Clinical trial NCT03179436
Conditions: Advanced Solid Tumors
Keywords: Programmed Cell Death Protein 1 (PD-1, PD1), Programmed Cell Death Ligand 1 (PD-L1, PDL1) Programmed Cell Death Ligand 2 (PD-L2, PDL2)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-07-02; Completion date: 2024-04-08
Enrollment: 415 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of escalating doses of quavonlimab when used in combination with pembrolizumab in participants with advanced solid tumors.

Detailed description:
After screening, participants will be assigned to the Dose Escalation, Dose Confirmation, Efficacy Expansion, or Coformulation Phase. The Dose Escalation Phase will evaluate available PK and safety data including dose limiting toxicities (DLTs). The Dose Confirmation Phase will gather additional safety, tolerability, PK, and preliminary efficacy data of quavonlimab in combination with pembrolizumab, and will include first-line advanced/metastatic non-small cell lung cancer (NSCLC) and second line (and beyond) advanced/metastatic small cell lung cancer (SCLC). The purpose of the Efficacy Expansion Phase is to gather preliminary anti-tumor efficacy data for quavonlimab in combination with pembrolizumab as well as for quavonlimab monotherapy in the specific target population of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) refractory melanoma. The Coformulation Phase will evaluate the safety and PK of a coformulated product of pembrolizumab/quavonlimab (MK-1308A) in comparison to that of the single, co-administered products given at the same dose and schedule, and include participants with advanced solid tumors and participants from mainland China.

Arms: arm 1: On Cycle 1, Day 1 of the Dose Escalation Phase, advanced solid tumor participants receive a single monotherapy dose lead-in with quavonlimab at dose level 1 (DL1). On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive quavonlimab at DL1 in combination with pembrolizumab (pembro) at pembrolizumab dose level 1 (PDL1) according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study. arm 2: On Cycle 1, Day 1 of the Dose Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with quavonlimab at DL2. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive quavonlimab at DL2 in combination with pembrolizumab at PDL1 according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study. arm 3: On Cycle 1, Day 1 of the Dose Escalation Phase, participants with advanced solid tumors except NSCLC receive a single monotherapy dose lead-in with quavonlimab at DL3. On Cycle 2, Day 1, and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants receive quavonlimab at DL3 in combination with pembrolizumab at PDL1 according to Schedule 1. For all subsequent cycles (starting with Cycle 6), all participants receive pembrolizumab monotherapy according to Schedule 1. Participants will be treated for up to 35 cycles total on study. arm 4: On Cycle 1, Day 1 of the Dose Confirmation Phase and during all subsequent cycles, participants with NSCLC receive quavonlimab at DL1 in combination with pembrolizumab at PDL1, both according to Schedule 1. Participants will be treated for up to 35 cycles total on study. arm 5: On Cycle 1, Day 1 of the Dose Confirmation Phase, participants with NSCLC receive quavonlimab at DL1 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and quavonlimab at DL1 according to Schedule 2. Participants will be treated for up to 35 cycles total on study. arm 6: On Cycle 1, Day 1 of the Dose Confirmation Phase, participants with NSCLC receive quavonlimab at DL2 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and at DL2 quavonlimab according to Schedule 2. Participants will be treated for up to 35 cycles total on study. arm 7: On Cycle 1, Day 1 of the Dose Confirmation Phase, participants with SCLC receive quavonlimab at DL2 in combination with pembrolizumab at PDL1. On all subsequent cycles, participants receive pembrolizumab at PDL1 according to Schedule 1 and quavonlimab at DL2 according to Schedule 2. Participants will be treated for up to 35 cycles total on study. arm 8: On Cycle 1, Day 1 of the Dose Confirmation Phase and during all subsequent cycles, participants with NSCLC receive quavonlimab at DL2 in combination with pembrolizumab at PDL1 according to Schedule 1. Participants will be treated for up to 35 cycles total on study. arm 9: On Cycle 1, Day 1 of the Efficacy Expansion Phase and during all subsequent cycles, participants with PD-1/PD-L1 refractory melanoma receive quavonlimab at DL1 in combination with pembrolizumab at pembrolizumab dose level 2 (PDL2). Both quavonlimab and pembrolizumab will be administered according to Schedule 2 for up to 24 months on study. arm 10: On Cycle 1, Day 1 of the Efficacy Expansion Phase and during all subsequent cycles, participants with PD-1/PD-L1 refractory melanoma receive quavonlimab at DL1 according to Schedule 2 for up to 24 months on study. Participants who demonstrate radiographically confirmed progressive disease in Arm G will be eligible to receive combination therapy with pembrolizumab (crossover). arm 11: On Cycle 1, Day 1 of the Coformulation Phase and during all subsequent cycles, participants with advanced/metastatic solid tumors receive pembrolizumab/quavonlimab according to Schedule 2 for up to 24 months on study. arm 12: On Cycle 1, Day 1 of the Coformulation Phase and during all subsequent cycles, participants in mainland China with advanced solid tumors receive pembrolizumab/quavonlimab according to Schedule 2 for up to 24 months on study.
Interventions: intervention 1: Quavonlimab intervention 2: Pembrolizumab intervention 3: Pembrolizumab/Quavonlimab
Intervention descriptions: intervention 1: Quavonlimab is administered intravenously (IV) during the Dose Escalation Phase and Dose Confirmation Phase at either DL1 or DL2, and is administered IV during the Efficacy Expansion Phase at DL2. intervention 2: Pembrolizumab is administered IV at PDL1 on Day 1 of each cycle starting Cycle 2 for the Dose Escalation Phase or starting Cycle 1 of the Dose Confirmation Phase. Pembrolizumab is administered IV at PDL2 on Day 1 of each cycle for the Efficacy Expansion Phase (Arm G). intervention 3: Pembrolizumab/Quavonlimab is a coformulated product composed of quavonlimab at DL1 in combination with pembrolizumab at dose level 2 (PDL2).

