe toxicity). For Part B, no dose 
reductions of MK-4280, pembrolizumab, or MK-4280A are permitted.
Reduction or holding of 1 agent and not the other agents is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to 1 of the study drugs. However for subject 
convenience in Arm 2, Arm 3, and Arm 4 (and crossover treatment), if 1 drug is delayed then 
the other drug(s) can be delayed until they can be administered. If, in the opinion of the 
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investigator, the toxicity is related to a combination of agents, both drugs should be held 
according to recommended dose modifications.
For Arm 6, subjects who interrupt or discontinue one or more drug(s) in the lenvatinib plus 
pembrolizumab plus MK-4280 combination due to toxicity can continue with the other 
drug(s) in the combination until criteria for treatment discontinuation are met (eg, 
unacceptable toxicity, disease progression). 
Refer to Section 5.2.6.4 for dose modification guidance for overlapping toxicity for the 
lenvatinib plus pembrolizumab plus MK-4280 combination.
Exceptional circumstances to following the dose modification tables below may be
considered after consultation with the Sponsor.
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue) 
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
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 monotherapy, 
coformulation, or IO combination 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 monotherapy, coformulation, or IO 
combination 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.  
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
In these cases where the toxicity is attributed to pembrolizumab coformulations or IO 
combinations, re-initiation of pembrolizumab as a monotherapy may be considered after 
communication with and agreement by the Sponsor.
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Holding Study Interventions: 
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions: 
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5 Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
   Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 
2 or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
   Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
   Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withhold a
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer anti-
hyperglycemic in participants 
with hyperglycemia
   Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
   Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
·   Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
   Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a   The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b   Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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Dose modification and toxicity management of infusion-reactions related to MK-4280 
and pembrolizumab (or MK-4280A)
Pembrolizumab and MK-4280 (or MK-4280A) 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 
study drug-related infusion reaction are provided in Table 6. 
Table 6 Pembrolizumab
and MK-4280
(or MK-4280A)
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 subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject 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 (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., 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 subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
Dose Modification and Toxicity Management of AEs Related to mFOLFOX7 
or FOLFIRI
mFOLFOX7
Dose delays and treatment restarts will be made at the discretion of the site investigator 
according to institutional guidelines or local standard practice. The recommended dose 
reduction is stepwise by 20%. Discontinuation of treatment should be considered if dose 
reduction below the following dosage is required: Oxaliplatin 50 mg/m2 and 5-FU infusion 
1600 mg/m2 46 to 48 hours.
FOLFIRI
Dose delays and treatment restarts will be made at the discretion of the site investigator 
according to institutional guidelines or local standard practice. The recommended dose 
reduction is stepwise by 20%. Discontinuation of treatment should be considered if dose 
reduction below the following dosage is required: Irinotecan 120 mg/m2 and 5-FU infusion 
1600 mg/m2 46 to 48 hours.
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Dose Modification with Lenvatinib
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib plus
pembrolizumab plus MK-4280 combination therapy-related toxicity will be in accordance 
with the dose modification guidelines described in Table 7. An interruption of study 
treatment for more than 28 days will require Sponsor approval before treatment can be 
resumed.
The starting dose of lenvatinib is 20 mg/day.  Dose reductions of lenvatinib occur in 
succession based on the previous dose level (14, 10, 8 mg/day). Any dose reduction below 
8 mg mg/day must be discussed with the Sponsor.  Once the lenvatinib dose has been 
reduced, it may not be increased at a later date, unless the dose has been mistakenly 
decreased; in this situation, the Sponsor’s approval is required to increase the dose.
Refer to the subsections below for management of hypertension (Section 5.2.6.3.1), 
proteinuria (Section 5.2.6.3.2), diarrhea (Section 5.2.6.3.3), hepatotoxicity (Section 
5.2.6.3.4), thromboembolic events (Section 5.2.6.3.5), posterior reversible encephalopathy 
syndrome/ reversible posterior leukoencephalopathy syndrome (PRES/RPLS; Section 
5.2.6.3.6), hypocalcemia (Section 5.2.6.3.7), hemorrhage (Section 5.2.6.3.8), gastrointestinal 
perforation or fistula formation (Section 5.2.6.3.9), QT prolongation (Section 5.2.6.3.10), and 
osteonecrosis of the jaw (Section 5.2.6.3.11) as appropriate, before consulting the dose 
modification table (Table 7). For overlapping toxicities of pembrolizumab, MK-4280, and 
lenvatinib, please refer to Section 5.2.6.4.
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
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Treatment-Related 
Toxicitya,b
Management
Dose Adjustment
Abbreviations: AE = adverse event; BMI = body mass index; CTCAE = Common Terminology Criteria for 
Adverse Events.
Note: For grading see CTCAE version 4.0. Collect all AE grades (ie, decreasing and increasing CTCAE 
grade). 
a. An interruption of study treatment for more than 28 days will require Sponsor approval before treatment 
can be resumed.
b. Initiate optimal medical management for nausea, vomiting, hypertension, hypothyroidism and/or diarrhea 
prior to any lenvatinib interruption or dose reduction. 
c. Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d. Obese subjects (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 subjects 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. See Section 5.2.6.3.5.
g. Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
5.2.6.3.1 Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects 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 6.3). Hypertension will 
be graded using NCI CTCAE v4.0, based on BP measurements only (and not on the number 
of antihypertensive medications).
If the subject’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 subject’s clinical 
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circumstances and follow standard medical practice. For previously normotensive subjects, 
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 subjects already on antihypertensive medication, treatment modification may be 
necessary if hypertension persists. 
Lenvatinib should be withheld in any instance where a subject 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 subject has been on 
the same antihypertensive medications for at least 48 hours and the BP is controlled, 
lenvatinib should be resumed as described below.
Subjects 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 
subject 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. A diary will be 
provided to the subject to capture the blood pressure evaluations between study visits.
The following guidelines should be followed for the management of systolic BP ≥160 mm 
Hg or diastolic BP ≥100 mm Hg confirmed on 2 BP assessments at least 30 minutes:
1. Continue study drug and institute antihypertensive therapy for subjects not 
already receiving this.
2. For those subjects 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 subject 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 subject 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 
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interrupted and restarted at a third dose reduction only when systolic BP ≤150 
mm Hg and diastolic BP ≤95 mm Hg and the subject has been on a stable dose 
of antihypertensive medication for at least 48 hours.
-
Additional dose reduction should be discussed with the Sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life threatening consequences):
1. Institute appropriate medical management
2. Discontinue study drug
5.2.6.3.2 Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the SoA (Section 6.3).  
Guidelines for assessment and management of proteinuria are as follows:
Detection and Confirmation
1. Perform urine dipstick testing or urinalysis per the SoA (Section 6.3). Urine 
dipstick testing is the preferred method for testing for urinary protein, however, 
urinalysis may be used if the use of urine dipsticks is not feasible.
2. A 24-hour urine collection initiated as soon as possible and at least within 72 
hours (or an immediate spot urine protein-to-creatinine ratio [UPCR] test) is 
required in the following situations:
-
The first (initial) occurrence of ≥2+ (≥100 mg/dL) proteinuria on urine 
dipstick (or urinalysis) while the subject 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 v4.0 will be based on the 24-hour urinary 
protein result if one has been obtained. If the participant has 4+ proteinuria by 
dipstick (≥1000 mg/dL by urinalysis), a 24-hour urinary protein result is required 
to confirm Grade 3 proteinuria. Management of lenvatinib administration will be 
based on the grade of proteinuria according to Table 7.
Monitoring
-
Urine dipstick or urinalysis testing for subjects 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.  
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-
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.
5.2.6.3.3 Management of Diarrhea
An anti-diarrheal agent should be recommended to the subject at the start of study treatment, 
and subjects 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 subject’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.
5.2.6.3.4 Management of Hepatotoxicity
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin 
levels) should be conducted as detailed in the SoA (Section 6.3) 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 v4.0) occurs, the study drug must be discontinued.
5.2.6.3.5 Management of Thromboembolic Events
Subjects 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, subjects 
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 subject
experiences a Grade 3 or a life threatening (Grade 4) thromboembolic reaction, including 
pulmonary embolism, lenvatinib must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
treatment discontinuation.
5.2.6.3.6 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 subjects with signs or symptoms of PRES/RPLS, 
instructions in Table 7 should be followed.
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5.2.6.3.7 Management of Hypocalcemia
Serum calcium should be monitored per the SoA (Section 6.3).  Corrected serum calcium 
should be used to assess the grade of hypocalcemia per CTCAE v4.0, using the following 
formula: 
Corrected calcium = ([4 – serum albumin in g/dL] × 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
5.2.6.3.8 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.
5.2.6.3.9 Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any subjects who develop gastrointestinal perforation 
of any grade or Grade 4 fistula.
5.2.6.3.10 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.
5.2.6.3.11 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 5.2.6.5). 
All study-related medical or dental decisions must be made by an investigator who is a 
qualified physician.
Dose Modifications for Overlapping Toxicities
Based on the known toxicity profiles of pembrolizumab, MK-4280, 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 and MK-
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4280 treatment. However, certain AEs, such as such as diarrhea, hypothyroidism, and liver 
enzyme elevation, may be initially considered attributable to any study drug. Therefore, 
evaluation of attribution is important for determining the study drug most likely related to the 
AE, or an alternative etiology, and subsequently proper clinical management. The following 
aspects should be considered:
1. Timing of AE onset 
Since lenvatinib is dosed daily and continuously due to a relatively short half-life 
(28 hours), and pembrolizumab is dosed Q3W due to a long half-life, lenvatinib 
can be interrupted to assess whether an AE improves/resolves with dechallenge 
(ie, interruption of treatment) based on the following 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 subject 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 all drugs and 
initiating treatment with a corticosteroid (with exception of hypothyroidism, 
TIDM) and other supportive care should be taken promptly.
3. Subjects receiving the combination therapy (pembrolizumab + MK-4280 + 
lenvatinib) must discontinue study therapy if any of the following occur: 
•
ALT or AST >5 X ULN for more than 2 weeks.
Pembrolizumab
and MK-4280
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 and MK-4280 to be withheld 
(interrupted), and Table 7 advises lenvatinib to have no dose modification or a 
reduction, if this criterion is met, all drugs must be permanently discontinued 
immediately.
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Other Allowed Dose Interruptions
If the subject 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.
Crossover Criteria 
After Sponsor consultation, subjects in Arm 1 of Part B may be allowed to crossover to Arm 
2C and receive MK-4280 in combination with pembrolizumab. In order to be eligible for 
crossover, the subject must have radiographically documented and confirmed disease 
progression per irRECIST 1.1 while in Arm 1. Subjects who discontinue treatment in Arm 1 
for any reason other than disease progression are not eligible for crossover.
If crossover is being considered, the risks and benefits of continuing treatment after disease 
progression should be reviewed prior to performing any crossover-related procedures. 
Subjects will continue receiving MK-4280 at the dose-level they were assigned (ie, 800 mg),
and pembrolizumab will be administered at the fixed 200 mg Q3W dose. Crossover will not 
be permitted until six subjects have completed the DLT period on Arm 2C. The subject may 
receive up to a total of 35 cycles of combination treatment (irrespective of how many cycles 
of monotherapy treatment they received).
Specific procedures to be performed for crossover subjects can be found in Section 6.3 –
Crossover Flow Chart. Special considerations regarding imaging and disease assessment for 
crossover subjects can be found in Section 7.1.2.6 – Disease Assessments.
Second Course of Study Treatment
All participants who have completed the first course may be eligible for up to an additional 
17 cycles of study treatment if there is investigator-determined progressive disease after 
initial treatment has been completed. This retreatment is the Second Course of this study.
Note: Sponsor consultation is required prior to starting participants on Second Course.
Participants may enter the Second Course if all of the following criteria are met:
1. No new anticancer treatment was administered after the last dose of study 
intervention
2. The participant meets all of the inclusion criteria and none of the exclusion criteria
3. The study is ongoing
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For participants in Arm 3, Arm 4 and Arm 6, continuation or resumption of the same 
concomitant therapy received during the initial treatment phase (ie, chemotherapy or 
lenvatinib) may be administered with Second Course MK-4280 and Pembrolizumab at the 
discretion of the Investigator. Note that chemotherapy or agent other than lenvatinib that is 
different from that received in the initial treatment phase is not permitted
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Treatment allocation by nonrandom, sequential assignment to Part A, Arm 1 or Arm 2 will 
occur centrally using an IVRS/IWRS. Randomization for Cohort E in Part B will be 
performed at a 1:1 ratio by an IVRS/IWRS. An IVRS/IWRS will be used to control the 
sequential enrollment of Part B. Enrollment to Arm 3 or Arm 4 will be guided by a subject’s 
eligibility for one arm or the other or, if eligible for both arms, will be determined by 
investigator choice. If Arms 1, 2C and 5 for 3L+ CRC subjects are enrolling at the same time, 
subjects will be assigned in an alternating fashion across the open arms at the study level 
through IVRS. Cohort F of Part B is only open to sites in China and these subjects will be 
assigned to Arm 5 only.  
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Acceptable & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications/Procedures
Listed below are some specific restrictions for concomitant therapy use during the course of 
the trial. All treatments that the investigator considers necessary for a subject’s welfare may 
be administered at the discretion of the investigator in keeping with the community standards 
of medical care. All concomitant medication will be recorded on the electronic case report 
form (eCRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV
medications and fluids. If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date will also be included on the eCRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
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is not permitted during the study; however, radiotherapy or procedures for symptom 
management are allowed.
All concomitant medications received within 30 days before the first dose of study treatment 
through the Safety Follow-up Visit should be recorded. After the Safety Follow-up Visit, all 
medications taken for SAEs as defined in Section 7.2 should be recorded.
In cases of melanoma, local surgical excision may be allowed after discussion with the 
Sponsor.
Prohibited Concomitant Medications/Procedures
Subjects are prohibited from receiving the following therapies/vaccinations during the 
Screening and Treatment Phases of this trial:

Immunotherapy not specified in this protocol

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol

Investigational agents not specified in this protocol

Radiation therapy; radiotherapy for symptom management is allowed

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed. However, intranasal 
influenza vaccines (eg, FluMist®) are live-attenuated vaccines, and are not allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication 
incompetent adenoviral vaccines, or inactivated vaccines.  These vaccines will be 
treated just as any other concomitant therapy.
Investigational vaccines (i.e., those not licensed or approved for Emergency Use) are 
not allowed

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
-
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
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
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
o
Note: Use of prophylactic corticosteroids as a part of anti-emetic therapy for 
chemotherapy is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary.  
Section 5.1.3 – Exclusion Criteria describes other medications that are prohibited in this trial.
There are no prohibited therapies during the follow-up visits.
Lenvatinib Drug Interactions
There are no drug-drug interaction (DDI)-related concomitant medication prohibitions or 
restrictions. 
Lenvatinib is not expected to clinically meaningfully alter exposure to CYP3A4/ P-
glycoprotein (Pgp) substrates based on results from a lenvatinib DDI study with midazolam 
(a sensitive CYP3A and Pgp substrate). 
Clinical studies also showed that co-administration of lenvatinib with either inducers or 
inhibitors of CYP3A4/Pgp are not of clinical concern.
No drug interaction is expected between pembrolizumab, MK-4280, and lenvatinib because 
of their divergent metabolic pathways. Pembrolizumab and MK-4280 are monoclonal 
antibodies and are primarily catabolized like other proteins, while lenvatinib is metabolized 
by enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes (lenvatinib IB).
Concomitant medications with potential for overlapping toxicity with study medications 
should be given judiciously and with close monitoring. QTc prolongation has been seen in 
some lenvatinib studies. Drugs known to prolong QTc interval (including Class Ia and III 
antiarrhythmics) must be used cautiously. Please refer to the lenvatinib IB.
Rescue Medications & Supportive Care
No rescue or supportive medications are specified to be used in this trial.
Supportive Care Guidelines
Subjects 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 in Table 5. For participants receiving
pembrolizumab + MK-4280 + lenvatinib, suggested supportive care measures for the 
management of AEs with potential immunologic etiology are outlined in Table 5 in Section 
5.2.6.1 along with the dose modification guidelines in Table 7 in Section 5.2.6.3. Where 
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appropriate, these guidelines include the use of oral or IV treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids. Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab, MK-4280, MK-4280A, or lenvatinib. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab,
MK-4280, MK-4280A, or lenvatinib the investigator does not need to follow the treatment 
guidance. Refer to Section 5.2.6 for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea, or vomiting.
Lifestyle Restrictions
Subjects receiving 5-FU (mFOLFOX7 or FOLFIRI) should avoid exposure to sunlight due to 
potential drug-induced photosensitivity.
Contraception
MK-4280, pembrolizumab, MK-4280A, and lenvatinib may have adverse effects on a fetus 
in utero. Refer to Section 12.8 for approved methods of contraception.
Use in Pregnant Women
If a subject inadvertently becomes pregnant while on study treatment, the subject will 
immediately be removed from the study. The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor within 24 hours if the outcome is a 
serious adverse experience (eg, death, abortion, congenital anomaly, or other disabling or 
life-threatening complication to the mother or newborn). The study investigator will make 
every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the Sponsor. If a male subject impregnates his female 
partner the study personnel at the site must be informed immediately and the pregnancy 
reported to the Sponsor and followed as described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether MK-4280 or pembrolizumab (or MK-4280A) is excreted in human 
milk. Because many drugs are excreted in human milk, and because of the potential for 
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serious adverse reactions in the nursing infant, subjects who are breastfeeding are not eligible 
for enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.
Discontinuation from treatment is permanent. Once a subject has discontinued treatment, 
even though they continue to be monitored in the trial, they shall not be allowed to begin 
treatment again. The only exception to this, as described in Section 5.2.6, is for subjects who 
discontinued treatment of MK-4280 after 8 cycles in accordance with the original protocol.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent