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1/2 Open Label, Multi-Arm, 
Multicenter Study of MK-1308 in Combination 
with Pembrolizumab in Subjects with Advanced 
Solid Tumors
NCT03179436
02-Dec-2022


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 1 / 2 Open Label, Multi-Arm, Multicenter Study of MK-1308 in 
Combination with Pembrolizumab in Subjects with Advanced Solid Tumors 
Protocol Number: 001-12
Compound Number: MK-1308
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER: 134,266
EudraCT NUMBER: 2019-003703-35
Approval Date: 02 December 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
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.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 12
02-DEC-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name 
change and update to the address.
Amendment 11
18-OCT-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name 
change and update to the address.
Amendment 10
14-DEC-2021
The protocol was amended to remove Arm J from the study.
Amendment 09
12-JUL-2021
The protocol was amended to update the dose modification and toxicity management 
guidelines for irAEs, to remove Arm L (Japan) from the study, to clarify PK collection 
timings, to align with the biomarker plan, and to remove Translational Oncology Research 
from the study.
Amendment 08
16-NOV-2020
This amendment added additional cohorts to evaluate a coformulated product of MK-
1308 + pembrolizumab (MK-1308A) in the global study as well as in China- and Japan-
specific Arms:

Arm J - participants with PD-1/L1 refractory melanoma in specific countries.

Arm K - Chinese participants who reside in China with a diagnosis of any relapsed or 
refractory solid tumor. Arm K is open to sites in mainland China only.

Arm L - Japanese participants who reside in Japan with a diagnosis of Stage IV 
NSCLC. Arm L is open to sites in Japan only.
Collection of pre- and on-treatment tumor biopsies from participants in Arms F, G, and J 
was added.
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Document
Date of Issue
Overall Rationale
Amendment 07
13-MAR-2020
This amendment added a cohort (Arm I) to evaluate a coformulated product of MK-1308 
+ pembrolizumab (MK-1308A).
Amendment 06
11-NOV-2019
This amendment added Process 2 material and incorporated FDA feedback on 
Amendment 05.
Amendment 05
08-FEB-2019
The protocol was amended to add new interim analysis safety and efficacy data that 
supports the RP2D used in the melanoma expansion arm.
Amendment 04
02-NOV-2018
The protocol was amended to add an efficacy expansion phase in melanoma and to 
improve overall protocol clarity and consistency as well as to correct typographical errors 
identified post publishing.
Amendment 03
25-JAN-2018
The protocol was amended to explore an additional dose escalation cohort and dose 
confirmation arm, to modify the DLT reporting period for dose confirmation, to clarify 
pre-treatment requirements for brain metastases, and to modify the futility analysis.
Amendment 02
04-OCT-2018
The protocol was amended to add additional exploratory biomarker, safety assessments, 
and exclusion criteria. 
Amendment 01
24-AUG-2017
Amendment developed due to requirement by regulatory authorities around safety 
monitoring of Japan-specific participants in the MK-1308-001 clinical trial.
Original Protocol
19-APR-2017
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 12
Overall Rationale for the Amendment:
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the address.
Summary of Changes Table:
Section # and 
Name
Description of Change
Brief Rationale
Section 12.3, 
Appendix 3:
Study 
Governance 
Considerations -
Code of Conduct 
for Clinical Trials
Sponsor entity name and 
address change.
Merck Sharp & Dohme Corp. underwent an entity name and address change 
to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1.
Synopsis.......................................................................................................................15
2.
Schedule of Activities (SoA)......................................................................................18
Dose Escalation Phase.............................................................................................18
Dose Confirmation Phase.......................................................................................23
Efficacy Expansion and Crossover Phases - Pembrolizumab Q6W + 
MK-1308 Q6W (Arm F) or MK-1308 Q6W Monotherapy (Arm G).................28
Coformulation Phase: Arm I (MK-1308A Q6W).................................................39
Coformulation Phase in China: Arm K (MK-1308A Q6W) ...............................45
3.
Introduction................................................................................................................54
Study Rationale .......................................................................................................54
Background..............................................................................................................55
Pharmaceutical and Therapeutic Background .....................................................55
MK-1308 Background ..................................................................................55
MK-1308A Background ...............................................................................56
Pembrolizumab (MK-3475) Background .....................................................57
Preclinical and Clinical Trials..............................................................................57
MK-1308.......................................................................................................57
Pembrolizumab (MK-3475)..........................................................................58
Ongoing Clinical Trials........................................................................................58
MK-1308.......................................................................................................58
Pembrolizumab (MK-3475)..........................................................................59
Benefit/Risk Assessment.........................................................................................59
4.
Objectives/Hypotheses and Endpoints.....................................................................59
5.
Study Design...............................................................................................................62
Overall Design .........................................................................................................62
Dose Escalation Phase for MK-1308 and Pembrolizumab..................................63
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Dose Confirmation Phase for MK-1308 and Pembrolizumab.............................64
Efficacy Expansion and Crossover Phases for MK-1308 and 
Pembrolizumab ....................................................................................................65
Coformulation Phase for MK-1308A (Arms I and K).........................................67
Trial Diagram.......................................................................................................70
Number of Participants ..........................................................................................71
Beginning and End of Study Definition ................................................................71
Clinical Criteria for Early Trial Termination.......................................................71
Scientific Rationale for Study Design....................................................................72
Rationale for Endpoints .......................................................................................72
Efficacy Endpoints........................................................................................72
Safety Endpoints...........................................................................................72
Pharmacokinetic Endpoints ..........................................................................73
Pharmacodynamic Endpoints........................................................................73
5.4.1.4.1
Anti-Drug Antibody Assessment...........................................................73
5.4.1.4.2
Exploratory Sample for T-cell Response...............................................73
5.4.1.4.3
Serum for Cytokine Testing...................................................................73
Planned Exploratory Biomarker Research....................................................73
Future Biomedical Research.........................................................................76
Justification for Dose ..............................................................................................76
Starting Dose for This Trial .................................................................................76
Maximum Dose/Exposure for This Trial.............................................................78
Rationale for Dose Interval and Trial Design......................................................78
MK-1308 (Dose Escalation, Dose Confirmation, and 
Coformulation)..............................................................................................78
Pembrolizumab (MK-3475)..........................................................................80
6.
Study Population........................................................................................................81
Inclusion Criteria....................................................................................................81
Exclusion Criteria ...................................................................................................86
Lifestyle Restrictions...............................................................................................89
Meals and Dietary Restrictions............................................................................89
Caffeine, Alcohol, and Tobacco ..........................................................................90
Activity ................................................................................................................90
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Screen Failures ........................................................................................................90
Participant Replacement Strategy.........................................................................90
7.
Treatments..................................................................................................................90
Treatments Administered.......................................................................................90
Definition of Dose-limiting Toxicity...................................................................92
Dose Modification (Escalation/Titration/Other)..................................................94
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).........................................................................................................94
Method of Treatment Assignment.......................................................................101
Stratification.......................................................................................................102
Blinding..................................................................................................................102
Preparation/Handling/Storage/Accountability ..................................................102
Dose Preparation................................................................................................102
Handling, Storage and Accountability...............................................................102
Treatment Compliance.........................................................................................103
Concomitant Therapy...........................................................................................103
Rescue Medications & Supportive Care............................................................104
Systemic Corticosteroid Use:......................................................................104
Treatment After the End of the Study ................................................................105
Clinical Supplies Disclosure.................................................................................105
Standard Policies...................................................................................................105
8.
Discontinuation/Withdrawal Criteria....................................................................105
Discontinuation of Study Treatment...................................................................105
Withdrawal from the Study .................................................................................106
Lost to Follow-Up..................................................................................................107
9.
Study Assessments and Procedures........................................................................107
Administrative and General Procedures ............................................................108
Informed Consent...............................................................................................108
General Informed Consent..........................................................................108
Consent and Collection of Specimens for Future Biomedical 
Research......................................................................................................108
Inclusion/Exclusion Criteria ..............................................................................109
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Participant Identification Card...........................................................................109
Medical History .................................................................................................109
Advanced Solid Tumor (ST), NSCLC, SCLC, and Melanoma 