The subject is lost to follow-up
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Confirmed disease progression per response assessment criteria (Section 7.1.2.6)

Investigator’s decision to withdraw the subject

Clinical progression

Subject has a confirmed pregnancy test

Unacceptable AEs

Intercurrent illness that prevents further administration of treatment

Administrative reasons

The subject completes 35 cycles of MK-4280 monotherapy (Arm 1) or MK-4280 in 
combination with pembrolizumab (Arm 2 and crossover). 
Note: For subjects in Arm 6, pembrolizumab and MK-4280 treatment will be 
discontinued once the subject has received 35 cycles (approximately 2 years). 
Subjects experiencing clinical benefit, according to the PI, may continue treatment 
with lenvatinib beyond 2 years with Sponsor consultation and approval.
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
Subjects receiving MK-4280 in combination with pembrolizumab and lenvatinib 
(Arm 6) 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 and MK-4280 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 and MK-4280 to be withheld 
(interrupted), and Table 7 advises lenvatinib to have no dose modification or a 
reduction, if this criterion is met, all drugs must be permanently discontinued 
immediately
Note: Subjects who discontinue treatment for reasons other than PD will have post-treatment 
follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up.
Subject Replacement Strategy
To determine safety, all subjects selected must meet the criteria for evaluability for Cycle 1. 
Subjects are considered nonevaluable and will be replaced if:

They are enrolled but not treated

They discontinue from the trial prior to completing all the safety evaluations for 
reasons other than treatment-related AEs

They receive less than 90% of the total MK-4280, pembrolizumab, MK-4280A or 
mFOLFOX7/FOLFIRI infusion in Cycle 1 (eg, because the infusion had to be 
discontinued due to an infusion reaction) and did not experience a DLT
Nonevaluable subjects will not be counted toward the cohort total for DLT evaluation.
If a subject experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion between the Sponsor and investigator. However, if the subject is deriving clinical 
benefit from the trial treatment, the subject may be allowed to continue after discussion 
between the Sponsor and the investigator.
Beginning and End of the Trial
The overall trial begins when the first subject (or their legally acceptable representative) 
provides documented informed consent. The overall trial ends when the last subject 
completes the last study-related contact, discontinues from the trial or is lost to follow-up 
(i.e. the subject is unable to be contacted by the investigator).
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 subject, 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.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:

Incidence or severity of adverse drug reactions in this or other trials suggest a 
potential health hazard to subjects

Plans to modify or discontinue the development of the trial drug

Poor adherence to protocol and regulatory requirements

Quality or quantity of data recording is inaccurate or incomplete
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-4280, MK-4280A, pembrolizumab, or lenvatinib.
08QZB0


Product:  MK-4280 
90
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
6.0 TRIAL FLOW CHART
Part A - Arm 1 and Arm 2; Part B - Arm 1, Arm 2A, Arm 2B, Arm 2C, and Arm 5 Flow Chart
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up27
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed Consent2
X
Informed Consent for Future 
Biomedical Research3
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Review 
X
X
X
X
X
X
X
X
X
X
X
X
Prior Oncology Treatment History
X
MK-4280 Drug Administration 
(Arm 1 and Arm 2 only)
X
X
X
X
Pembrolizumab Drug Administration4
(Arm 2 only)
X
X
X
X
MK-4280A Drug Administration
(Arm 5 only)
X
X
X
X
08QZB0


Product:  MK-4280 
91
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up27
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Clinical Procedures/Assessments
Adverse Events Monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X5
X5
X5
X5
X
X
Height
X
Weight
X
X
X
X
X
X
X
Vital Signs (respiratory rate, blood 
pressure, pulse, temperature)6
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram7
X
X5
X5
X
ECOG Performance Status
X
X5
X5
X5
X5
X
X
Survival Status27
X
Efficacy Procedures/Assessments
Tumor Imaging and irRECIST 
Response Assessment8
X
X8
X8
X8
Laboratory 
Procedures/Assessments –Analysis 
by Local Lab
Complete blood count (CBC) with 
differential
X9
X5,10
X
X5,10
X
X5,10
X5,10
X
X
PT/INR and aPTT
X9
08QZB0


Product:  MK-4280 
92
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up27
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Chemistry Panel
X9
X5,10
X
X5,10
X
X5,10
X5,10
X
X
CEA Testing (subjects in Part B with 
CRC only)28
X9
X5
X28
X28
X28
Lactate dehydrogenase (LDH), 
gamma-glutamyl transferase (GGT)
X9
X5
X5
X5
Pregnancy Test – Urine Serum β-
human chorionic gonadotropin 
(β-hCG), if applicable11
X
X
Urinalysis
X9
Thyroid Function (thyroxine [T4], 
triiodothyronine [T3], thyroid 
stimulating hormone [TSH])12
X5
X5
X5
X
X
BRAF Status29
X
HIV, Hepatitis B and C13
X
Laboratory 
Procedures/Assessments-Analysis to 
be Performed by Central Lab
Cytokine Panel14
X5
X
X
X14
Anti-MK-4280 Antibodies15
X
X
X
X
X
08QZB0


Product:  MK-4280 
93
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up27
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
PK for MK-4280 15, 16
(Arm 1 only)
X
X
X
X
X
X
X
X
X
X
X
Anti-Pembrolizumab Antibodies17
(Arm 2 and Arm 5 only)
X
X
X
X
X
PK for Pembrolizumab
and MK-4280 17, 18
(Arm 2 and Arm 5 only)
X
X
X
X
X
X
X
X
X
X
X
Blood for DNA Correlative Studies19, 
30
X
X
X
Blood for RNA Correlative Studies19, 
30
X
X
X
Blood for Genetic Analysis20, 30
X
Blood for Exploratory Protein 
Analysis (serum)19, 30
X
X
X
Pharmacodynamic receptor 
availability23, 24, 30
X
X
X
X24
X
X
X24
X
X
X
X
Lipase and Amylase25, 30
X
X
X
X
X
X
X
T-cell flow cytometry analysis26, 30
X
X
X
X
X
08QZB0


Product:  MK-4280 
94
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up27
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Tumor Tissue Collection
Archival or New Obtained Tumor 
Tissue21, 30
X
Post Treatment Tumor Biopsy22, 30
X
1.
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after the 
scheduled Day 1. 
2.
Documented informed consent must be obtained prior to performing any protocol-specific procedure. Tests performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame.
3.
Providing documented informed consent for Future Biomedical Research (FBR) is optional, and may be provided at any time during the subject’s participation in the trial. Detailed instructions 
for the collection and management of FBR specimens are provided in the Procedure Manual. FBR is not applicable to subjects in Cohort F.
4.
In Arm 2 of Part A and Part B, pembrolizumab is administered first and then, following a 30-minute interval, MK-4280 will be administered.
5.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing. If Screening was performed ≤72 hours prior to dosing in Cycle 1, the results obtained 
at Screening can also be used for the Cycle 1, Day 1 predose values.
6.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. On Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for 
each) after start of the MK-4280 or MK-4280A infusion. Beginning with Cycle 5, collect VS predose on Day 1 of each cycle for all subjects. 
7.
Twelve-lead electrocardiogram (ECG) should be performed at screening for all subjects and repeated only for subjects in Arm 1 of Part A and Arm 5 of Part B prior to and within 30 minutes 
after the end of the MK-4280 or MK-4280A infusion in Cycles 1-4, and at the Safety Follow-up Visit.
8.
Tumor imaging (computerized tomography [CT] scan or magnetic resonance imaging [MRI]) should be performed within 28 days of enrollment. Tumor imaging and response assessment are to
be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging assessments should be repeated every 9 weeks and follow calendar days and should not be adjusted 
for delays in cycle starts. If institutional standard of care for imaging frequency differ from these guidelines, follow the institutional standard of care after confirming with the Sponsor. The 
same imaging technique should be used on a subject throughout the trial. Information for disease assessments may be requested and submitted for central review.
9.
Laboratory tests at Screening are to be performed within 7 days prior to the first dose of study treatment.
10.
On Day 1 in Cycles 1-4, CBC with differential and the Chemistry Panel should be drawn prior to dosing.
11.
For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours of receiving the first dose of study medication. If urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
12.
Thyroid function testing is to be performed starting in Cycle 1 and then every other cycle and at the post treatment Safety Follow-up Visit.
13.
Include HCV RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (eg, HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
14.
Collect cytokine panel on Day 1 predose and 1 hr and 4 hrs after the start of the first infusion and on Day 2 of Cycle 1 for all subjects in Part A. Also collect cytokine panel on Day 1 predose of 
Cycles 2-4 for subjects in Part A, Arm 1 and Cycles 2-6 in Part A, Arm 2.  Cytokine panel will not be collected for subjects in Part B.
08QZB0


Product:  MK-4280 
95
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
15.
MK-4280 PK (predose; Arm 1 – Part A and Part B) and ADA samples (predose; all subjects) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, and 8, and every 
4 cycles thereafter. For Cohort F only: Additional MK-4280 ADA samples (predose) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycle 5 and Cycle 9.
16.
Postdose PK in Arm 1 – (Part A and Part B): Postdose MK-4280 PK samples will be drawn on Day 1 of Cycles 1-4, 6, and 8 at the end of MK-4280 infusion (+10 minutes) and 2 hrs after the 
start of the MK-4280 infusion (±10 minutes). Additional postdose MK-4280 PK samples in Cycles 1-4 will be collected on Day 2 (Cycle 1 only), Day 8, and Day 15. PK samples will also be 
drawn at Discontinuation, and at the Safety Follow-up Visit.
17.
Pembrolizumab and MK-4280 PK samples (predose) and pembrolizumab ADA samples (predose) will be drawn from subjects in Arm 2A, Arm 2B, Arm 2C  and Arm 5 within 24 hours prior to
start of infusion on Day 1 of Cycles 1-4, 6, 8 and every 4 cycles thereafter. For Cohort F only: Additional pembrolizumab and MK-4280 PK samples (predose) and pembrolizumab ADA samples
(predose) will be drawn from subjects within 24 hours prior to start of infusion on Day 1 of Cycle 5 and Cycle 9. 
18.
Postdose PK in Arm 2A, Arm 2B, Arm 2C, and Arm 5: Postdose pembrolizumab and MK-4280 PK samples will be drawn on Day 1 of Cycles 1, 2, 4, 6, and 8 at the end of the pembrolizumab 
infusion (+10 minutes; Arm 2 only; pembrolizumab PK assessed alone), at the end of MK-4280 (or MK-4280A) infusion (+10 minutes), and 2 hrs after the start of the MK-4280 (or MK-4280A) 
infusion (±10 minutes). Additional postdose pembrolizumab and MK-4280 PK samples in Cycles 1, 2, and 4 will be collected on Day 2 (Cycle 1 only), Day 8, and Day 15. PK samples will also 
be drawn at Discontinuation and at the Safety Follow-up Visit. For Cohort F only: Additional postdose pembrolizumab and MK-4280 PK samples will also be drawn in Cycle 4 on Day 2 and in 
Cycle 8 on Day 2, Day 8, and Day 15.
19.
Blood for correlative studies (RNA and DNA samples) and serum for exploratory protein analysis will be drawn prior to dosing on Day 1 of Cycle 1, on Day 1 of Cycle 2 (or Day 22 of Cycle 1 
for subjects who do not receive a second dose of MK-4280 or MK-4280A), and at discontinuation. Detailed instructions for the collection and management of these samples are provided in the 
Procedure Manual.
20.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation prohibiting collection, 
or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is collected, leftover extracted DNA will be 
stored for FBR if the subject (or their legally acceptable representative) provides documented informed consent for FBR. If the planned genetic analysis is not approved, but FBR is approved and 
consent is given, this sample will be collected for the purpose of FBR.
21.
Tumor tissue (archival or newly obtained biopsy) will be required at Screening for all subjects. For all subjects in Part B (except subjects in Cohort F), PD-L1 testing will be performed but does 
not need to be completed during Screening. For subjects in Part B (except subjects in Cohort F) with HNSCC (of oropharyngeal origin, only), prior HPV testing is required. For subjects with 
gastric cancer (except subjects in Cohort F), prior HER2/neu and EBV testing are required. For subjects with CRC and gastric cancer (except subjects in Cohort F), prior MSI testing is required. 
If subjects with HNSCC, gastric cancer, or CRC have not had these tests previously performed, they should be performed by the local laboratory at Screening. Leftover tissue may also be saved 
for Future Biomedical Research if the subject provides documented informed consent for FBR.
22.
Post treatment tumor biopsy is optional, but strongly encouraged, for all subjects (except subjects in Cohort F) in Cycle 1 between Day 8 and Day 15. Leftover tissue may also be saved for FBR 
if the subject provides documented informed consent for FBR.
23.
Pharmacodynamic receptor availability samples (predose) for all subjects (except subjects in Cohort F) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, 8, and 
every 4 cycles thereafter
24.
Postdose pharmacodynamic receptor availability samples will be drawn on Day 1 of Cycles 1, 2, 4, 6, and 8 at the end of the pembrolizumab infusion (for subjects receiving pembrolizumab; +10 
minutes), at the end of the MK-4280 (or MK-4280A) infusion (+10 minutes), and 2 hrs after the start of the MK-4280 (or MK-4280A) infusion (±10 minutes). Additional postdose 
pharmacodynamic receptor availability samples in Cycles 1, 2, and 4 will be collected on Day 2 (Cycle 1 only), Day 8, and Day 15. Pharmacodynamic receptor availability samples will also be 
drawn at Discontinuation.
25.
On Day 1 in Cycles 1-4, amylase and lipase samples should both be drawn predose and repeated 4 hours (±10 mins) after the start of the first infusion. Beginning with Cycle 5, amylase and 
lipase should be drawn predose on Day 1 for all subjects (except subjects in Cohort F).
26.
Predose T-cell flow cytometry analysis samples will be drawn from subjects in Part B within 24 hours prior to start of infusion on Day 1 of Cycles 1-4. Postdose samples will be drawn from 
subjects in Part B on Day 8 of Cycle 1 only and on Day 15 of Cycles 1-4. The Sponsor may direct certain sites to not perform this assessment if it is determined to be infeasible for logistical or
administrative reasons.
27.
After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted 
for their survival status (excluding subjects that have a death event previously recorded).
28.
For subjects in Part B with CRC, CEA will be assessed during screening and predose at every other cycle beginning with Cycle 1 (C1, C3, C5, etc.).
29.
For subjects with CRC only. If BRAF status is unknown at the time of screening, the site should submit sample for local testing. If local testing is not available and a subject’s BRAF status is 
unknown, this procedure does not need to be performed.
30.
Not applicable to subjects in Cohort F.
08QZB0


Product:  MK-4280 
96
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Part B - Arm 3 and Arm 4 Flow Chart
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post treatment Phase
Treatment Cycle/Title
Screening
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up23
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative 
Procedures
Informed Consent2
X
Informed Consent for 
Future Biomedical 
Research3
X
Inclusion/Exclusion 
Criteria
X
Subject Identification 
Card
X
Demographics and 
Medical History
X
Prior and Concomitant 
Medication Review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior Oncology 
Treatment History
X
MK-4280 Administration
X
X
X
X
X
X
08QZB0