History ........................................................................................................109
Prior and Concomitant Medications Review .....................................................109
Prior Medications........................................................................................109
9.1.5.1.1
Prior Treatment for Advanced Solid Tumor Cancer ...........................110
Concomitant Medications...........................................................................110
Assignment of Screening Number.....................................................................110
Assignment of Treatment/Randomization Number...........................................110
Treatment Administration..................................................................................110
Timing of Dose Administration..................................................................111
9.1.8.1.1
Timing of Dose Administration of MK-1308/MK-1308A..................111
9.1.8.1.2
Timing of Dose Administration of Pembrolizumab ............................111
Trial Communication Plan Summary .........................................................111
Withdrawal/Discontinuation..............................................................................112
Withdrawal From Future Biomedical Research .........................................112
Participant Blinding/Unblinding........................................................................112
Calibration of Critical Equipment......................................................................112
Efficacy Assessments.............................................................................................113
Tumor Imaging and Assessment of Disease......................................................113
Initial Tumor Imaging.................................................................................113
Brain Imaging .............................................................................................114
Imaging for Bone Metastases......................................................................115
Tumor Imaging During the Study...............................................................115
End of Treatment and Follow-up Tumor Imaging......................................116
Crossover Phase Tumor Imaging................................................................116
RECIST 1.1 Assessment of Disease...........................................................116
irRECIST Assessment of Disease (Dose Escalation Phase and 
Dose Confirmation Phase)..........................................................................117
iRECIST Assessment of Disease (Efficacy Expansion Phase and 
Coformulation Phase) .................................................................................118
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events.....................................................................................................................120
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Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ................................................................121
Method of Detecting AE and SAE.....................................................................122
Follow-up of AE, SAE, and Other Reportable Safety Event 
Information ........................................................................................................123
Regulatory Reporting Requirements for SAE ...................................................123
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs................................................................................123
Pregnancy and Exposure During Breastfeeding ................................................123
Events of Clinical Interest (ECI)........................................................................124
Treatment of Overdose.........................................................................................124
Safety......................................................................................................................124
Physical Examinations.......................................................................................125
Vital Signs..........................................................................................................125
Electrocardiograms ............................................................................................125
Clinical Safety Laboratory Assessments............................................................125
Pregnancy Testing..............................................................................................126
Pharmacokinetics..................................................................................................126
Blood Collection for Serum MK-1308 ..............................................................127
Blood Collection for Serum Pembrolizumab.....................................................127
Blood Collection for Anti-Pembrolizumab Antibodies .....................................127
Blood Collection for Anti-MK-1308 Antibodies...............................................127
Pharmacodynamics...............................................................................................127
Future Biomedical Research Sample Collection................................................128
Biomarkers ............................................................................................................128
Planned Genetic Analysis Sample Collection....................................................129
Visit Requirements................................................................................................129
Screening............................................................................................................129
Treatment Period................................................................................................130
Discontinued Participants Continuing to be Monitored in the Study ................130
Post-Study..........................................................................................................130
Survival Follow-up ............................................................................................130
Survival Status ...................................................................................................131
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10.
Statistical Analysis Plan ..........................................................................................131
Statistical Analysis Plan Summary......................................................................131
Responsibility for Analyses/In-House Blinding..................................................133
Hypotheses/Estimation .........................................................................................134
Analysis Endpoints................................................................................................134
Efficacy/Immunogenicity/Pharmacokinetics Endpoints....................................134
Safety Endpoints ................................................................................................134
Analysis Populations.............................................................................................134
Safety Analysis Populations ..............................................................................134
Pharmacokinetic Analysis Populations..............................................................135
Efficacy Populations ..........................................................................................135
Statistical Methods................................................................................................135
Statistical Methods for Efficacy Analysis..........................................................135
Statistical Methods for Safety Analysis.............................................................136
Summaries of Baseline Characteristics, Demographics and Other 
Analyses.............................................................................................................136
Demographic and Baseline Characteristics ................................................136
Pharmacokinetic and Pharmacodynamic Modeling Analysis.....................136
Sample Size and Power Calculations ..................................................................138
Subgroup Analyses................................................................................................139
Compliance (Medication Adherence)..................................................................140
Extent of Exposure................................................................................................140
11.
References.................................................................................................................140
12.
Appendices................................................................................................................145
Appendix 1: Abbreviations and Trademarks.....................................................145
Appendix 2: Clinical Laboratory Tests...............................................................149
Appendix 3: Study Governance Considerations ................................................151
Code of Conduct for Clinical Trials...............................................................................151
Financial Disclosure.......................................................................................................153
Data Protection...............................................................................................................153
CCI
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Confidentiality of Participant Records...........................................................................154
Confidentiality of IRB/IEC Information........................................................................154
Publication Policy ..........................................................................................................154
Compliance with Trial Registration and Results Posting Requirements.......................154
Compliance with Law, Audit and Debarment ...............................................................155
Data Quality Assurance .................................................................................................155
Source Documents .........................................................................................................156
Study and Site Closure...................................................................................................156
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................157
Definition of AE ............................................................................................................157
Definition of SAE ..........................................................................................................158
Additional Events reported in the same manner as SAE ...............................................159
Recording AE and SAE .................................................................................................160
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor................163
Appendix 5: Contraceptive Guidance.................................................................165
Definitions......................................................................................................................165
Contraception Requirements..........................................................................................166
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................167
Appendix 7: Country-specific Requirements .....................................................171
France Requirements .........................................................................................171
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression...............................................................................................175
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LIST OF TABLES
    