Product:  MK-4280 
97
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post treatment Phase
Treatment Cycle/Title
Screening
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up23
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Pembrolizumab 
Administration4
X
X
X
X
X
X
mFOLFOX7 (Arm 3) or 
FOLFIRI (Arm 4) 
Administration
X
X
X
X
X
X
X
X
X
Clinical Procedures/
Assessments
Adverse Events 
Monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examination
X
X5
X5
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Vital Signs (respiratory 
rate, blood pressure, 
pulse, temperature)6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
Electrocardiogram
X
ECOG Performance 
Status
X
X5
X
X
X
X
X
X
X
08QZB0


Product:  MK-4280 
98
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post treatment Phase
Treatment Cycle/Title
Screening
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up23
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Survival Status22
X
Efficacy Procedures/
Assessments
Tumor Imaging and 
irRECIST Response 
Assessment7
X
X7
Laboratory 
Procedures/
Assessments –Analysis 
by Local Lab
Complete blood count 
(CBC) with differential
X8
X5
X
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
PT/INR and aPTT
X8
Chemistry Panel
X8
X5
X
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
CEA Testing
X8
X5
X5
X5
X5
X5
X5
Lactate dehydrogenase
(LDH), gamma-glutamyl 
transferase (GGT)
X8
X5
X5
X5
X5
X5
X5
08QZB0


Product:  MK-4280 
99
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post treatment Phase
Treatment Cycle/Title
Screening
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up23
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Pregnancy Test – Urine 
Serum β-human 
chorionic 
gonadotropin (β-hCG), 
if applicable9
X
X
Urinalysis
X8
X5
X5
X5
X
X
Thyroid Function 
(thyroxine [T4], 
triiodothyronine [T3], 
thyroid stimulating 
hormone [TSH])
X
X
5
X5
X5
X5
X5
X5
X
X
BRAF Status24
X
HIV, Hepatitis B and C10
X
Laboratory 
Procedures/
Assessments-Analysis 
to be Performed by 
Central Lab
Anti-MK-4280 
Antibodies11
X
X
X
X
X11
X
08QZB0


Product:  MK-4280 
100
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post treatment Phase
Treatment Cycle/Title
Screening
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up23
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Anti-Pembrolizumab 
Antibodies11
X
X
X
X
X11
X
PK for Pembrolizumab
and MK-428012, 13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK for Oxaliplatin 
(Arm 3)14
X
PK for Irinotecan 
(Arm 4)14
X
PK for 5-FU14
X
Blood for DNA 
Correlative Studies15
X
X
X
Blood for RNA 
Correlative Studies15
X
X
X
Blood for Genetic 
Analysis16
X
Blood for Exploratory 
Protein Analysis 
(serum)15
X
X
X
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post treatment Phase
Treatment Cycle/Title
Screening
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up23
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Pharmacodynamic 
receptor availability17, 18
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipase and Amylase19
X
X
X
X
X
X
X
X
T-cell flow cytometry 
analysis20
X
X
X
X
X
X
X
X
X
Tumor Tissue 
Collection
Archival or New 
Obtained Tumor Tissue21
X
Post Treatment Tumor 
Biopsy22
X
1.
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after the 
scheduled Day 1. 
2.
Documented informed consent must be obtained prior to performing any protocol-specific procedure. Tests performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame.
3.
Providing documented informed consent for Future Biomedical Research (FBR) is optional, and may be provided at any time during the subject’s participation in the trial. Detailed instructions 
for the collection and management of FBR specimens are provided in the Procedure Manual.
4.
Pembrolizumab is administered first and then, following a 30-minute interval, MK-4280 will be administered.
5.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing. If Screening was performed ≤72 hours prior to dosing in Cycle 1, the results 
obtained at Screening can also be used for the Cycle 1, Day 1 predose values.
6.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. On Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for 
each) after start of the MK-4280 infusion. Beginning with Cycle 5, collect VS predose on Day 1 of each cycle for all subjects. .
7.
Tumor imaging (computerized tomography [CT] scan or magnetic resonance imaging [MRI]) should be performed within 28 days of enrollment. Tumor imaging and response assessment are to 
be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging assessments should be repeated every 9 weeks and follow calendar days and should not be adjusted 
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for delays in cycle starts. If institutional standard of care for imaging frequency differ from these guidelines, follow the institutional standard of care after confirming with the Sponsor. The 
same imaging technique should be used on a subject throughout the trial. Information for disease assessments may be requested and submitted for central review.
8.
Laboratory tests at Screening are to be performed within 7 days prior to the first dose of study treatment.
9.
For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours of receiving the first dose of study medication. If urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
10.
Include HCV RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (eg, HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
11.
MK-4280 and pembrolizumab ADA samples (predose; all subjects) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, and 8, and every 4 cycles thereafter. 
12.
Pembrolizumab and MK-4280 PK samples (predose) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, 8 and every 4 cycles thereafter.
13.
Postdose pembrolizumab and MK-4280 PK samples will be drawn on Day 1 of Cycles 1, 2, 4, 6, and 8 at the end of the pembrolizumab infusion (+10 minutes; pembrolizumab PK assessed 
alone), at the end of MK-4280 infusion (+10 minutes), and 2 hrs after the start of the MK-4280 infusion (±10 minutes). Additional postdose pembrolizumab and MK-4280 PK samples in 
Cycles 1, 2, and 4 will be collected on Day 2 (Cycle 1 only), Day 8, and Day 15. PK samples will also be drawn at Discontinuation and at the Safety Follow-up Visit.
14.
PK samples for oxaliplatin (Arm 3), irinotecan and its active metabolite SN-38 (Arm 4), and 5-FU (Arm 3 and Arm 4) will be collected pre-dose and at the end of their respective second
infusions (+10 minutes, ie Day 15 of Cycle 1). Subjects must return to the study site when the 5-FU infusion ends (46-48 hours after Cycle 1 Day 15, ie on Day 17) to provide this post-infusion 
sample (+10 minutes).
15.
Blood for correlative studies (RNA and DNA samples) and serum for exploratory protein analysis will be drawn prior to dosing on Day 1 of Cycle 1, on Day 1 of Cycle 2 (or Day 22 of Cycle 1 
for subjects who do not receive a second dose of MK-4280), and at discontinuation. Detailed instructions for the collection and management of these samples are provided in the Procedure 
Manual.
16.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation prohibiting 
collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is collected, leftover extracted 
DNA will be stored for FBR if the subject (or legally acceptable representative) provides documented informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
17.
Pharmacodynamic receptor availability samples (predose) for all subjects will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, 8, and every 4 cycles thereafter
18.
Postdose pharmacodynamic receptor availability samples will be drawn on Day 1 of Cycles 1, 2, 4, 6, and 8 at the end of the pembrolizumab infusion (+10 minutes), at the end of the MK-4280 
infusion (+10 minutes), and 2 hrs after the start of the MK-4280 infusion (±10 minutes). Additional postdose pharmacodynamic receptor availability samples in Cycles 1, 2, and 4 will be 
collected on Day 2 (Cycle 1 only), Day 8, and Day 15. Pharmacodynamic receptor availability samples will also be drawn at Discontinuation.
19.
On Day 1 in Cycles 1-4, amylase and lipase samples should both be drawn predose and repeated 4 hours (±10 mins) after the start of the first infusion. Beginning with Cycle 5, amylase and 
lipase should be drawn predose on Day 1 for all subjects.
20.
Predose T-cell flow cytometry analysis samples will be drawn from subjects within 24 hours prior to start of infusion on Day 1 of Cycles 1-4. Postdose samples will be drawn on Day 8 of Cycle 
1 only and on Day 15 of Cycles 1-4. The Sponsor may direct certain sites to not perform this assessment if it is determined to be infeasible for logistical or administrative reasons.
21.
Tumor tissue (archival or newly obtained biopsy) will be required at Screening for all subjects. PD-L1 testing will be performed but does not need to be completed during Screening. Prior MSI 
testing is required. If subjects have not had these tests previously performed, they should be performed by the local laboratory at Screening. Leftover tissue may also be saved for Future 
Biomedical Research if the subject provides documented informed consent for FBR.
22.
Post treatment tumor biopsy is optional, but strongly encouraged, for all subjects in Cycle 1 between Day 8 and Day 15. Leftover tissue may also be saved for FBR if the subject provides 
documented informed consent for FBR.
23.
After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted 
for their survival status (excluding subjects that have a death event previously recorded).
24.
For subjects with CRC only. If BRAF status is unknown at the time of screening, the site should submit sample for local testing. If local testing is not available and a subject’s BRAF status is 
unknown, this procedure does not need to be performed.
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Part B – Arm 6 Flow Chart
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed Consent3
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Prior Oncology Treatment History
X
MK-4280 Drug Administration
X
X
X
X
Pembrolizumab Drug Administration4
X
X
X
X
Lenvatinib Dispensed5
X
X
X
X
Lenvatinib Container Returned
X
X
X
X
Clinical Procedures/Assessments
Adverse Events Monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination (including 
oral examination)
X
X6
X6
X6
X6
X
X
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Height
X
Weight
X
X
X
X
X
X
X
Vital Signs (respiratory rate, blood 
pressure, pulse, temperature)7
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram8
X
X
X
X
X
X
X
MUGA or ECHO for LVEF 
assessment
X
X
ECOG Performance Status
X
X6
X6
X6
X6
X
X
Survival Status2
X
Efficacy Procedures/Assessments
Tumor Imaging and irRECIST 
Response Assessment9
X
X9
X9
X9
Laboratory 
Procedures/Assessments –Analysis 
by Local Lab
Complete blood count (CBC) with 
differential
X10
X6,11
X
X
X6,11
X
X6,11
X6,11
X
X
PT/INR and aPTT
X10
Chemistry Panel
X10
X6,11
X
X6,11
X
X6,11
X6,11
X
X
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
CEA Testing12
X10
X6
X12
X12
X12
Lactate dehydrogenase (LDH), 
gamma-glutamyl transferase (GGT)
X10
X6
X6
X6
Pregnancy Test – Urine Serum β-
human chorionic gonadotropin 
(β-hCG), if applicable13
X
X
X
X
X
X
X
Urinalysis
X10
Urine dipstick testing14
X10
X
X
X
X
X
X
X
X
Thyroid Function (thyroxine [T4], 
triiodothyronine [T3], thyroid 
stimulating hormone [TSH])15
X
X6
X6
X6
X
X
BRAF Status16
X
HIV, Hepatitis B and C17
X
Laboratory 
Procedures/Assessments-Analysis to 
be Performed by Central Lab
Anti-MK-4280 Antibodies and Anti-
Pembrolizumab Antibodies18
X
X
X
X
X
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after 
last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
PK for Pembrolizumab
and MK-428019
X
X
X
X
X
X
X
X
X
PK for Lenvatinib20
X
X
X
Blood for DNA Correlative Studies21
X
X
X
Blood for RNA Correlative Studies21
X
X
X
Blood for Genetic Analysis22
X
Blood for Exploratory Protein 
Analysis (serum)21
X
X
X
Pharmacodynamic receptor 
availability23
X
X
X
X
X
X
X
X
X
Lipase and Amylase24
X
X
X
X
X
X
X
T-cell flow cytometry analysis25
X
X
X
X
X
Tumor Tissue Collection
Archival or New Obtained Tumor 
Tissue26
X
Post Treatment Tumor Biopsy27
X
1.
Trial treatment may be administered up to 3 days before or 3 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 3 days after the 
scheduled Day 1. 
2.
After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted 
for their survival status (excluding subjects that have a death event previously recorded).
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3.
Documented informed consent must be obtained prior to performing any protocol-specific procedure. Tests performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame.
4.
Pembrolizumab is administered first and then, following a 30-minute interval, MK-4280 will be administered.
5.
Lenvatinib will be administered 0 to 4 hours after completion of the MK-4280 administration. Lenvatinib will also be administered in the clinic on Cycle 1 Day 15 to allow for predose and 
postdose PK sample collections.
6.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing. If Screening was performed ≤72 hours prior to dosing in Cycle 1, the results obtained 
at Screening can also be used for the Cycle 1, Day 1 predose values.
7.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. Blood pressure and pulse will be measured after the subject has been resting for 5 minutes. On 
Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for each) after start of the MK-4280 infusion. Beginning with Cycle 5, collect VS predose on Day 1 of each 
cycle. 
8.
Twelve-lead electrocardiogram (ECG) at screening, Day 1 of Cycle 1 and Cycle 2, Day 1 of every 4th cycle (12 weeks) thereafter (eg, Cycle 6, Cycle 10, Cycle 14, etc), Discontinuation, and the 
Safety Follow-up Visit. ECG at Cycle 1, Day 1 and Cycle 2, Day 1 should be performed approximately 2 hours post-lenvatinib dose. For high-risk patients (Section 7.1.2.5), conduct ECG 
monitoring every cycle. If lenvatinib is discontinued, ECGs are only required at the Discontinuation and Safety Follow-up visits.
9.
Tumor imaging (computerized tomography [CT] scan or magnetic resonance imaging [MRI]) should be performed within 28 days of enrollment. Tumor imaging and response assessment are to 
be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging assessments should be repeated every 9 weeks and follow calendar days and should not be adjusted 
for delays in cycle starts. If institutional standard of care for imaging frequency differ from these guidelines, follow the institutional standard of care after confirming with the Sponsor. The same 
imaging technique should be used on a subject throughout the trial. Information for disease assessments may be requested and submitted for central review.
10.
Laboratory tests at Screening are to be performed within 7 days prior to the first dose of study treatment.
11.
On Day 1 in Cycles 1-4, CBC with differential and the Chemistry Panel should be drawn prior to dosing. 
12.
CEA will be assessed during screening and predose at every other cycle beginning with Cycle 1 (C1, C3, C5, etc.).
13.
For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 24 hours of receiving the first dose of study medication. If more than 24 hours have 
elapsed prior to the first dose of study intervention, another pregnancy test is required prior to starting study intervention. If urine pregnancy test cannot be confirmed as negative, a serum 
pregnancy test is required.
14.
Urine dipstick testing is to be performed at screening, Day 1 and Day 15 of Cycle 1 and Cycle 2, Day 1 of every cycle thereafter, and at the Discontinuation and Safety Follow-up visits.
Urinalysis may be used if the use of urine dipsticks is not feasible.
15.
Thyroid function testing is to be performed at screening, Cycle 1 Day 1 and then Day 1 of every other cycle, and at the post treatment Safety Follow-up Visit.
16.
If BRAF status is unknown at the time of screening, the site should submit sample for local testing. If local testing is not available and a subject’s BRAF status is unknown, this procedure does 
not need to be performed.
17.
Include HCV RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (eg, HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
18.
Pembrolizumab and MK-4280 ADA samples (predose) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, and 8, and every 4 cycles thereafter.
19.
Pembrolizumab and MK-4280 PK samples (predose) will be drawn from subjects within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, and 8, and every 4 cycles thereafter. 
Postdose pembrolizumab and MK-4280 PK samples will be drawn on Day 1 of Cycle 1 at the end of the pembrolizumab infusion (+10 minutes; pembrolizumab PK assessed alone), at the end of 
MK-4280 infusion (+10 minutes), and 2 hrs after the start of the MK-4280 infusion (±10 minutes). Additional postdose pembrolizumab and MK-4280 PK samples in Cycle 1 will be collected on 
Day 2, Day 8, and Day 15. PK samples will also be drawn at Discontinuation and at the Safety Follow-up Visit. 
20.
Lenvatinib PK samples will be drawn on Cycle 1 Day 1 (between 0.5 hr to 4 hrs and 6 to 10 hours postdose), on Cycle 1 Day 15 (predose and between 2 to 12 hours postdose), and on Cycle 2 
Day 1 (predose and between 0.5 hr to 4 hrs and 6 to 10 hours postdose). No predose sampling on Cycle 1 Day 1. All predose samples should be collected within 2 hours of lenvatinib dosing. 
Postdose samples are not needed if lenvatinib administration is skipped.
21.
Blood for correlative studies (RNA and DNA samples) and serum for exploratory protein analysis will be drawn prior to dosing on Day 1 of Cycle 1, on Day 1 of Cycle 2 (or Day 22 of Cycle 1 
for subjects who do not receive a second dose of MK-4280), and at discontinuation. Detailed instructions for the collection and management of these samples are provided in the Procedure 
Manual.
22.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation prohibiting collection, 
or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. 
23.
Pharmacodynamic receptor availability samples (predose) will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, 8, and every 4 cycles thereafter. Postdose 
pharmacodynamic receptor availability samples will be drawn on Day 1 of Cycle 1 at the end of the pembrolizumab infusion (+10 minutes), at the end of the MK-4280 infusion (+10 minutes), 
and 2 hrs after the start of the MK-4280 infusion (±10 minutes). Additional postdose pharmacodynamic receptor availability samples in Cycle 1 will be collected on Day 2, Day 8, and Day 15. 
Pharmacodynamic receptor availability samples will also be drawn at Discontinuation.
24.
On Day 1 in Cycles 1-4, amylase and lipase samples should both be drawn predose and repeated 4 hours (±10 mins) after the start of the first infusion. Beginning with Cycle 5, amylase and 
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lipase should be drawn predose on Day 1.
25.
Predose T-cell flow cytometry analysis samples will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4. Postdose samples will be drawn on Day 8 of Cycle 1 only and on 
Day 15 of Cycles 1-4. The Sponsor may direct certain sites to not perform this assessment if it is determined to be infeasible for logistical or administrative reasons.
26.
Tumor tissue (archival or newly obtained biopsy) will be required at Screening. PD-L1 testing will be performed but does not need to be completed during Screening. Prior MSI testing is also 
required. If subjects have not had these tests previously performed, they should be performed by the local laboratory at Screening. 
27.
Post treatment tumor biopsy is optional, but strongly encouraged, in Cycle 1 between Day 8 and Day 15. 
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Crossover Flow Chart
Subjects who discontinue MK-4280 in Arm 1 of Part B due to confirmed disease progression per irRECIST 1.1 may, at the 
investigator’s discretion and after consultation with the Sponsor, crossover to Arm 2 and receive MK-4280 in combination with 
pembrolizumab. The list and schedule of procedures to be performed are provided in the following flow chart.
Treatment Phase
Cycle = 21 days
End of Treatment
Post Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles ≥ 21
Discon.
Safety Follow-up 
Visit
Survival Follow-
up2
Cycle Day
1
8
1
Every 9 weeks
30 days after last 
dose
Every 12 weeks
Scheduling Window (Days)
±3
±7
±7
±7
Administrative Procedures
Concomitant Medication Review
X
X
X
X
X
MK-4280 Drug Administration 
X
X
Pembrolizumab Drug Administration3
X
X
Clinical Procedures/Assessments
Adverse Events Monitoring 
X
X
X
X
X
Full Physical Examination
X4
X4
X
X
Weight
X
X
X
X
Vital Signs (respiratory rate, blood pressure, pulse, 
temperature)5
X5
X
X5
X
X
12-Lead Electrocardiogram
X4
X
ECOG Performance Status
X4
X4
X
X
Survival Status2
X
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Treatment Phase
Cycle = 21 days
End of Treatment
Post Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles ≥ 21
Discon.
Safety Follow-up 
Visit
Survival Follow-
up2
Cycle Day
1
8
1
Every 9 weeks
30 days after last 
dose
Every 12 weeks
Scheduling Window (Days)
±3
±7
±7
±7
Efficacy Procedures/Assessments
Tumor Imaging and irRECIST Response 
Assessment6
X7
X7
Laboratory Procedures/Assessments –Analysis 
by Local Lab
Complete blood count (CBC) with differential
X4, 7
X
X4
X
X
PT/INR and aPTT
X
Chemistry Panel
X4, 7
X
X4, 7
X
X
CEA Testing (subjects in Part B with CRC only)
X4
X4
Lactate dehydrogenase (LDH), gamma-glutamyl 
transferase (GGT)
X4
Thyroid Function (thyroxine [T4], triiodothyronine
[T3], thyroid stimulating hormone [TSH])8
X4
X4
X
Laboratory Procedures/Assessments-Analysis 
to be Performed by Central Lab
PK for Pembrolizumab and MK-42809, 10
X10
X
X
X
X
Anti-MK-4280 Antibodies9
X
X
X
Anti-Pembrolizumab Antibodies9
X
X
X
Pharmacodynamic receptor availability11, 12
X12
X
X
X
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Treatment Phase
Cycle = 21 days
End of Treatment
Post Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles ≥ 21
Discon.
Safety Follow-up 
Visit
Survival Follow-
up2
Cycle Day
1
8
1
Every 9 weeks
30 days after last 
dose
Every 12 weeks
Scheduling Window (Days)
±3
±7
±7
±7
Lipase and Amylase13
X
X
X
X
Biopsy14
X
1.
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after the 
scheduled Day 1. Note that cycle numbering resets during crossover. Subjects may receive up to 35 cycles of combination treatment regardless of how many cycles of monotherapy treatment 
they received.
2.
After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted 
for their survival status (excluding subjects that have a death event previously recorded).
3.
Pembrolizumab is administered first and then, following a 30-minute interval, MK-4280 will be administered.
4.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing.
5.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. On Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for 
each) after start of the MK-4280 infusion. Beginning with Cycle 5, collect VS predose on Day 1 of each cycle for all subjects.
6.
If ≥4 weeks have passed between the scan used to confirm disease progression (and allow crossover) and Day 1 of Cycle 1, imaging should be repeated and these results should become the new 
baseline images. Tumor imaging and response assessment are to be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging assessments should be repeated 
every 9 weeks and follow calendar days and should not be adjusted for delays in cycle starts. If institutional standard of care for imaging frequency differ from these guidelines, follow the 
institutional standard of care after confirming with the Sponsor. The same imaging technique should be used on a subject throughout the trial. Information for disease assessments may be 
requested and submitted for central review.
7.
On Day 1 in Cycles 1-4, CBC with differential and the Chemistry Panel should be drawn prior to dosing 
8.
Thyroid function testing is to be performed starting in Cycle 1 and then every other cycle and at the post treatment Safety Follow-up Visit.
9.
Pembrolizumab and MK-4280 PK samples (predose) and ADA samples (predose) will be drawn from subjects within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, 8 and every 4 
cycles thereafter. Pembrolizumab and MK-4280 ADA samples will also be drawn at the Safety Follow-up Visit.
10. Postdose pembrolizumab and MK-4280 PK samples will be drawn on Day 1 of Cycle 1 at the end of the pembrolizumab infusion (+10 minutes; pembrolizumab PK assessed alone), at the end 
of MK-4280 infusion (+10 minutes), and 2 hrs after the start of the MK-4280 infusion (±10 minutes). Additional postdose pembrolizumab and MK-4280 PK samples in Cycle 1 will be 
collected on Day 8. PK samples will also be drawn at Discontinuation and at the Safety Follow-up Visit.
11. Pharmacodynamic receptor availability samples (predose) for all subjects will be drawn within 24 hours prior to start of infusion on Day 1 of Cycles 1-4, 6, 8, and every 4 cycles thereafter.
12. Postdose pharmacodynamic receptor availability samples will be drawn on Day 1 of Cycle 1 at the end of the pembrolizumab infusion (+10 minutes), at the end of the MK-4280 infusion (+10 
minutes), and 2 hrs after the start of the MK-4280 infusion (±10 minutes). Additional postdose pharmacodynamic receptor availability samples in Cycle 1 will be collected on Day 8. 
Pharmacodynamic receptor availability samples will also be drawn at Discontinuation.
13. On Day 1 in Cycles 1-4, amylase and lipase samples should both be drawn predose and repeated 4 hours (±10 mins) after the start of the first infusion. Beginning with Cycle 5, amylase and 
lipase should be drawn predose on Day 1.
14. An optional, but strongly encouraged, biopsy should be performed for subjects before they receive the first dose of crossover therapy. Leftover tissue may also be saved for FBR if the subject
provides documented informed consent for FBR.
08QZB0


Product:  MK-4280 
112
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Second Course - Part A - Arm 1 and Arm 2; Part B - Arm 1, Arm 2A , Arm 2B, Arm 2C, and Arm 5 Flow Chart
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up15
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed Consent2
X
Inclusion/Exclusion Criteria
X
Prior and Concomitant Medication 
Review 
X
X
X
X
X
X
X
X
X
X
X
MK-4280 Drug Administration 
(Arm 1 and Arm 2 only)
X
X
X
X
Pembrolizumab Drug Administration3
(Arm 2 only)
X
X
X
X
MK-4280A Drug Administration
(Arm 5 only)
X
X
X
X
Clinical Procedures/Assessments
Adverse Events Monitoring 
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X4
X4
X4
X4
X
X
Weight
X
X
X
X
X
X
Vital Signs (respiratory rate, blood 
pressure, pulse, temperature)5
X
X
X
X
X
X
X
X
X
X
X
08QZB0


Product:  MK-4280 
113
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up15
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
12-Lead Electrocardiogram6
X4
X4
X
ECOG Performance Status
X4
X4
X4
X4
X
X
Survival Status14
X
Efficacy Procedures/Assessments
Tumor Imaging and irRECIST Response 
Assessment7
X7
X7
X7
Laboratory Procedures/Assessments –
Analysis by Local Lab
Complete blood count (CBC) with 
differential
X8,9
X
X4,9
X
X4,9
X4,9
X
X
PT/INR and aPTT11
X
Chemistry Panel
X4,9
X
X4,9
X
X4,9
X4,9
X
X
CEA Testing (subjects in Part B with 
CRC only)12
X8
X12
X12
X12
Lactate dehydrogenase (LDH), gamma-
glutamyl transferase (GGT)
X4
X4
X4
Pregnancy Test – Urine Serum β-human 
chorionic gonadotropin (β-hCG), if 
applicable10
X
Urinalysis11
X
08QZB0


Product:  MK-4280 
114
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up15
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
Thyroid Function (thyroxine [T4], 
triiodothyronine [T3], thyroid stimulating 
hormone [TSH])13
X4
X4
X4
X
X
HIV, Hepatitis B and C14
1.
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after the 
scheduled Day 1. 
2.
Documented informed consent must be obtained prior to performing any protocol-specific procedure. Tests performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame.
3.
In Arm 2 of Part A and Part B, pembrolizumab is administered first and then, following a 30-minute interval, MK-4280 will be administered.
4.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing.
5.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. On Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for 
each) after start of the MK-4280 or MK-4280A infusion. Beginning with Cycle 5, collect VS predose on Day 1 of each cycle for all subjects. 
6.
Twelve-lead electrocardiogram (ECG) should be performed at for all subjects and repeated only for subjects in Arm 1 of Part A and Arm 5 of Part B prior to and within 30 minutes after the end 
of the MK-4280 or MK-4280A infusion in Cycles 1-4, and at the Safety Follow-up Visit.
7.
If ≥4 weeks have passed between the scan used to confirm disease progression (and allow retreatment in second course) and Day 1 of Cycle 1, imaging should be repeated and these results 
should become the new baseline images. Tumor imaging and response assessment are to be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging 
assessments should be repeated every 9 weeks and follow calendar days and should not be adjusted for delays in cycle starts. If institutional standard of care for imaging frequency differ from 
these guidelines, follow the institutional standard of care after confirming with the Sponsor. The same imaging technique should be used on a subject throughout the trial. Information for disease 
assessments may be requested and submitted for central review.
8.
Performed locally within 7 days before first dose. After C1, collect within 3 days prior to dosing.
9.
On Day 1 in Cycles 1-4, CBC with differential and the Chemistry Panel should be drawn prior to dosing. 
10.
For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours of receiving the first dose of study medication. If urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
11.
Laboratory tests to be performed within 7 days prior to the first dose of study treatment.
12.
For subjects in Part B with CRC, CEA will be assessed predose at every other cycle beginning with Cycle 1 (C1, C3, C5, etc.).
13.
Thyroid function testing is to be performed starting in Cycle 1 and then every other cycle and at the post-treatment Safety Follow-up Visit.
14.
Include HCV RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (eg, HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
15.
After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted 
for their survival status (excluding subjects that have a death event previously recorded).
08QZB0


Product:  MK-4280 
115
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Second Course - Part B - Arm 3 and Arm 4 Flow Chart
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-treatment Phase
Treatment Cycle/Title
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up13
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative 
Procedures
Informed Consent2
X
Inclusion/Exclusion 
Criteria
X
Prior and Concomitant 
Medication Review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MK-4280 Administration
X
X
X
X
X
X
Pembrolizumab 
Administration3
X
X
X
X
X
X
mFOLFOX7 (Arm 3) or 
FOLFIRI (Arm 4) 
Administration4
X
X
X
X
X
X
X
X
X
Clinical Procedures/
Assessments
Adverse Events 
Monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
08QZB0


Product:  MK-4280 
116
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-treatment Phase
Treatment Cycle/Title
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up13
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Full Physical 
Examination
X5
X5
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
Vital Signs (respiratory 
rate, blood pressure, 
pulse, temperature)6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
Electrocardiogram
X
ECOG Performance 
Status
X5
X
X
X
X
X
X
X
Survival Status13
X
Efficacy Procedures/
Assessments
Tumor Imaging and 
irRECIST Response 
Assessment7
X
X7
08QZB0


Product:  MK-4280 
117
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-treatment Phase
Treatment Cycle/Title
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up13
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory 
Procedures/
Assessments –Analysis 
by Local Lab
Complete blood count 
(CBC) with differential
X8,5
X
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
PT/INR and aPTT9
X
Chemistry Panel
X9,5
X
X
X5
X
X5
X
X5
X
X5
X
X5
X
X
X
CEA Testing
X8,5
X5
X5
X5
X5
X5
Lactate dehydrogenase
(LDH), gamma-glutamyl 
transferase (GGT)
X5
X5
X5
X5
X5
X5
Pregnancy Test – Urine 
Serum β-human 
chorionic 
gonadotropin (β-hCG), 
if applicable10
X
Urinalysis
X9
X5
X5
X5
X
X
08QZB0


Product:  MK-4280 
118
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-treatment Phase
Treatment Cycle/Title
Cycle 1
Cycle 21
Cycle 31
Cycle 41
Odd 
Number 
Cycles1
(Cycle 5, 
7, 9 etc.)
Even 
Number 
Cycles1
(Cycle 6, 
8, 10 etc.)
Discon
Safety 
Follow-
up Visit
Survival 
Follow-
up13
Cycle Day
1
2
8
15
1
8
15
1
8
15
1
8
15
1
15
1
8
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window 
(Days)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Thyroid Function 
(thyroxine [T4], 
triiodothyronine [T3], 
thyroid stimulating 
hormone [TSH])
X5
X5
X5
X5
X5
X5
X
X
HIV, Hepatitis B and C12
1.
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after the 
scheduled Day 1. 
2.
Documented informed consent must be obtained prior to performing any protocol-specific procedure. Tests performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame.
3.
Pembrolizumab is administered first and then, following a 30-minute interval, MK 4280 will be administered.
4.
Continuation or resumption of same chemotherapy as received in the First Course Treatment Phase may be administered in the Second Course Phase at the discretion of the investigator. Note that 
chemotherapy different from that received in the First Course Treatment Phase is not permitted.
5.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing.
6.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. On Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for each) 
after start of the MK-4280 infusion. Beginning with Cycle 5, collect VS predose on Day 1 of each cycle for all subjects. .
7.
If ≥4 weeks have passed between the scan used to confirm disease progression (and allow retreatment in second course) and Day 1 of Cycle 1, imaging should be repeated and these results should 
become the new baseline images. Tumor imaging and response assessment are to be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging assessments should 
be repeated every 9 weeks and follow calendar days and should not be adjusted for delays in cycle starts. If institutional standard of care for imaging frequency differ from these guidelines, follow 
the institutional standard of care after confirming with the Sponsor. The same imaging technique should be used on a subject throughout the trial. Information for disease assessments may be 
requested and submitted for central review.
8.
Performed locally within 7 days prior to the first dose. After C1, collect within 3 days before dosing.
9.
Laboratory tests are to be performed within 7 days prior to the first dose of study treatment.
10. For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours of receiving the first dose of study medication. If urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
11. Laboratory tests to be performed within 7 days prior to the first dose of study treatment
12. Include HCV RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (eg, HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
13. After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted 
for their survival status (excluding subjects that have a death event previously recorded).
08QZB0


Product:  MK-4280 
119
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Second Course - Part B – Arm 6 Flow Chart
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
Administrative Procedures
Informed Consent3
X
Inclusion/Exclusion Criteria
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
MK-4280 Drug Administration
X
X
X
X
Pembrolizumab Drug Administration4
X
X
X
X
Lenvatinib Dispensed5
X
X
X
X
Lenvatinib Container Returned
X
X
X
X
Clinical Procedures/Assessments
Adverse Events Monitoring 
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination (including 
oral examination)
X6
X6
X6
X6
X
X
Weight
X
X
X
X
X
X
Vital Signs (respiratory rate, blood 
pressure, pulse, temperature)7
X
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram8
X
X
X
X
X
X
08QZB0