Table 1
Toxicity Assessment.............................................................................................68
Table 2
Predicted Pharmacokinetic Parameters in Humans and the Relative Fold 
Differences at the NOAEL in Cynomolgus Monkeys..........................................77
Table 3
Adequate Organ Function Laboratory Values......................................................82
Table 4
Study Treatments..................................................................................................91
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................96
Table 6
Infusion Reaction Dose Modification and Treatment Guidelines ......................100
Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease................................................................................................................119
Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events....................................................................................122
Table 13
Protocol-Required Safety Laboratory Assessments ...........................................149
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LIST OF FIGURES
          
Figure 1
Trial Design for Dose Escalation and Dose Confirmation...................................70
Figure 2
Trial Design for Efficacy Expansion Phase (Arm F and G).................................70
Figure 3
Trial Designs for Coformulation Arms I and K....................................................71
Figure 4
Predicted Serum Concentration-time Profiles of MK-1308 in the 
Proposed Clinical Study at Doses of 0.3 mg/kg to 10 mg/kg MK 1308 
When Administered by Intravenous Infusion Once Every 21 Days.....................77
Figure 5
Imaging and Treatment for Clinically Stable Participants After First 
Radiologic Evidence of PD Assessed by the Investigator..................................120
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1.
Synopsis
Protocol Title:  
A Phase 1 / 2 Open Label, Multi-Arm, Multicenter Study of MK-1308 in 
Combination with Pembrolizumab in Subjects with Advanced Solid Tumors 
Short Title: 
A Phase 1 / 2 Trial of MK-1308 in Combination with Pembrolizumab
Objectives/Hypotheses and Endpoints:
In male and female participants who are at least 18 years of age with advanced solid 
tumors:
Objective
Endpoint
Primary

To determine the safety and 
tolerability of MK-1308 in 
combination with pembrolizumab 
and to establish a preliminary
recommended Phase 2 dose when 
used in combination with 
pembrolizumab (Dose Escalation and 
Confirmation phases)

Number of participants with ≥1 DLT

Number of participants with ≥1 AE

Number of participants discontinuing 
study treatment due to an AE

To determine the safety and 
tolerability of MK-1308 as 
monotherapy (Efficacy Expansion
phase)

Number of participants with ≥1 AE

Number of participants discontinuing 
study treatment due to an AE

To determine the safety and 
tolerability of MK-1308A
(Coformulation phase)

Number of participants with ≥1 AE

Number of participants discontinuing 
study treatment due to an AE

Number of participants with ≥1 DLT 
(Arm I only)

To evaluate ORR as assessed by 
BICR per RECIST 1.1 in the efficacy 
expansion phase (Arms F and G). 
RECIST 1.1 is adjusted to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per 
organ (see Section 5.4.1.1)

Objective Response: CR or PR 
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Secondary

To characterize the PK profiles and 
incidence of ADA, as appropriate, of 
pembrolizumab, of MK-1308 as 
monotherapy, and of MK-1308 when 
used in combination and in 
coformulation with pembrolizumab 
in the dose escalation phase as well 
as in Arms A, B, C, D, E, F, G, and I.

To characterize PK profiles and 
incidence of ADA of both MK-1308 
and pembrolizumab in Chinese 
participants in Arm K when the study 
drugs are administered as a 
coformulated product (MK-1308A).