Product:  MK-4280 
120
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
MUGA or ECHO for LVEF assessment9
X
X
ECOG Performance Status
X6
X6
X6
X6
X
X
Survival Status2
X
Efficacy Procedures/Assessments
Tumor Imaging and irRECIST Response 
Assessment10
X9
X9
X9
Laboratory Procedures/Assessments –
Analysis by Local Lab
Complete blood count (CBC) with 
differential
X11,12
X
X
X6,12
X
X6,12
X6,12
X
X
PT/INR and aPTT15
X
Chemistry Panel
X11,12
X
X6,12
X
X6,12
X6,12
X
X
CEA Testing13
X6
X13
X13
X13
Lactate dehydrogenase (LDH), gamma-
glutamyl transferase (GGT)
X6
X6
X6
Pregnancy Test – Urine Serum β-human 
chorionic gonadotropin (β-hCG), if 
applicable14
X
X
X
X
X
X
Urinalysis15
X
Urine dipstick testing9,16
X
X
X
X
X
X
X
X
08QZB0


Product:  MK-4280 
121
Protocol/Amendment No.: 001-13
MK-4280-001-13 Final Protocol
01-Dec-2022
Confidential
Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
Thyroid Function (thyroxine [T4], 
triiodothyronine [T3], thyroid 
stimulating hormone [TSH])17
X6
X6
X6
X
X
HIV, Hepatitis B and C18
1.
Trial treatment may be administered up to 3 days before or 3 days after the scheduled Day 1 of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 3 days after the 
scheduled Day 1. 
2.
After confirmed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their survival status (excluding subjects that have a death event previously recorded).
3.
Documented informed consent must be obtained prior to performing any protocol-specific procedure. Tests performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame.
4.
Pembrolizumab is administered first and then, following a 30-minute interval, MK-4280 will be administered.
5.
Lenvatinib is allowed during Second Course at the discretion of the investigator. Antineoplastic therapy different from lenvatinib is not permitted.  Lenvatinib will be administered 0 to 4 hours 
after completion of the MK-4280 administration.
6.
These samples and procedures required predose on Day 1 may be performed up to 72 hours prior to dosing.
7.
Vital signs (VS) to include temperature, pulse, respiratory rate, and blood pressure for all subjects. Blood pressure and pulse will be measured after the subject has been resting for 5 minutes. 
On Day 1 of Cycles 1-4, collect prior to dosing and at 2 hrs, 4 hrs, and 6 hrs (±10 mins for each) after start of the MK-4280 infusion. Beginning with Cycle 5, collect VS predose on Day 1 of 
each cycle. 
8.
Twelve-lead electrocardiogram (ECG) at screening, Day 1 of Cycle 1 and Cycle 2, Day 1 of every 4th cycle (12 weeks) thereafter (eg, Cycle 6, Cycle 10, Cycle 14, etc), Discontinuation, and 
the Safety Follow-up Visit. ECG at Cycle 1, Day 1 and Cycle 2, Day 1 should be performed approximately 2 hours post-lenvatinib dose. For high-risk patients (Section 7.1.2.5), conduct ECG 
monitoring every cycle. If lenvatinib is discontinued, ECGs are only required at the Discontinuation and Safety Follow-up visits. If Lenvatinib was not administered in second course then 
ECG is only required at Cycle 1, Day 1 and Safety Follow-up.
9.
Only to be performed if lenvatinib is administered during Second Course.
10.
If ≥4 weeks have passed between the scan used to confirm disease progression (and allow retreatment in second course) and Day 1 of Cycle 1, imaging should be repeated and these results 
should become the new baseline images. Tumor imaging and response assessment are to be performed 9 weeks after first dose, then every 9 weeks until disease progression. Imaging 
assessments should be repeated every 9 weeks and follow calendar days and should not be adjusted for delays in cycle starts. If institutional standard of care for imaging frequency differ from 
these guidelines, follow the institutional standard of care after confirming with the Sponsor. The same imaging technique should be used on a subject throughout the trial. Information for 
disease assessments may be requested and submitted for central review.
11.
Performed locally within 7 days before first dose. After C1, collect within 3 days before dosing.
12.
On Day 1 in Cycles 1-4, CBC with differential and the Chemistry Panel should be drawn prior to dosing. 
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Treatment Phase
Cycle = 21 days
End of 
Treatment
Post-Treatment Phase
Treatment Cycle/Title
Cycle 1
Cycles 2-41
Cycles 
5-81
Cycle 9 
and 
Beyond1
Discon.
Safety 
Follow-
up Visit
Survival 
Follow-up2
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
±3
±3
±3
±3
±7
±7
±7
13.
CEA will be assessed during screening and predose at every other cycle beginning with Cycle 1 (C1, C3, C5, etc.).
14.
For women of reproductive potential, a urine pregnancy test will be performed within 24 hours of receiving the first dose of study medication. If more than 24 hours have elapsed prior to the 
first dose of study intervention, another pregnancy test is required prior to starting study intervention. If urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is 
required.
15.
Laboratory tests to be performed within 7 days prior to the first dose of study treatment
16.
Urine dipstick testing is to be performed at screening, Day 1 and Day 15 of Cycle 1 and Cycle 2, Day 1 of every cycle thereafter, and at the Discontinuation and Safety Follow-up visits.
Urinalysis may be used if the use of urine dipsticks is not feasible.
17.
Thyroid function testing is to be performed at screening, Cycle 1 Day 1 and then Day 1 of every other cycle, and at the post-treatment Safety Follow-up Visit.
18.
Include HCV RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (eg, HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed). 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented informed consent from each 
potential subject or their legally acceptable representative prior to participating in this clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate documented informed consent is in place.
7.1.1.1.1 General Informed Consent
Informed consent given by the subject or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion. 
A copy of the signed and dated informed consent form should be given to the subject (or 
their legally acceptable representative) before participation in the trial.
The initial informed consent form, any subsequent revised informed consent form, and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the trial.  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 subject’s or the subject’s legally acceptable 
representative’s dated signature.
Specifics about the trial and the trial population are to be included in the trial informed 
consent form.  
Informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, or the subject’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to Future Biomedical Research.  A copy of the informed consent will be given to the subject 
before performing any procedure related to Future Biomedical Research.
Future Biomedical Research will not be applicable to Arm 6 or Cohort F.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides documented informed consent. At the time of treatment allocation/randomization, 
site personnel will add the treatment/randomization number to the Subject Identification 
Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered clinically significant by the investigator. Details regarding the disease for 
which the subject has been enrolled in the trial will be recorded separately and should not be 
listed in medical history.
Prior and Concomitant Medications Review
7.1.1.5.1 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 subject 
within 30 days before starting the trial. Treatment for the disease for which the subject has 
been enrolled in this trial will be recorded separately and should not be listed in prior 
medications.
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7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial and through the 30-day Safety Follow-up Visit. After the Safety Follow-up 
Visit, record all medications related to reportable SAEs and ECIs as defined in Section 7.2.
If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial 
treatment, the 30-day Safety Follow-up Visit must occur before the first dose of the new 
therapy.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
Subjects in Cohort E of Part B will be randomly allocated to 1 of 2 doses of MK-4280 and 
will receive a treatment/randomization number accordingly.  If Arms 1, 2C and 5 for 3L+ 
CRC subjects are enrolling at the same time, subjects will be assigned in an alternating 
fashion across the open arms at the study level through IVRS.   
All other eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  
The treatment/randomization number identifies the subject for all procedures occurring after 
treatment allocation/randomization.  For subjects that are being allocated to their treatment, 
and not ‘randomized’, the unique number is still termed a randomization number throughout 
the protocol for operational purposes. Allocation to either Arm 1 or Arm 2 of Part A, and 
enrollment and/or randomization in Part B, will be managed by the Sponsor through an 
IVRS/IWRS.
Once a treatment/randomization number is assigned to a subject, it can never be re-assigned 
to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment(s) for 12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
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If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption of study intervention or infusion/injection 
cessation will be documented in the participant’s medical record. Refer to Section 5.2.6 for 
Dose Modification and Toxicity Management Guidelines.
For subjects in Arm 6, lenvatinib compliance will be calculated by the Sponsor based on the 
drug accountability documented by the site staff and monitored by the Sponsor/designee. The 
objective is 100% compliance and investigators and their staff should evaluate compliance at 
each visit and take appropriate steps to optimize compliance.
Administration of Study Treatments
MK-4280 and pembrolizumab (or MK-4280A) will be administered using intravenous 
infusion. The Pharmacy Manual contains specific instructions for the preparation and 
administration of the infusion solutions.  
Designated site personnel will be responsible for preparing and administering MK-4280 and 
pembrolizumab (or MK-4280A), and will be required to record limited information during 
each infusion (eg, infusion date/time, lot number and expiry date for product administered, 
total dose/volume administered). See Pharmacy Manual for further details.
In Arm 2 of Part A and Part B, pembrolizumab is administered first and then, following a 
30-minute interval, MK-4280 will be administered.
In Arm 3 and Arm 4, pembrolizumab is administered first and then, following a 30-minute 
interval, MK-4280 will be administered. At visits where MK-4280, pembrolizumab, and 
chemotherapy are to be administered, chemotherapy will be administered in accordance with 
their approved labeling and in keeping with local clinical practice 30 minutes after the end of 
the MK-4280 infusion. Every attempt should be made to record limited information during 
each infusion (eg, infusion date/time, lot number and expiry date for product administered, 
total dose/volume administered) as per local guidelines. More details can be found in the 
Pharmacy Manual.
In Arm 6 of Part B, pembrolizumab is administered first and then, following a 30-minute 
interval, MK-4280 will be administered. Lenvatinib will be taken orally with water (with or 
without food) at approximately the same time each day in 21-day cycles. However, on visit 
days when pembrolizumab and MK-4280 are also administered, lenvatinib will be 
administered 0 to 4 hours after the MK-4280 infusion is complete.
If a lenvatinib dose is missed and cannot be taken within 12 hours, then that dose should be 
skipped and the next dose should be taken at the usual time of administration.
Subjects in Arm 1 of Part B who discontinue MK-4280 due to confirmed disease progression 
per irRECIST may be allowed to crossover to Arm 2 (see Section 5.2.5). The subject may 
receive up to 35 cycles of combination treatment (irrespective of how many cycles of 
monotherapy treatment they received).
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Disease Details and Treatments
7.1.1.10.1
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.
7.1.1.10.2
Prior Oncology Treatment History
The investigator or qualified designee will record all prior anti-cancer treatments including 
systemic treatments, radiation and surgeries radiations and surgeries regardless of time prior 
to first dose of trial treatment.
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated. Adverse events will be graded according to NCI CTCAE Version 4.0. Toxicities 
will be characterized in terms of seriousness, causality, toxicity grade, and action taken with 
regard to trial treatment. 
This is a dose-escalation trial to establish the MTD/MAD of MK-4280 monotherapy and an 
RP2D for MK-4280 when given in combination with pembrolizumab; therefore, each dose 
escalation will be based on the safety and tolerability experienced by subjects at each dose 
level. The safety and tolerability of each cohort for the DLT evaluation period will be 
reviewed prior to the start of the next cohort in each arm. The Sponsor and the principal 
investigators will review the safety and tolerability of each trial treatment, the 
appropriateness of dose escalation, when each cohort is completed and the next cohort is 
opened for enrollment. Frequency of these communications will depend on the enrollment of 
each cohort, as well as any potential new information regarding a safety concern in this trial 
or other relevant trials.
As a Phase 1 trial, there is no plan for an external safety reviewer. Data from individual 
subjects will be closely followed on an ongoing basis by the principal investigator and the 
Sponsor.
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant findings from the screening exam should be recorded 
as medical history. 
A full physical exam should be repeated according to the frequency defined in Section 6.0 –
Trial Flow Chart. After the first dose of study treatment, new clinically significant abnormal 
findings should be recorded as AEs.
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For subjects receiving lenvatinib on Arm 6: A complete physical examination including oral 
examination will be conducted by an investigator or medically qualified designee (consistent 
with local requirements) per institutional standard.
Vital Signs, Height, and Weight
The investigator or qualified designee will take vital signs for all study subjects at Screening,
and on Day 1 of Cycles 1-4 prior to dosing, and at 2 hours, 4 hours, and 6 hours after the start 
of the MK-4280 (or MK-4280A) infusion. Subjects in Arm 2C, Arm 5, and Arm 6 will also 
be monitored for 6 hours after the start of the MK-4280 (or MK-4280A) infusion for signs of 
infusion reaction in Cycles 1-4. Beginning with Cycle 5, vital signs are to be collected prior 
to dosing on Day 1 of each cycle for all subjects, and at the Safety Follow-up Visit as 
specified in the Trial Flow Chart. Vital signs should include temperature, pulse, respiratory 
rate, blood pressure (BP), and weight at the frequency defined in Section 6.0 – Trial Flow 
Chart.
Height will be obtained at Screening only.
For subjects receiving lenvatinib on Arm 6:
•
BP and heart rate will be measured after the subject 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 subjects with systolic BP <140 mm Hg and 
diastolic BP <90 mm Hg. If the subject’s first BP measurement of the current assessment 
is elevated (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), the BP 
measurement should be repeated at least 5 minutes later. One BP assessment is defined as 
the mean value of 2 measurements at least 5 minutes apart. If the BP assessment (ie, the 
mean of the 2 BP measurements obtained at least 5 minutes apart) shows an elevated BP 
(systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory assessment 
should be obtained at least 30 minutes later by performing 2 measurements (at least 5 
minutes apart) to yield a mean value.
•
If required, subjects will have BP measured between clinic visits. If the subject does not 
return to the study site for this BP measurement, BP may be measured, for example, at 
home or at a local pharmacy, and the results will be reviewed with the investigator or 
designee. The investigator/site may provide a diary as a tool to aid the subject in 
collecting BP evaluations between clinic visits. The Sponsor will not provide diaries to 
the site. If BP result raises concerns, the investigator may require additional follow-up, 
including an on-site BP re-test, or other clinically appropriate intervention(s).  
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess the ECOG performance status as the 
time points specified in the Section 6.0 – Trial Flow Chart.
Electrocardiogram
A 12-lead ECG will be performed by the investigator or qualified designee at the time points 
outlined in Section 6.0 – Trial Flow Chart.
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For subjects receiving lenvatinib on Arm 6:
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. Subjects 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 
Section 7.2) 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 Section 6.3 – Arm 6 Flow Chart) 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.
Echocardiogram or Multiple Gated Acquisition Scan
For subjects receiving lenvatinib on Arm 6, a MUGA scan (using technetium-based tracer) or 
an echocardiogram will be performed to assess left ventricular ejection fraction (LVEF) as 
designated in the SoA (Section 6.3). 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 subject at baseline should 
be repeated for all subsequent LVEF assessments for that subject. LVEFs as assessed by the 
institution will be entered onto the CRF. Investigator assessment will be based upon 
institutional reports.
Pregnancy Testing
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.2.
-
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 subject's participation in the study.
Arm 6 only:
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in 5.1.2.
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Disease Assessments
Initial imaging (CT scans or MRI) must be performed within 28 days prior to the first dose of 
treatment, and should be repeated every 9 weeks (±7 days) from the first dose of treatment
until confirmed disease progression, the start of new anticancer therapy, withdrawal of 
consent, death, or end of the study, whichever comes first.
The same imaging technique should be performed at each time point.
Information for disease assessments may be requested and submitted for central review.
Response will be assessed using RECIST 1.1 criteria by investigator assessment. However, 
clinical decisions as to whether discontinue study treatment should be made using irRECIST 
criteria along with clinical judgement.
Immunotherapeutic agents, such as MK-4280 and pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune response. The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with typical cytotoxic agents, and can manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Therefore, the subject should not be 
discontinued from the trial unless the initial assessment of PD is confirmed at least 4 weeks 
later (Section 4.2.3.1).
Subjects who have initial evidence of radiological PD by RECIST 1.1 after starting study 
treatment, should, at the discretion of the investigator, continue on study treatment until 
repeat imaging is obtained ≥4 weeks later to confirm PD. This clinical judgement decision 
should be based on the subject’s overall clinical condition, including performance status, 
clinical symptoms, and laboratory data. Clinical stability is defined as the following:
(1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values
(2) No decline in ECOG performance status
(3) Absence of rapid progression of disease 
(4) Absence of progressive tumor at critical anatomical sites (eg, spinal cord compression)  
Any subject deemed clinically unstable should be discontinued from trial treatment and is not 
required to have repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased on the follow-up 
scan per RECIST 1.1, the local site investigator should consider target and nontarget lesions,
as well as any incremental new lesion(s).
Progressive disease will be confirmed at repeat imaging if ANY of the following occur:

Tumor burden remains ≥20% and there is at least a 5 mm absolute increase compared 
to the nadir

Nontarget disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) are identified since the last evaluation
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
Additional new nontarget progression is identified since the last evaluation
For subjects who crossover Part B from Arm 1 to Arm 2C due to confirmed disease 
progression, the following criteria apply:

The imaging results used for determination of disease progression and crossover 
(confirmatory scans, if performed) should become the new baseline imaging results 
from which subsequent progression is to be determined.