Pharmacokinetic parameters including 
AUC, Cmin, Cmax

Anti-drug antibody levels

To evaluate ORR as assessed by 
investigator per RECIST 1.1 in the 
dose escalation phase, the dose
confirmation phase, and Arms I and
K in the coformulation phase

Objective response: CR or PR 

To evaluate DOR per RECIST 1.1 as 
assessed by BICR in the efficacy 
expansion phase (Arms F and G)

DOR: The time from first documented 
evidence of CR or PR until disease 
progression or death due to any cause, 
whichever occurs first (for responders 
only)
Overall Design:
Trial Phase
Phase I / II
Clinical Indication
The treatment of participants with advanced/metastatic 
solid tumors
Population
Participants1 with advanced/metastatic solid tumors
Trial Type
Interventional
Type of design
Uncontrolled, combination, dose escalation, dose
confirmation, efficacy expansion
Type of control
No treatment control
Trial Blinding
Unblinded Open-label
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Estimated duration 
of trial
The Sponsor estimates that the trial will require 
approximately 6 years from the time the first participant
signs the informed consent until the last participant’s last 
study-related phone call or visit.
Duration of 
Participation
Each participant will participate in the study for 
approximately 3 years from the time the participant 
provides documented informed consent through the final 
contact. After a screening phase of 28 days, each 
participant will receive assigned intervention for 
approximately 24 months. After the end-of-treatment each 
participant will be followed for 1 year.
After the end-of-treatment, each participant will be 
followed for the occurrence of AEs and spontaneously 
reported pregnancy. All participants will be followed for 
overall survival until death, withdrawal of consent, or end 
of the study.
Number of Participants:
Approximately 348 participants will be enrolled.
1. Sponsor has changed the terminology referring to individuals who take part in clinical trials as “Participant” 
from the previously used term “Subject.” For the purpose of any trial-related documents using the previous 
terminology, the term “Participant” is equivalent to “Subject.”
A list of abbreviations used in this document can be found in Appendix 1. Study 
governance considerations are outlined in Appendix 3.
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2.
Schedule of Activities (SoA)
Dose Escalation Phase
Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treat-
ment
Safety 
Follow-
up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
Visit Timing / Cycle Day
Up to 28 
days prior to 
first dose
1
8
15
1
8
15
1
1
Treat-
ment 
discon-
tinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Administrative
Procedures
ICF and ICF for Future
Biomedical Research
X
Any leftover biomarker samples will be stored for FBR if the 
participant signs the FBR consent. 
Inclusion/Exclusion
Criteria
X
Participant Identification
Card
X
X
Update at C1D1
Demographics and 
Medical History 
X
Medical, Oncology
Disease Status and Prior
Oncology Treatment
History
X
Concomitant Medication
Review
X
X
X
X
X
X
X
X
X
X
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treat-
ment
Safety 
Follow-
up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
Visit Timing / Cycle Day
Up to 28 
days prior to 
first dose
1
8
15
1
8
15
1
1
Treat-
ment 
discon-
tinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Clinical
Procedures/
Assessments
Full Physical
Examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Required once per cycle
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
To be collected at pre-dose and at the end of infusion.
[Japan only: Vitals will also include pulse oximetry (SpO2)]
ECOG Performance
Status
X
X
X
X
X
X
X
ECOG Status must be performed within 3 days of beginning of 
Cycle 1 and prior to each treatment administration.
12-Lead ECG
X
X
X
X
X
X
X
Required up to C3D1 only.
ECG may also be taken if clinically indicated.
MK-1308 Dosinga
X
X
X
Pembrolizumab Dosinga
X
X
X
AE/SAE Monitoring
X
X
X
X
X
X
X
X
X
X
X
Continuous Reporting
Tumor Imaging and 
RECIST Response 
Assessment
X
X
X
X
Every 9 weeks (±7 days) from first dose of study; after 54 
weeks, every 12 weeks (±7 days)
New Anticancer Therapy
Status
X
X
Survival Status
X
Refer to Sections 9.10.5 & 9.10.6.
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treat-
ment
Safety 
Follow-
up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
Visit Timing / Cycle Day
Up to 28 
days prior to 
first dose
1
8
15
1
8
15
1
1
Treat-
ment 
discon-
tinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Laboratory
Procedures/
Assessments
– LOCAL
Hematology/
Chemistry (blood glucose)
X
X
X
X
X
X
X
X
X
X
X
Samples to be collected pre-dose. Screening samples should be 
collected within 14 days prior to dosing. 
Urinalysis
X
X
X
X
X
X
KL-6, SP-D
X
X
X
X
X
X
X
(Applies only to Japan)
PT/INR/aPTT
X
Participants on anticoagulant therapy should be monitored
throughout the trial. Equivalent type testing is permissible.
LDH/GGT/CRP
X
X
X
X
X
X
Thyroid Function Testing 
(T4, T3, TSH), ACTH 
and cortisol
X
X
X
X
X
X
X
After Cycle 6 samples are collected every other cycle; samples 
for cortisol and ACTH should be collected in the morning at 
the earliest feasible time. Investigator must review all of these 
results prior to C1D1 if participant has had prior anti-PD-1 or 
PD-L1 therapy.
Pregnancy Test for 
WOCBP
X
X
X
X
X
X
X
Hepatitis Screen
X
Laboratory
Procedures/
Assessments
– CENTRAL
MK-1308 PKb
X
X
X
X
X
X
X
X
X
X
Anti-MK-1308 Abb
X
X
X
X
X
X
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treat-
ment
Safety 
Follow-
up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
Visit Timing / Cycle Day
Up to 28 
days prior to 
first dose
1
8
15
1
8
15
1
1
Treat-
ment 
discon-
tinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Pembrolizumab PKc
X
X
X
X
X
X
X
Anti-Pembrolizumab Abc
X
X
X
X
X
Serum Cytokine
X
X
X
X
X
X
X
X
X
Samples to be collected:
C1D1(pre-dose, 30 min post-MK-1308 dose), C1D8, C1D15; 
C2D1(pre-dose, 30 min post-MK-1308 dose), C2D8, C2D15;
C3D1(pre-dose, 30 min post-MK-1308 dose) C3D8, C3D15
C4D1 & C5D1(pre-dose)
Blood for T-Cell 
Receptor Repertoire
X
X
X
X
Samples to be collected Cycles 1-4: Day 1 (pre-dose) 
Peripheral Blood for 
Immunophenotyping 
Biomarker Analyses
X
X
X
X
X
X
X
X
Sample to be collected: Cycles 1-3: Day 1(pre-dose), Days 8, 
and Day 15. 
Cycles 4-5: Day 1 (pre-dose) 
Peripheral Blood for 
Mononuclear cells 
biomarker analysis
X
X
X
X
X
Samples to be collected Cycles 1-9: Day 1 (pre-dose) 
Blood for RNA Analyses
X
X
X
X
Samples to be collected Cycles 1-4: Day 1 (pre-dose) 
Blood for Genetic 
Analysis
X
Collect pre-dose. See Section 9.9.1.
Stool for Biomarker 
Analysis
X (2
samples)
X
X
X
X
Samples to be collected at home for all time points: First 
pre-dose sample (optional), collect any time in screening 
between 7 and 4 days before C1D1; second pre-dose sample 
(required) collect at least 2 days after first pre-dose sample; 
Post-dose samples (required) collect 2-5 days after dosing at C1, 
C2, C4 & C12, if clinically feasible
Blood for ctDNA
X
X
X
Samples to be collected Cycles 1, 4 and 12: Day 1 (pre-dose)
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treat-
ment
Safety 
Follow-
up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
Visit Timing / Cycle Day
Up to 28 
days prior to 
first dose
1
8
15
1
8
15
1
1
Treat-
ment 
discon-
tinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Tumor Tissue
Collection
X
a. In the dose escalation phase, MK-1308 will be administered on Cycle 1, Day 1 then every 21 days for a total of 5 doses (Day 1 of Cycle 1- 5). The first dose will be administered without 
pembrolizumab. Pembrolizumab will be administered every 21 days starting with Cycle 2 for a maximum of 35 cycles.
b. Pharmacokinetic/ Anti-drug antibody of MK-1308: For dose escalation phase: Pre-dose trough PK and ADA samples at Cycles 1, 2, 3, 5, 6, 7, 9 and every 4 cycles thereafter. All pre-dose trough 
samples should be drawn within 24 hours before infusion of drug from all participants. PK only of MK-1308: post-dose PK samples should be drawn within 30 minutes after end of infusion of 
MK-1308 at Cycles 1, 2, 3, 5, and 9. Additional post-dose PK samples in the dose escalation phase should be drawn on Day 8 and on Day 15 in Cycles 1, 2, and 3. After discontinuation of study 