Imaging for subjects who crossover should continue per the regular imaging schedule 
(every 9 weeks calculated from first dose of study treatment and not adjusted for 
delays)

Management of crossover subjects will be identical to the management of new 
subjects entering Arm 2C of the study (ie, combination treatment should be 
discontinued once disease progression is documented and, if applicable, confirmed 
per irRECIST 1.1)

All participants who have completed the first course may be eligible for second 
course of treatment after Sponsor consultation if there is investigator-determined 
progressive disease after initial treatment has been completed. Please refer to 
Sections 5.2.8, 6.5, 6.6, and 6.7 for additional details for imaging in second course.
Tumor Tissue Collection and Biomarker Assessment
Subjects will be requested to provide a tumor sample (archival or newly obtained 
pretreatment sample) as specified in the Procedure Manual. Sample collection, storage, and 
shipment instructions for correlative study samples, archival tumor samples, and newly 
obtained biopsy specimens will be provided in the Procedure Manual.
For all subjects in Part B, PD-L1 assessment will be performed but does not need to take 
place during the screening period.
For subjects in Part B with HNSCC (of oropharyngeal origin, only), HPV testing by p16 
IHC, polymerase chain reaction (PCR), or fluorescent in situ hybridization is required before 
or during screening. For subjects in Part B with gastric cancer, HER2/neu testing via IHC
and EBV testing via Epstein–Barr virus-encoded small RNAs (EBER1) in situ hybridization 
are required before or during screening. For subjects in Part B with gastric cancer or CRC, 
MSI testing by IHC or PCR is required before or during screening.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pretrial to posttrial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
Laboratory Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, urinalysis and others are specified in Table 8.
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Table 8 Laboratory Tests
Hematology
Chemistry
Urinalysis/Urine Dipstick 
Testingf
Other
Hematocrit
Albumin
Blood
Blood 
for 
correlative 
studies
Hemoglobin
Alkaline phosphatase
Glucose
β-hCGa
Platelet count
ALT
Protein
 Blood for genetics
White blood cells 
(WBC) (total and 
differential)
AST
Specific gravity 
  PT (INR)d
Red
blood 
cells 
(RBC)
Bicarbonate or carbon dioxide 
(CO2)b
Microscopic 
exam, 
if 
abnormal results are noted
  aPTT/PTTd
Absolute 
neutrophil count
Calcium
Urine pregnancy testa
TSH (T3, T4, TSH)e
Chloride
CEA
Creatinine
BRAF
Glucose
Phosphorus
LDH and GGT
Potassium
Sodium
Total bilirubin  
Direct bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood urea nitrogen
Ureac
Uric Acid
Magnesiumg
a.
Perform on women of childbearing potential only. Urine pregnancy test is preferred. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
b.
If these tests are not done as part of standard of care in a particular region then these tests do not need to be 
performed.
c.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
d.
Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all subjects. 
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
e.
Total T3 is preferred; if not available free T3 may be tested.
f.
For subjects in Arm 6, if urine protein is ≥2+ (≥100 mg/dL) (first occurrence or a subsequent increase in severity of 
urine dipstick or urinalysis proteinuria occurring on the same lenvatinib dose level), then a 24-hour urine collection 
or an immediate spot urine protein to-creatinine (UPCR) test should be done to quantify the 24-hour urine protein 
excretion. A 24 hour urine collection (initiated as soon as possible and at least within 72 hours) to verify the grade 
of proteinuria is required when UPCR is ≥2.4.
g.
For subjects in Arm 6 only.
Laboratory tests for Screening should be performed within 7 days prior to the first dose of 
study treatment. After Cycle 1, predose laboratory tests can be performed up to 72 hours 
prior to dosing. Results must be reviewed by the investigator of qualified designee and found 
to be acceptable prior to each dose of study treatment.
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For subjects in Arm 6, CBC with differential and clinical chemistry results must be reviewed 
before administration of study treatment. Electrolytes such as potassium, calcium, and 
magnesium should be monitored and abnormalities, when considered clinically significant, 
should be corrected in all subjects before starting study treatment.
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Blood Collection for Analysis
Sample collection, storage, and shipment instructions for blood and plasma samples will be 
provided in the study Procedures Manual. For subjects in Arms 2-6 of Part A and Part B, 
only one set of PK samples needs to be collected to assay for both MK-4280 and 
pembrolizumab.
To evaluate the immunogenicity and exposure of pembrolizumab, MK-4280, mFOLFOX7, 
FOLFIRI, and lenvatinib in these indications, sample collections for analysis of ADA and PK 
are currently planned as shown in the Trial Flowchart. Blood samples for PK and ADA 
collected may be stored only at this time. Further analysis may be performed if required. If 
ongoing PK, PD, and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may 
be reduced or discontinued.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the appendix section.
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:
DNA for future research.
Leftover archival or newly obtained tumor tissue for future research.
Leftover RNA and serum for future research.
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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 trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Approximately 28 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. 
Screening procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the 
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specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of trial treatment except for the following:

Screening laboratory tests are to be performed within 7 days prior to the first dose of 
trial treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site 
laboratory, will be required.

For Arm 6 only: All women who are being considered for participation in Arm 6 of 
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. 
Treatment Visit Period
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided in Section 7.1 - Trial Procedures.
After a screening phase of up to 28 days, eligible subjects will be assigned by either 
randomization or nonrandom allocation to a specific cohort. MK-4280, pembrolizumab, 
MK-4280A, mFOLFOX7, FOLFIRI treatment, and lenvatinib will be administered as 
outlined in Section 5.2 - Trial Treatment(s). After the EOT, all subjects will be followed for 
30 days for AEs. Subjects in Arm 1 of Part A and Part B will also be followed for 30 days for 
SAEs, whereas subjects in Arms 2-6 of Part A and Part B will be followed for 90 days for
SAEs.
Post-Trial
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first. Subjects with an AE of Grade 2 or higher will be further followed until the 
resolution of the AE to Grade 0-1 or until beginning a new anticancer therapy, whichever 
occurs first. Subjects who are eligible for retreatment in second course (see Section 5.2.8 –
Second Course of Study Treatment) may have up to 2 safety follow-up visits, one after the 
initial Treatment Period and one after the Second Course Phase.
7.1.5.3.2 Survival Follow-up
Subjects who experience confirmed disease progression or start a new anticancer therapy will 
move into the Survival Follow-up Phase and should be contacted approximately every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
trial, whichever occurs first.
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Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an interim 
and/or final analysis. Upon Sponsor notification, all subjects who do not/will not have a 
scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their survival status (excluding subjects that have a previously recorded death 
event in the collection tool).
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the subject provides documented informed consent but 
before treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. From the time of treatment allocation/randomization through 30
days following cessation of treatment, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. The investigator will make every attempt to follow all 
subjects with non-serious adverse events for outcome.
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Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by at least 1000 mg (5 times the dose), 20% or more above the 
prescribed dose for MK-4280 or MK-4280A, and any dose above the protocol-prescribed 
dose of lenvatinib if associated with an adverse event. No specific information is available on 
the treatment of overdose of pembrolizumab, MK-4280, MK-4280A, or lenvatinib. In the 
event of overdose, pembrolizumab, MK-4280, MK-4280A, or lenvatinib should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
Sponsor does not recommend specific treatment for an overdose. Decisions regarding dose 
interruptions or modifications will be made by the investigator in consultation with the 
Sponsor Clinical Director based on the clinical evaluation of the participant.
There is no specific antidote for an overdose of lenvatinib. Due to its high degree of plasma 
protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients 
receiving single doses of lenvatinib as high as 40 mg were similar to those in clinical studies 
at the recommended dose for differentiated thyroid cancer, RCC, and HCC.
Refer to the approved prescribing information and local practice guidelines regarding the 
definition of and treatment for an overdose of mFOLFOX7 or FOLFIRI.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
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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.
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the subject provides documented informed 
consent but before treatment allocation/randomization must be reported by the investigator if 
they cause the subject to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure.  Pregnancies and lactations that occur from the time of 
treatment allocation/randomization through 120 days following cessation of study treatment 
(or 30 days following cessation of study treatment if the subject initiates new anticancer 
therapy, whichever is earlier) must be reported by the investigator. All reported pregnancies 
must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
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●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 9 for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
For the time period beginning when the subject provides documented informed consent until 
treatment allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of study treatment (or 30 days following cessation of study treatment if 
the subject initiates new anticancer therapy, whichever is earlier), any serious adverse event, 
or follow up to a serious adverse event, including death due to any cause, whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the subject provides documented informed consent until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
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limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
a.
an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
b.
an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 9. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 9 for instructions in evaluating adverse events.
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., 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 adverse experience to the single agent.
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Table 9 Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a MSD product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event 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 drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
8.0 STATISTICAL ANALYSIS PLAN
This Section outlines the statistical analysis plan (SAP) strategies and procedures for the 
primary and key secondary analyses of the study. Exploratory and other non-confirmatory 
analyses will be outlined in a separate supplemental Statistical Analysis Plan (sSAP). 
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
Changes to analyses made after the protocol has been finalized, but prior to database lock, 
will be documented in the sSAP and referenced in the Clinical Study Report (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
This Section contains a brief summary of the statistical analyses for this trial. Full detail is 
found in the subsequent Sections.
Study Design Overview
Phase 1/1b Trial of MK-4280 as Monotherapy, in Combination with 
Pembrolizumab,
in combination with Pembrolizumab and either 
mFOLFOX7, FOLFIRI or lenvatinib, and as a co-formulated product 
with pembrolizumab (MK-4280A) in Subjects With Advanced Solid 
Tumors. A 3+3 design in Part A to identify preliminary MTD; TPI design 
for dose confirmation and efficacy expansion cohorts for combination 
therapy (HNSCC and CRC), a randomized dose finding cohort (gastric 
cancer), MK-4280 monotherapy cohorts (CRC and gastric) and a MK-
4280A cohort in Part B.
Analysis Populations
Safety (Primary): All-Subjects-as-Treated (ASaT)
PK (Secondary): Per-Protocol (PP)
Efficacy (Secondary & Exploratory): Full Analysis Set (FAS)
Primary Endpoint(s)
Safety: DLTs
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Key Secondary Endpoints
PK parameters of single-agent MK-4280, MK-4280 in combination with 
pembrolizumab,
in combination with pembrolizumab and either 
mFOLFOX7, FOLFIRI or lenvatinib, and as a co-formulated product 
with pembrolizumab; PK profile of pembrolizumab in combination with 
MK-4280 with or without mFOLFOX7, FOLFIRI or lenvatinib, and as 
part of MK-4280A
ORR measured by RECIST 1.1 as assessed by investigator review
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Serum concentrations of MK-4280 in each arm will be summarized by 
planned visit and time for each dose separately; PK parameters will be 
summarized by dose.
For each tumor type separately, the point estimate and 95% confidence 
interval (CI) for ORR will be evaluated in subjects treated with MK-4280
monotherapy, 
in 
combination 
with 
pembrolizumab
(sequential 
administration and co-formulated product) or in combination with 
pembrolizumab and either mFOLFOX7, FOLFIRI or lenvatinib, using 
exact binomial distribution. A between dose comparison for ORR in the 
gastric combination therapy cohort will be conducted.
Treatment Assignment
In Part A, subjects are allocated to increasing doses of single-agent 
MK-4280 and MK-4280 coadministered with pembrolizumab without 
randomization centrally through IVRS; the study is open-label. In Part B
Arm 2, subjects with gastric cancer will be randomized in a 1:1 fashion 
through IVRS to 1 of 2 doses of MK-4280 in combination with a fixed 
dose of pembrolizumab. Enrollment to Arm 3 or Arm 4 will be guided by 
a subject’s eligibility for one arm or the other or, if eligible for both arms, 
will be determined by investigator choice.  If any of Arms 1, 2C and 5 in
Part B for 3L+ CRC subjects are enrolling at the same time, subjects will 
be assigned in an alternating fashion across the open arms at the study 
level through IVRS.  Otherwise, all other subjects in Part B will receive 
the same treatment within their assigned arm and therefore will not be 
randomized; an IVRS will be used to control enrollment.  
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentage, mean, standard deviation, etc.) 
will be provided for the safety endpoints as appropriate. The estimate of 
the DLT rate among subjects treated with the recommended MK-4280
Phase 2 dose when used in combination with pembrolizumab, and in 
combination with pembrolizumab and either mFOLFOX7, FOLFIRI or 
lenvatinib, and the 80% Bayesian Credible Interval for the estimate will 
be provided.
Interim Analyses
Safety will be monitored by cumulative data reviews throughout the trial. 
Data will be examined on a continuous basis to allow for dose-escalation 
decisions using the 3+3 design in Part A and dose-confirmation decisions 
using the TPI design in Part B. An interim analysis for efficacy will be 
performed for the CRC and PD-1-treatment-naïve HNSCC combination 
cohorts in Part B to determine tumor-specific cohort expansion to a 
maximum of 40 (HNSCC) or 100 (CRC) subjects. Safety and efficacy 
data will be monitored for the 2 different doses of MK-4280 administered
with pembrolizumab in the gastric cancer cohort on a continuous basis to 
aid in internal decision making and to determine if an additional 20 
subjects with gastric cancer will be enrolled to receive MK-4280 
monotherapy at the RP2D.  
Multiplicity
No multiplicity adjustment is planned in this Phase 1/1b study.
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Sample Size and Power 
The sample size of the dose escalation and dose confirmation/efficacy 
expansion (Parts A and B) depends on the observed DLT profiles of 
MK-4280
monotherapy 
and 
MK-4280
coadministered 
with 
pembrolizumab. A target sample size of 576 subjects will be used for 
study planning purposes. 
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is conducted as an open-label trial, ie, subjects, investigators, and Sponsor 
personnel will be aware of subject treatment assignments after each subject is enrolled and 
treatment is assigned.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints are listed below, followed by the descriptions of the 
derivations of selected endpoints.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Objective response rate in subjects treated with MK-4280 alone, in combination with 
pembrolizumab, or in combination with pembrolizumab and either mFOLFOX7, FOLFIRI or 
lenvatinib is a secondary endpoint of the trial and is defined as the proportion of subjects in 
the analysis population who experience complete response (CR) or partial response (PR) 
using RECIST 1.1 criteria as assessed by investigator review. Other efficacy endpoints (eg, 
Duration of Response [DOR], progression-free survival [PFS], Overall Survival [OS]) or the 
use of irRECIST 1.1 criteria are exploratory endpoints in this trial and will be defined in the 
sSAP.
Pharmacokinetic endpoints include serum concentrations of MK-4280, pembrolizumab, and 
lenvatinib, and derived PK parameters.
For the comparison of MK-4280 and pembrolizumab pharmacokinetics administered as a co-
formulated product (MK-4280A, Cohort A, Arm 5) with that of its individual components
administered sequentially (Cohort A, Arm 2C), the pharmacokinetic endpoints of interest are 
AUC0-21days and Cmax from the first cycle.  Additional PK parameters such as AUC0-∞and 
soluble LAG-3 exposure parameters such as AUC0-21days from the first cycle administration of 
MK-4280A and MK-4280 administered in sequential combination with pembrolizumab are
also of interest.
To characterize the pharmacokinetics in subjects from China, pharmacokinetic endpoints 
include serum concentrations of MK-4280 and pembrolizumab, and derived PK parameters:
•
Single dose parameters: AUC0-21days, Cmax, Tmax, and t1/2. 
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•
Multiple dose parameters: Ctrough, AUC0-21days, and Cmax at steady state, 
accumulation ratio.
Safety Endpoints
The primary safety endpoint is DLT. Safety will be monitored by cumulative data reviews 
throughout the trial. The toxicities and grades experienced by subjects who have received 
study treatment, including AEs and SAEs, will be summarized.  Of particular interest are 
infusion related reactions and immune-related AEs. Other safety measures evaluated in all 
parts of the study include laboratory safety assessments, ECGs, vital signs, and physical 
examinations.
Derivations of Safety Endpoints
Description of safety measures is provided in Section 7.1.
Analysis Populations
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all subjects who received at least 1 dose of study treatment. In case of 
treatment administration errors, subjects will be analyzed according to the treatment they 
actually received. For DLT evaluation, ASaT subjects that were observed for safety for 21 
days after the first dose of assigned treatment or experienced a DLT prior to 21 days after the 
first dose of assigned treatment will be used.
At least 1 laboratory or vital sign measurement obtained subsequent to 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.
Pharmacokinetic Analysis Populations
The PP population will be used for the PK analyses and target engagement. The PP 
population consists of all subjects who comply with the protocol sufficiently to ensure that 
these data will be likely to exhibit the effects of treatment, according to the underlying 
scientific model. Compliance covers such considerations as exposure to treatment, 
availability of measurements and absence of major protocol violations. Major protocol 
violators will be identified to the extent possible prior to database lock by individuals 
responsible for data collection/compliance, and its analysis and interpretation. Any subjects 
or data values excluded from analysis will be identified, along with their reason for 
exclusion, in the CSR. At the end of the study, all subjects who are compliant with the study 
procedure as aforementioned and have available data from at least 1 treatment will be 
included in the analysis dataset.  
Efficacy Analysis Populations
The FAS population will be used for the analysis of secondary and exploratory efficacy data 
in this trial. The FAS population consists of all subjects with a baseline scan with measurable 
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disease by investigator assessment who were administered a dose of study treatment 
regardless of dose level.
Statistical Methods
This Section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory endpoints will be described in the sSAP.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
Dose limiting toxicities will be listed, and DLTs and AEs will be summarized as counts and 
frequencies for each MK-4280 dose level administered as monotherapy, in combination with 
pembrolizumab, or in combination with pembrolizumab and either mFOLFOX7, FOLFIRI or 
lenvatinib that had at least 3 subjects treated and listed for other dose levels. The estimate of 
the DLT rate among subjects treated with the preliminary RP2D and the 80% Bayesian 
credible interval based on a prior distribution of Beta (1,1) for the estimate will be provided.
Laboratory assessments, vital signs, and other safety endpoints will be summarized as 
appropriate.
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug-related AE, an SAE, an AE that is both drug-related and 
serious, and who discontinued due to an AE will be summarized for dose levels with at least 
3 subjects treated and listed for other doses.
Data from subjects who experienced disease progression in the Part B monotherapy arm and 
crossed over into the combination arm will be presented separately.  
Data from subjects in Arm 3, Arm 4 and Arm 6 will be summarized separately.
The difference and 95% CI for the rates of infusion related reactions and immune related 
AEs between MK-4280 administered as a co-formulated product with pembrolizumab (MK-
4280A, Arm 5) and MK-4280 and pembrolizumab administered sequentially (Arm 2C, 
equivalent dose to Arm 5) will be calculated.  
Statistical Methods for Efficacy Analyses
Clinical responses will be listed for subjects in Part A for both the MK-4280 monotherapy 
arm and the MK-4280 in combination with pembrolizumab arm by dose level.
For the secondary endpoint of ORR, the point estimate and 95% CI will be evaluated 
separately in Part B subjects treated with MK-4280 monotherapy, in combination with 
pembrolizumab
(separately 
for
co-formulated 
product 
or 
following 
sequential 
administration), and in combination with pembrolizumab and either mFOLFOX7, FOLFIRI
or lenvatinib at the RP2D for each tumor cohort separately, using an exact method based on 
binomial distribution (Clopper-Pearson interval).    
A comparison will be conducted for ORR between the 2 doses of MK-4280 in combination 
with pembrolizumab administered in the gastric cancer cohort.  Miettinen and Nurminen’s 
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method will be used to estimate the treatment difference between the 2 doses and its 95% CI.
Other exploratory endpoints may also be compared between doses (eg, DOR, PFS).  Data 
from subjects who experienced disease progression in the Part B monotherapy gastric arm 
and crossed over into the combination arm will be summarized separately and will not be 
included in the dose comparison analysis.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The number and percentage of subjects screened, randomized/allocated, the primary reasons 
for screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
Pharmacokinetics and Pharmacodynamics Modeling Analysis
Serum concentrations of MK-4280 in each arm, serum concentrations of pembrolizumab in 
each arm, and plasma concentrations of lenvatinib in Arm 6 will be summarized by planned 
visit and time for each dose separately. Pharmacokinetic parameters will be summarized by 
dose. Pharmacokinetic data from subjects from China (Cohort F, Arm 5) will be summarized 
separately to characterize the PK in this group. Descriptive statistics will be provided for 
each dose with at least 3 subjects; for other doses, the results will be listed. These analyses 
will be done on an ongoing basis throughout the study and at the end of the study.
The data from the study will be used to quantitatively explore the relationships among 
pharmacokinetics, target engagement, exploratory biomarkers, and tumor
response 
measurements.
Statistical Methods for Biocomparability Analyses
To compare the pharmacokinetics between MK-4280A and that of its individual components
administered sequentially, pharmacokinetic data from Cohort A, Arm 5 (MK-4280A) and 
Arm 2C (CRC subjects receiving MK-4280 and pembrolizumab sequentially at the 
equivalent dose of Arm 5) will be used.
Individual MK-4280 AUC0-21days and Cmax values from Cycle 1 will be natural log-
transformed and analyzed separately in ANCOVA models with effects for treatment, body 
weight and baseline sLAG-3. Additional covariates deemed significant during PK analysis 
may also be considered.  A 90% CI for the difference in treatment means on the log scale 
will be calculated using the mean square error from the model and referencing a t-distribution 
for each endpoint.  These confidence limits will be exponentiated to obtain the 90% CI for 
the ratio of geometric means (MK-4280 from MK-4280A / MK-4280 administered 
sequentially with pembrolizumab) for MK-4280 AUC0-21days and Cmax.  Pembrolizumab 
AUC0-21days and Cmax from Cycle 1 will be analyzed in a similar fashion. Additional PK 
parameters such as AUC0-∞and soluble LAG-3 exposure parameters (AUC0-21days) from 
Cycle 1 may also be analyzed in a similar manner.   
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Interim Analyses
In this study there will be no hypothesis testing. Safety data will be examined on a 
continuous basis to allow for dose-escalation and dose-confirmation decisions. 
In Part B, Arm 2A of the study, an interim analysis will be performed for the CRC and
PD-1-treatment-naïve 
HNSCC
cohorts
receiving MK-4280 in combination with 
pembrolizumab. For these tumor cohorts, after 10 subjects have been enrolled and have at 
least 1 post-baseline scan assessment, the ORR will be evaluated. If an individual cohort 
experiences an ORR of 20% or greater (ie, at least 2 of 10 subjects), this cohort will be 
expanded to enroll a maximum of 30 (PD-1-treatment-naïve HNSCC) or 90 (CRC) additional
subjects, for a maximum of 40 or 100 subjects in the particular cohort. Enrollment to these 
cohorts will not be paused in the time period between when 10 subjects have been enrolled 
and when the interim analysis is performed. If fewer than 2 of 10 subjects experience an 
objective response in a given cohort, the totality of data will be evaluated to decide whether 
or not to continue enrollment in that cohort. The operating characteristics of the interim 
analysis rule are provided in Table 10.
Table 10 Operating Characteristics of Interim Analysis Rule for Each Tumor Type 
True ORR
Probability of ≤1 of 10 Subjects Respond
10%
0.74
15%
0.54
20%
0.38
25%
0.24
30%
0.15
35%
0.09
40%
0.05
45%
0.02
50%
0.01
To aid in internal decision making, an interim analysis of efficacy may be performed 
comparing the 2 doses of MK-4280 in combination with pembrolizumab (Part B, Arm 2A, 
2B) administered in the gastric cancer cohort after approximately 25 subjects per dose have 
been enrolled and have at least 1 post-baseline scan.  
Additionally, if antitumor activity is observed in this cohort (≥8 of 40 subjects with an 
objective response, irrespective of dose) an additional 20 subjects with gastric cancer will be 
enrolled to receive MK-4280 monotherapy at the RP2D.  The operating characteristics of the 
interim analysis rule are provided in Table 11. If this predetermined ORR is not observed, the 
Sponsor will evaluate all available data before determining whether to enroll these additional 
subjects or not.
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Table 11 Operating Characteristics of Interim Analysis Rule for Determining Conduct of 
Gastric Cancer Monotherapy Cohort
True ORR for the Combination
Probability Gastric Cancer Monotherapy Cohort 
Conducted (≥8 of 40 Combination Subjects Respond)
10%
0.04
15%
0.24
20%
0.56
25%
0.82
30%
0.94
Multiplicity
There will be no multiplicity control in this study.
Sample Size and Power Calculations
Dose Escalation and Dose Confirmation
The primary purpose of the dose-escalation and dose-confirmation parts of the trial is to 
investigate the safety and tolerability of MK-4280 monotherapy, MK-4280 in combination
with pembrolizumab, and MK-4280 in combination with pembrolizumab and either 
mFOLFOX7, FOLFIRI or lenvatinib in adult subjects with advanced solid tumors (Part A 
and first 14 subjects in the PD-1-treatment-naïve HNSCC and CRC cohorts in Part B Arm 
2A, and Arm 3, Arm 4 and Arm 6 in Part B) and to establish RP2Ds for MK-4280 in 
combination with pembrolizumab and in combination with pembrolizumab and either 
mFOLFOX7, FOLFIRI or lenvatinib.  
The final number of subjects enrolled in the dose-escalation and dose-confirmation parts of 
the study will depend on the empirical safety (DLT) observations, in particular, at what dose 
the 3+3 design is triggered and what dose is identified as the preliminary RP2D. Sample 
sizes for a few possible scenarios as well as the estimated time required to enroll all subjects 
and the time required to determine the preliminary RP2D are provided below. The time 
required to estimate the preliminary RP2D is the time from the first subject’s first dose to the 
end of the 3-week observation period following the first dose of the last subject enrolled in 
the dose confirmation part. The study duration is derived as the time from the first subject’s 
first dose to the end of 2-year treatment period following the enrollment of the last Part B
subject. 
Scenario 1. No DLTs during Part A. For MK-4280, in a scenario where no DLTs are 
encountered during the dose escalation and dose confirmation parts so that Part A continues 
to the highest dose in Table 3 for both arms, the sample size to determine the preliminary