drug, samples should be collected at the Safety Follow-Up (30-day) visit.  
c. Pharmacokinetic/ Anti-drug antibody of pembrolizumab: For dose escalation phase: Pre-dose trough PK and ADA samples at Cycles 2, 3, 5, 6, 7, 9 and every 4 cycles thereafter. All pre-dose 
trough samples should be drawn within 24 hours before infusion of drug from all participants. PK only of pembrolizumab: post-dose PK samples should be drawn within 30 minutes after end of 
infusion of pembrolizumab in Cycles 2, 3, 5, and 9. Additional post-dose PK samples in the dose escalation phase should be drawn on Day 8 and on Day 15 in Cycles 2 and 3.  After 
discontinuation of study drug, samples should be collected at the Safety Follow-Up (30-day) visit.
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Dose Confirmation Phase
Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-
up
Disease 
Status 
Follow-up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 days 
prior
to first dose
1
8
15
1
8
15
1
1
Treatment 
discontinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Administrative
Procedures
ICF and ICF for Future
Biomedical Research
X
Any leftover biomarker samples will
be stored for FBR if the participant
signs the FBR consent
Inclusion/Exclusion
Criteria
X
Participant Identification
Card
X
X
Update at C1D1
Demographics and 
Medical History 
X
Medical, Oncology Disease
Status and Prior Oncology 
Treatment History
X
Concomitant Medication
Review
X
X
X
X
X
X
X
X
X
X
Clinical
Procedures/
Assessments
Full Physical
Examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Required once per cycle
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-
up
Disease 
Status 
Follow-up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 days 
prior
to first dose
1
8
15
1
8
15
1
1
Treatment 
discontinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
To be collected at pre-dose and at the 
end of infusion.
([Applies only to Japan: Vitals will 
include pulse oximetry (SpO2)]
ECOG Performance
Status
X
X
X
X
X
X
X
Must be performed within 3 days of 
beginning of Cycle 1 and prior to each 
treatment administration.
12-Lead ECG
X
X
X
X
X
X
X
Required up to C3D1 only.
ECG may also be taken if clinically 
indicated
MK-1308 Dosinga
X
X
X
X
Pembrolizumab Dosinga
X
X
X
X
AE/SAE Monitoring
X
X
X
X
X
X
X
X
X
X
X
Continuous Reporting
Tumor Imaging and RECIST
Response Assessment
X
X
X
X
Every 9 weeks (±7 days) from first
dose of study. 
After 54 weeks, every 12 weeks (±7 
days)
MRI brain
X
X
X
X
Required for all thyroid cancer, 
melanoma, and SCLC participants at 
screening and at other time points as 
needed.
Also required for other participants 
with new neurologic symptoms or 
prior history of brain metastasis.
New Anticancer Therapy
Status
X
X
Survival Status
X
Refer to Sections 9.10.5 & 9.10.6.
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-
up
Disease 
Status 
Follow-up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 days 
prior
to first dose
1
8
15
1
8
15
1
1
Treatment 
discontinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Laboratory
Procedures/
Assessments
– LOCAL
Hematology/Chemistry 
(blood glucose)
X
X
X
X
X
X
X
X
X
X
X
Samples to be collected pre-dose. 
Screening samples should be collected 
within 14 days prior to dosing.
Urinalysis
X
X
X
X
X
X
KL-6, SP-D
X
X
X
X
X
X
X
(Applies only to Japan)
PT/INR/aPTT
X
Participants on anticoagulant therapy 
should be monitored throughout the 
trial. Equivalent type testing is 
permissible.
LDH/GGT/CRP
X
X
X
X
X
X
Thyroid Function Testing 
(T4, T3, TSH), ACTH and 
cortisol
X
X
X
X
X
X
X
After Cycle 6 samples are collected 
every other cycle, samples for cortisol 
and ACTH should be collected in the 
morning at the earliest feasible time.
Pregnancy Test for WOCBP
X
X
X
X
X
X
X
Hepatitis Screen
X
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-
up
Disease 
Status 
Follow-up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 days 
prior
to first dose
1
8
15
1
8
15
1
1
Treatment 
discontinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Clinical
Procedures/Assessments
Laboratory
Procedures/
Assessments
– CENTRAL
MK-1308 PKb
X
X
X
X
X
X
X
X
X
X
Anti-MK-1308 Abb
X
X
X
X
X
X
Pembrolizumab PKc
X
X
X
X
X
X
X
X
X
X
Anti-Pembrolizumab Abc
X
X
X
X
X
X
Serum Cytokine d
X
X
X
X
X
X
X
X
X 
Samples to be collected:
C1D1(pre-dose, 30 min post-MK-
1308 dose), C1D8, C1D15; 
C2D1 (pre-dose, 30 min post-MK-
1308 dose), C2D8, C2D15;
C3D1 (pre-dose, 30 min post-MK-
1308 dose) C3D8, C3D15;
C4D1 & C5D1(pre-dose)
Blood for T-Cell Receptor
(TCR) Repertoire
X
X
X
X
X
Samples to be collected Cycles 1-6: 
Day 1 (pre-dose) 
Peripheral Blood for 
Immunophenotyping 
Biomarker Analyses*
X
X
X
X
X
X
X
X
X
Sample to be collected Cycles 1-3: 
Day 1 (pre-dose, Days 8, Day 15). 
Cycles 4-9: Day 1 (pre-dose) 
Peripheral Blood for 
Mononuclear cells 
biomarker analysis
X
X
X
X
X
Samples to be collected All Cycles: 
Day 1 (pre-dose) 
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Visit / Treatment Cycle
Screening
Treatment Period Cycle = 21 days
Post-Treatment Period
Notes
Cycle 1
Cycles 2-3
Cycles 
4-5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-
up
Disease 
Status 
Follow-up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 days 
prior
to first dose
1
8
15
1
8
15
1
1
Treatment 
discontinua-
tion
30 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
Blood for RNA analyses*
X
X
X
X
Samples to be collected Cycles 1 to 4: 
Day 1 (pre-dose) 
Blood for genetic analysis
X
Collect pre-dose. See Section 9.9.1.
Tumor Tissue
Collection
X
Known PD-L1 status should be 
reported. EGFR mutation and ALK 
trans. docs must be provided. 
On-Treatment Tumor
Biopsy
X
A single biopsy can be collected at 
any date after C3D1. 
Stool for Biomarker 
Analysis
X (2 samples)
X
X
X
X
Samples to be collected at home for
all time points: First pre-dose sample 
(optional), collect any time in 
screening between 7 and 4 days before 
C1D1; second pre-dose sample 
(required) collect at least 2 days after 
first pre-dose sample. Post-dose 
samples (required) collect 2-5 days 
after dosing at C1, C2, C4 & C12, if 
clinically feasible
Blood for ctDNA
X
X
X
Samples to be collected Cycles 1, 4 
and 12: Day 1 (pre-dose)
a.
In the dose confirmation phase: For Arm A & E, MK-1308 will be administered every 21 days (Q3W). For Arms B, C, and D MK-1308 will be administered every 42 days (Q6W). 
Pembrolizumab will be administered every 21 days starting with Cycle 1 for a maximum of 35 cycles.
b.
Pharmacokinetic/Anti-drug antibody of MK-1308: For dose confirmation phase: Pre-dose trough PK and ADA samples at Cycles 1, 2, 3, 4, 5, 6, 8, and every 4 cycles thereafter. All pre-dose 
samples should be drawn within 24 hours of the infusion of drug from all participants. PK only of MK-1308: post-dose PK samples should be drawn within 30 minutes after end of infusion of 
MK-1308 at Cycles 1, 2, 3, 4, and 8. Additional post-dose samples in the dose confirmation phase should be drawn at 168 hours (Day 8), and 336 hours (Day 15) in Cycle 1, 2, and 3. After 
discontinuation of study drug, samples should be collected at the Safety Follow-Up (30-day) visit. In Arms B, C, and D, where MK-1308 is given every 6 weeks, PK samples 30 minutes 
post-MK-1308 infusion should not be collected at C2, C4 and C8. However, PK samples for MK-1308 should be collected in Arm B, C, and D at C3D8 and C3D15.
c.
Pharmacokinetic/ADA of pembrolizumab: For dose confirmation phase: Pre-dose trough PK and ADA samples at Cycles 1, 2, 3, 4, 5, 6, 8 and every 4 cycles thereafter. All pre-dose trough 
samples should be drawn within 24 hours before infusion of drug from all participants. PK only of pembrolizumab: Post-dose PK samples should be drawn within 30 minutes after end of 
infusion of pembrolizumab at Cycles 1, 2, 3, 4, and 8. Additional post-dose samples in the dose confirmation phase should be drawn at 168 hours (Day 8), and 336 hours (Day 15) at Cycles 1, 2, 
and 3.  After discontinuation of study drug, samples should be collected at the Safety Follow-Up (30-day) visit.
d.
In Arms B, C, and D, where MK-1308 is given every 6 weeks, the C2D1 30-minute post-MK-1308 sample is not collected. However, cytokine samples should still be collected at C2D8 and 
C2D15.
08SHQR