RP2D is 44 subjects (15 in each of the 2 arms of Part A and the first 14 subjects enrolled in 
Part B Arm 2A who are dosed via the TPI design).
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It will take a minimum of 21 weeks to enroll and observe for DLTs in MK-4280
monotherapy and combination subjects in Part A. Total follow-up for the Part A, Arm 2
subjects treated with pembrolizumab would be 104 weeks plus an additional 90 days to 
observe subjects with SAEs. The duration for Part A, then, is approximately 125 weeks or 
slightly greater than 2 ½ years.  
Part B
includes up to a total of 516 subjects.  The first 14
subjects
in the 
PD-1-treatment-naïve HNSCC and CRC cohorts enrolled to Part B Arm 2A will be used to
further refine the MK-4280 plus pembrolizumab RP2D through the TPI design. The first 14 
subjects in each of Arm 3, Arm 4 and Arm 6 from Part B will be used to refine the MK-4280 
plus pembrolizumab plus either mFOLFOX7, FOLFIRI or lenvatinib RP2D through the TPI 
design. It will take approximately 20 months to enroll all subjects for Part B.
Scenario 2: Flat DLT dose-response. Suppose dose escalation in Part A, Arm 1 and Arm 2, 
continues to the highest dose with flat dose-response so that all 5 doses (including the top 
one) are given to 6 subjects each. Also suppose that the top dose is confirmed as the 
preliminary RP2D dose without de-escalation in Part B. Thus, the sample size to determine 
the preliminary RP2D for MK-4280 plus pembrolizumab is 74 subjects (30 in each of Arm 1
and Arm 2 in Part A and the first 14 subjects enrolled in Part B Arm 2A who are dosed via 
the TPI design, i.e., 30+30+14=74).
Part B
includes up to a total of 516 subjects.
The first 14 subjects in the 
PD-1-treatment-naïve HNSCC and CRC cohorts enrolled to Part B Arm 2A will be used to 
further refine the MK-4280 plus pembrolizumab RP2D through the TPI design. The first 14 
subjects in each of Arm 3, Arm 4 and Arm 6 from Part B will be used to refine the MK-4280 
plus pembrolizumab plus either mFOLFOX7, FOLFIRI or lenvatinib RP2D through the TPI 
design. It will take approximately 20 months to enroll all subjects for Part B.
Any dose de-escalations and/or re-escalations in Part B will increase the sample size in these
examples.
Precision of the DLT Rate at Preliminary RP2D
Since the TPI approach will be used during the dose confirmation part of the study (Part B
Arm 2A), the estimated DLT rate, and its 80% Bayesian Credibility Interval will be 
calculated from the posterior distribution of the DLT rate at the preliminary RP2D using the 
model specified in the TPI approach. If 40 subjects are finally dosed at the MK-4280 plus 
pembrolizumab RP2D during the efficacy expansion for a given tumor type, the estimated 
DLT rate and its 80% credibility interval should be similar to one of the rows in Table 12.  
This table also applies for the N=40 subjects dosed at the RP2D of MK-4280 plus 
pembrolizumab plus lenvatinib (Arm 6).  Table 13 presents similar calculations for N=20 
subjects dosed at the RP2D for MK-4280 plus pembrolizumab plus either mFOLFOX7 or 
FOLFIRI.
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Table 12 Precision of the Estimated DLT Rates at MK-4280 Plus Pembrolizumab RP2D
Number of Subjects 
Dosed at RP2D
Number of DLT 
Events
Estimated DLT 
Rate
Lower Bound of 
80% credibility 
interval
Upper Bound of 
80% credibility 
interval
40
4
0.10
0.061
0.186
40
6
0.15
0.098
0.243
40
8
0.20
0.137
0.298
40
10
0.25
0.178
0.351
40
12
0.30
0.221
0.402
40
14
0.35
0.264
0.453
Assume non-informative prior distribution of DLT.
Table 13 Precision of the Estimated DLT Rates at MK-4280 Plus Pembrolizumab Plus 
Either mFOLFOX7 or FOLFIRI RP2D
Number of Subjects 
Dosed at RP2D
Number of DLT 
Events
Estimated DLT 
Rate
Lower Bound of 
80% credibility 
interval
Upper Bound of 
80% credibility 
interval
20
2
0.10
0.054
0.237
20
3
0.15
0.087
0.295
20
4
0.20
0.123
0.350
20
5
0.25
0.160
0.402
20
6
0.30
0.200
0.453
20
7
0.35
0.240
0.502
Assume non-informative prior distribution of DLT.
Efficacy Expansion
Table 14, Table 15 and Table 16 show the ORR estimate and the 95% CI (Clopper-Pearson 
interval) for various sample sizes among the Part B expansion cohorts or additions to cohorts 
under protocol amendments.
Table 14 Estimate and 95% CI of ORR (N=40)
Number of Responses 
(PR/CR)
Observed 
ORR
95% CI of ORR
3
7.5%
(1.6%, 20.4%)
4
10.0%
(2.8%, 23.7%)
5
12.5%
(4.2%, 26.8%)
6
15.0%
(5.7%, 29.8%)
7
17.5%
(7.3%, 32.8%)
8
20.0%
(9.1%, 35.6%)
9
22.5%
(10.8%, 38.5%)
10
25.0%
(12.7%, 41.2%)
11
27.5%
(14.6%, 43.9%)
12
30.0%
(16.6%, 46.5%)
13
32.5%
(18.6%, 49.1%)
14
35.0%
(20.6%, 51.7%)
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Number of Responses 
(PR/CR)
Observed 
ORR
95% CI of ORR
15
37.5%
(22.7%, 54.2%)
16
40.0%
(24.9%, 56.7%)
Table 15 Estimate and 95% CI of ORR (N=60)
Number of Responses 
(PR/CR)
Observed 
ORR
95% CI of ORR
5
8.3%
(2.8%, 18.4%)
6
10.0%
(3.8%, 20.5%)
7
11.7%
(4.8%, 22.6%)
8
13.3%
(5.9%, 24.6%)
9
15.0%
(7.1%, 26.6%)
10
16.7%
(8.3%, 28.5%)
Table 16 Estimate and 95% CI of ORR (N=100)
Number of Responses 
(PR/CR)
Observed 
ORR
95% CI of ORR
8
8.0%
(3.5%, 15.2%)
9
9.0%
(4.2%, 16.4%)
10
10.0%
(4.9%, 17.6%)
11
11.0%
(5.6%, 18.8%)
12
12.0%
(6.4%, 20.0%)
13
13.0%
(7.1%, 21.2%)
14
14.0%
(7.9%, 22.4%)
15
15.0%
(8.6%, 23.5%)
16
16.0%
(9.4%, 24.7%)
Though no hypothesis testing will be performed, with 40 subjects per dose level in the gastric 
cancer cohort, the study has 80% power to detect a ~30% difference in ORR (for example, 
55% versus 25%) at alpha=5% (1-sided) between 2 dose levels.
In the Part B MK-4280 monotherapy arms (Arm 1), 20 subjects will be enrolled in each 
cohort (CRC and gastric, if conducted).  If the true ORR is either 5% or 10% for a given 
cancer type, then the chance of observing at least 1 responder among the 20 subjects will be 
64% or 88%, respectively.  For each cohort, if there are 0 responses, then there is 88% power 
to rule out a true ORR >10%. 
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Pharmacokinetic Comparison Between MK-4280A (Co-formulated Product) and 
MK-4280 and Pembrolizumab Administered Sequentially
The following precision calculations are based on assumed true between subject standard 
deviations of 0.429 and 0.463 for MK-4280 ln-AUC0-21days and ln-Cmax, respectively, and 
0.339 and 0.398 for pembrolizumab ln-AUC0-21days and ln-Cmax, respectively.  These 
estimates are based on currently available Cycle 1 pharmacokinetic data from subjects in this 
study who received either MK-4280 200 mg or 700 mg and pembrolizumab 200 mg.  
With 40 subjects receiving MK-4280A (Cohort A, Arm 5), and 40 subjects from Part B Arm 
2C receiving the equivalent dose of Arm 5:
MK-4280 AUC0-21days: The half-width of the 90% CI for the ratio of geometric means (MK-
4280 from MK-4280A / MK-4280 administered sequentially with pembrolizumab) on the log 
scale will be 0.159. The lower and upper 90% confidence limits for the ratio of geometric 
means will be given by OBS/1.17 and OBS*1.17, where OBS is the observed ratio. Thus, for 
example, if the observed ratio was 1, the 90% CIwould be (0.85, 1.17).
MK-4280 Cmax: The half-width of the 90% CIfor the ratio of geometric means (MK-4280 
from MK-4280A / MK-4280 administered sequentially with pembrolizumab) on the log scale 
will be 0.172. The lower and upper 90% confidence limits for the ratio of geometric means 
will be given by OBS/1.19 and OBS*1.19, where OBS is the observed ratio. Thus, for 
example, if the observed ratio was 1, the 90% CIwould be (0.84, 1.19).
Pembrolizumab AUC0-21days: The half-width of the 90% CIfor the ratio of geometric means 
(Pembrolizumab from MK-4280A / Pembrolizumab administered sequentially with MK-
4280) on the log scale will be 0.126. The lower and upper 90% confidence limits for the ratio 
of geometric means will be given by OBS/1.13 and OBS*1.13, where OBS is the observed 
ratio. Thus, for example, if the observed ratio was 1, the 90% CIwould be (0.88, 1.13).
Pembrolizumab Cmax: The half-width of the 90% CIfor the ratio of geometric means 
(Pembrolizumab from MK-4280A / Pembrolizumab administered sequentially with MK-
4280) on the log scale will be 0.148. The lower and upper 90% confidence limits for the ratio 
of geometric means will be given by OBS/1.16 and OBS*1.16, where OBS is the observed 
ratio. Thus, for example, if the observed ratio was 1, the 90% CIwould be (0.86, 1.16).
Subgroup Analyses
Within each tumor cohort, analyses of the efficacy endpoint ORR will be conducted by 
baseline PD-L1 status, separately for the monotherapy and combination arms.
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial.  Any deviation 
from protocol-directed administration will be reported.
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Extent of Exposure
A subject’s extent of exposure to MK-4280 is defined as the total number of doses of 
MK-4280 the subject received. A subject’s extent of exposure to pembrolizumab is defined 
as the total number of doses of pembrolizumab the subject received.
Extent of exposure will be summarized for all MK-4280 and MK-4280 in combination with 
pembrolizumab dose levels with at least 3 subjects enrolled, and listed for other dose levels.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 17.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 17 Product Descriptions
Product Name & Potency
Dosage Form
IMP or NIMP2
MK-4280 50 mg/vial 
(25 mg/mL)
Solution for Infusion
IMP
MK-4280 200 mg/vial 
(25 mg/mL)
Solution for Infusion
IMP
Pembrolizumab (MK-3475)
50 mg/vial
Lyophilized Powder for IV
Injection/Infusion
IMP
Pembrolizumab (MK-3475)
100 mg/4 mL1
Solution for Infusion1
IMP
MK-4280A
(20 mg/mL MK-4280 and 
5 mg/mL pembrolizumab for a 
total protein content of 
25 mg/mL)
Solution for Infusion
IMP
Lenvatinib (MK-7902) 10 mg 
Capsule 
IMP
Lenvatinib (MK-7902) 4 mg
Capsule 
IMP
1. Solution will not be supplied at initiation of the trial. It is considered a backup formulation only.
2. Defining Investigational Medicinal Product (IMP) and Non- Investigational Medicinal Product (NIMP) is based on 
guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP/NIMP may 
exist. In these circumstances, local legislation is followed.
All supplies indicated in Table 17 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
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Any commercially available product not included in Table 17 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial 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.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial 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.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
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Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  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.
Compliance with Financial Disclosure Requirements
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 
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Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
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 Section 12.1 -
Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
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The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports,
subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
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anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  MSD, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  MSD entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
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relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial 
(REGONIVO, 
EPOC1603). 
J 
Clin 
Oncol. 
2020;38(18):2053-61. 
Supplemental material; 5 p.
[42]
Ling J, Zhou H, Jiao Q, Davis HM. Interspecies scaling of therapeutic 
monoclonal antibodies: initial look. J Clin Pharmacol 2009;49:1382-402.
[43]
Taylor M, Dutcus CE, Schmidt E, Bagulho T, Li D, Shumaker R, et al. A 
phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients 
with selected solid tumors [abstract]. Annals of Oncology 2016, 27 (6 
Suppl): vi266–vi295. Abstract no. 776PD.
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[44]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: 
immune-related response criteria using unidimensional measurements. Clin 
Cancer Res. 2013 Jul 15;19(14):3936-43.
[45]
Baixeras E, Huard B, Miossec C, Jitsukawa S, Martin M, Hercend T, et al. 
Characterization of the lymphocyte activation gene 3-encoded protein. A 
new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992 
Aug 1;176(2):327-37.
[46]
Huard B, Mastrangeli R, Prigent P, Bruniquel D, Donini S, El-Tayar N, et al. 
Characterization of the major histocompatibility complex class II binding 
site on LAG-3 protein. Proc Natl Acad Sci U S A. 1997 May 
27;94(11):5744-9.
[47]
Li N, Wang Y, Forbes K, Vignali KM, Heale BS, Saftig P, et al. 
Metalloproteases regulate T-cell proliferation and effector function via LAG-
3. EMBO J. 2007 Jan 24;26(2):494-504.
[48]
Woo SR, Li N, Bruno TC, Forbes K, Brown S, Workman C, et al. 
Differential subcellular localization of the regulatory T-cell protein LAG-3 
and the coreceptor CD4. Eur J Immunol. 2010 Jun;40(6):1768-77.
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12.0 APPENDICES
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
MSD Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, conducts clinical trials worldwide to 
evaluate the safety and effectiveness of our products. As such, we are committed to designing, implementing, 
conducting, analyzing and reporting these trials in compliance with the highest ethical and scientific standards. 
Protection of subject safety is the overriding concern in the design of clinical trials. In all cases, MSD clinical trials 
will be conducted in compliance with local and/or national regulations and in accordance with the ethical principles 
that have their origin in the Declaration of Helsinki. 
B. Scope
Such 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the 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 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in MSD trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  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, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, MSD seeks to publish the results of trials it conducts.  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 
of multiplicity.
MSD’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  MSD funding of a trial will be acknowledged in publications. 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and MSD will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a MSD clinical trial. 
All participation in MSD clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a 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 subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically 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 subjects 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 subject referrals.  However, MSD may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
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 IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
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.
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.4 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the MSD Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
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trial are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@MSD.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
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with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (ie, only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. 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
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair.
5
Dead
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE), Version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.htm)
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List of Abbreviations and Definitions of Terms
Abbreviation or Term
Definition
β-hCG
serum β-human chorionic gonadotropin
%CV
percent coefficient of variation
ADA
antidrug antibody
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
ASaT
all-subjects-as-treated
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
BICR
blinded independent central radiology
BOR
best overall response
CBC
complete blood count
CD
cluster of differentiation 
CD3ζ
CD3 zeta
CEA
carcinoembryonic antigen
CI
confidence interval
CL
clearance
Cmax
maximum serum concentration 
CNS
central nervous system
CO2
carbon dioxide
CR
complete response / complete remission
CRC
colorectal cancer
CrCl
creatinine clearance 
CSR
clinical study report
CT
computerized tomography
CTCAE
common terminology criteria for adverse events
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DKA
diabetic ketoacidosis
DLT
dose limiting toxicity
dMMR
mismatch repair deficient
DNA
deoxyribonucleic acid
DOR
duration of response
EBER1
Epstein–Barr virus-encoded small RNA
EBV
Epstein-Barr virus 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
end of treatment
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Abbreviation or Term
Definition
EPO
erythropoietin
ERC
ethics review committee
FAS
Full Analysis Set
FBR
future biomedical research
FDA
Food & Drug Administration
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
FIH
first-in-human
FOLFIRI
irinotecan/leucovorin/5-FU
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GEJ
gastric-esophageal junction
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal 
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCV 
hepatitis C virus 
HER2/neu
human epidermal growth factor receptor 2 
HIV
Human Immunodeficiency Virus
HNSCC
head and neck squamous cell cancer
HPV
human papillomavirus
HRT
hormone replacement therapy
HUVEC
human umbilical vein endothelial cell
IB
Investigator Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
IEC
independent ethics committee
IFN-γ
interferon gamma
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
IMP
Investigational Medicinal Product
IMR
immunomodulatory receptor
INR
international normalized ratio
IO
immune-oncology
irAE
immune-related adverse event
IRB
institutional review board
irRECIST
immune-related response evaluation criteria in solid tumors
ITIM
immunoreceptor tyrosine-based inhibition motif
ITSM
immunoreceptor tyrosine-based switch motif
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
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Abbreviation or Term
Definition
LAG-3
lymphocyte-activation gene 3
LDH
lactate dehydrogenase
mAB
monoclonal antibody
MAD
maximum administered dose
mFOLFOX7
oxaliplatin/leucovorin/5-FU
MHC
major histocompatibility complex
MRI
magnetic resonance imaging
mRNA
messenger RNA 
MSI
microsatellite instability 
MSI-H
microsatellite instability-high
MSS
microsatellite stable
MTD
maximum tolerated dose
N/A
not applicable
NCI
National Cancer Institute
NHP
nonhuman primate
NIMP
Non-Investigational Medicinal Product
NOAEL
no-observed-adverse-effect level
NSAID
non-steroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ONJ
osteonecrosis of the jaw
ORR
objective response rate
OTC
over-the-counter
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease
PFS
progression-free survival
PI
probability interval
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PO
orally
PP
per-protocol
PR
partial response
PSN
peripheral sensory neuropathy
PT
prothrombin time
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
RAG
recombination-activating gene
RBC
red blood cell
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RTK
receptor tyrosine kinase
SAC
scientific advisory committee
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Abbreviation or Term
Definition
SAE
serious adverse event
SAP
statistical analysis plan
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
sLAG-3
soluble LAG-3
SOC
standard of care
sSAP
supplemental statistical analysis plan
T1DM
type 1 diabetes mellitus 
T3
triiodothyronine
T4
thyroxine
TAM
tumor-associated macrophage
TCR
T-cell receptor
TKI
tyrosine kinase inhibitor
TNF-
tumor necrosis factor-alpha
Treg
regulatory T-cell
TPI
toxicity probability interval
TPS
tumor proportion score
TSH
thyroid stimulating hormone
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
VS
vital signs
WBC
white blood cell
ZAP70
zeta-chain-associated protein kinase
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Country-specific Requirements
China
Section 2.1 Trial 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
Japan
Japan has country-specific requirements for the protocol which are summarized below.
Section 5.1.2 - Inclusion Criterion 1d:
To be eligible for enrollment into the gastric cancer cohort of Part B, in addition to meeting 
the criteria in Inclusion Criterion 1d, the subject must also satisfy the following requirement:
The subject must have no available therapy that may convey clinical benefit.
Section 5.2.4 – Definition of Dose Limiting Toxicity:
In addition to all DLTs listed, the following will be considered a DLT for subjects in Japan:
Thrombocytopenia if associated with bleeding that requires a platelet transfusion.
Section 5.5.2 – Prohibited Concomitant Medications/Procedures:
In addition to all prohibited concomitant medications/procedures listed, the following is a 
prohibited concomitant medication for subjects in Japan:
Prophylactic use of granulocyte colony-stimulating factor (G-CSF) during the DLT 
observation period is not permitted.
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Section 6.0 and 7.1.2 – Trial Flow Chart & Clinical Procedures/Assessments
In addition to all procedures and assessments listed, the following procedures should be performed as indicated for subjects in Japan:
Japan-specific Trial Flow Chart (for All Arms)
Screening 
Phase
Treatment Phase 
Cycle = 21 days
End of 
Treat-
ment
Post-Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-4
Cycles 
5-8
Cycle 9 
and 
Beyond
Discon.
Safety 
Follow-up 
Visit
Survival 
Follow-up27
Cycle Day
1
2
8
15
1
8
15
9 weeks 
after 1st
dose
1
1
30 days 
after last 
dose
Every 12 
weeks
Scheduling Window (Days)
-28 to -1
±3
±3
±3
±3
±7
±7
±7
Clinical Procedures/Assessments
Pulse Oximetry (SpO2)
X
X
X
X
X
X
X
X
X
X
X
X
CBC with differential
X
Chemistry Panel
X
For subjects in Japan only, pulse oximetry will be performed using local standard procedures by the investigator or qualified designee 
at the time points outlined in Table above.
For subjects in Japan only, CBC with differential and Chemistry Panel samples will be collected on C1D15, in addition to all 
scheduled timepoints in Section 6.0.
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Clinical Study Conduct System
The clinical study conduct system in Japanese is included in the accompanying documents. 
The contents are as follows:
1. Sponsor
1.1 Name and Address of Sponsor
1.2 Sponsor’s Representative
1.3 Medical Expert
1.4 Field Monitor (CRA) Representative
2. Contract Research Organization
2.1 External Monitoring Agency
2.2 Patient Registration Center
2.3 MSD Emergency Center
2.4 Central Laboratory Testing Facilities
3. Investigators
4. Japan Enrollment Policy
Germany
Throughout the Protocol
Legally Acceptable Representative 
Persons of legal age, who are incapable of comprehending the nature, significance and 
implications of the clinical trial and of determining their will, are excluded from the trial at 
German sites; therefore, all references to a participant’s “legally acceptable representative” in 
the protocol are not applicable for participants in Germany.
Exclusion of MUGA (multigated-acquisition) scans
Starting from Protocol version 10, Section 5.1.3 (Subject exclusion criteria) and 7.1.2 
(Clinical Procedures/Assessments) as well as other sections of the protocol refer to MUGA 
scans or ECHO scans for LVEF assessments. As per protocol, MUGA or echocardiogram 
scans should be performed locally in accordance with the institution’s standard practice. 
This is to clarify that in Germany MUGA scans are not standard practice and were not 
notified to the Federal Office for Radiation Protection (BfS). Therefore, only ECHO scans 
will be done at the German sites. No MUGA scans will be done in Germany.
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Section 6.3 Part B – Arm 6 Flow Chart
SAEs will be monitored for 120 days after the last dose of study intervention.
Pregnancy testing will be continued for 120 days after the last dose of study intervention, 
regardless of initiation of subsequent anticancer therapy.
Section 5.1.3 Subject Exclusion Criteria

Has a known history of human immunodeficiency virus (HIV) infection. HIV testing 
is required at Screening.

Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. Testing for Hepatitis B or Hepatitis C is required at Screening.
Canada
Please refer to the current lenvatinib product monograph for management of AEs associated 
with lenvatinib administration.
Section 5.2.6.3.9 Management of Gastrointestinal Perforation or Fistula Formation
Lenvatinib should be discontinued in any subject who develops gastrointestinal perforation 
of any grade or ≥Grade 3 fistula.
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Contraceptive Guidance
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the 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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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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