Product:  MK-1308 
28
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion and Crossover Phases - Pembrolizumab Q6W + MK-1308 Q6W (Arm F) or MK-1308 Q6W 
Monotherapy (Arm G)
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
ICF and ICF for 
Future Biomedical
Research
X
Any leftover 
biomarker
samples will be
stored for FBR if 
the participant
signs the FBR
consent.
Inclusion/Exclusion
Criteria
X
Participant
Identification
Card
X
X
Update at C1D1
Demographics and 
Medical History 
X
Medical, Oncology
Disease Status and
Prior Oncology 
Treatment History
X
Concomitant
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
08SHQR


Product:  MK-1308 
29
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Full Physical
Examination
X
X
X
X
X
X
X
X
X
X
X
Directed Physical
Examination
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
Required once per 
cycle
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collected at pre-
dose and at the 
end of infusion.
ECOG Performance
Status
X
X
X
X
X
X
X
X
X
X
X
Must be 
performed within 
3 days of 
beginning of 
Cycle 1 and prior 
to each treatment 
administration.
12-Lead ECG
X
Repeat if 
clinically 
indicated
MK-1308 Q6W
Dosinga
X
X
X
X
X
X
08SHQR


Product:  MK-1308 
30
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Pembrolizumab Q6W
Dosinga
X
X
X
X
X
X
Does not apply to 
monotherapy MK-
1308 Arm G
AE/SAE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous 
Reporting
Tumor Imaging and 
RECIST Response 
Assessment
X
X
X
X
Every 9 weeks
(±7 days) from 
first dose of study. 
After 54 weeks,
every 12 weeks
(±7 days)
Submission of Pre-
trial Imaging
X
The site must 
have reviewed 
and submitted 
pre-trial images 
that are of 
diagnostic quality 
from at least 3 
dates to determine 
that radiographic 
progression has
occurred.
08SHQR


Product:  MK-1308 
31
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
MRI brain
X
X
X
Required at 
screening for all 
melanoma 
participants. For
subsequent tumor 
assessment time 
points, brain MRI 
is required only if 
brain disease was 
observed at 
screening or if 
clinically 
indicated.
08SHQR


Product:  MK-1308 
32
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
BRAF Testing
X
BRAF V600 
mutation analysis
should be 
performed locally 
by the sites during 
screening in
participants 
without 
documented
BRAF status. If 
the local
laboratory is 
unable to perform
BRAF testing, the 
site should submit 
the sample to the 
central laboratory 
for testing.
Survival Status
X
Refer to Sections 
9.10.5 & 9.10.6.
08SHQR


Product:  MK-1308 
33
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Hematology/
Chemistry
(blood glucose)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Samples to be 
collected pre-
dose. For C1D1 
samples need to 
be collected 
within 72 hours 
prior to the first 
dose.
Urinalysis
X
X
X
X
X
X
X
X
X
X
PT/INR/aPTT
X
X
Equivalent type 
testing is 
permissible.
LDH
X
X
Thyroid Function 
Testing (T4, T3,
TSH), ACTH and 
cortisol
X
X
X
X
X
X
X
X
X
X
X
After Cycle 6 
samples are 
collected every 
other cycle; 
samples for 
cortisol and 
ACTH should be 
collected in the 
morning at the 
earliest feasible 
time.
08SHQR


Product:  MK-1308 
34
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Pregnancy Test for 
WOCBP
X
X
X
X
X
X
X
X
X
Hepatitis Screen
X
HBsAg and HBV-
DNA. Hep C Ab,
quantitative HCV 
RNA
MK-1308 PK
X
X
X
X
X
X
X
X
X
X
PK should be 
taken within 24 h
pre-dose and 
within 30 minutes 
post end of 
infusion on C1D1, 
C2D1, C3D1, and 
C4D1. Additional 
PK should be 
taken on C1D21, 
C2D21, C3D21 
and C4D21.
Anti-MK-1308 Ab
(ADA) 
X
X
X
X
X
X
Serum antibody 
samples should be 
taken within 24 h
pre-dose on 
C1D1, C2D1, 
C3D1, and C4D1.
08SHQR


Product:  MK-1308 
35
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Exploratory Sample 
for T-cell Response
X
X
X
X
Whole blood 
sample at pre-
dose C1D1, 
C1D21, C2D1, 
and at EoT. 
Pembrolizumab PK
(For Arm F only)
X
X
X
X
X
X
X
X
X
X
PK should be 
taken within 24 h
pre-dose and 
within 30 minutes 
post-dose on 
C1D1, C2D1, 
C3D1, and C4D1. 
Additional PK 
should be taken 
C1D21, C2D21, 
C3D21 and 
C4D21. 
Anti-Pembrolizumab 
Ab
(ADA for Arm F 
only)
X
X
X
X
X
X
Serum antibody 
samples should be 
taken within 24 h
pre-dose on Day 1 
of C1, C2, C3 and 
C4. Does not 
apply to Arm G.
08SHQR


Product:  MK-1308 
36
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Peripheral Blood for 
Immunophenotyping 
Biomarker Analyses
X
X 
Sample to be 
collected pre-dose 
C1D1 and C1D8. 
Blood for RNA 
analyses
X
X
X
X
X
Samples to be 
collected Cycles 1 
to 4: Day 1 (pre-
dose) 
Blood for genetic 
analysis
X
Collect pre-dose. 
See Section 9.9.1.
08SHQR


Product:  MK-1308 
37
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Stool for Biomarker 
Analysis
X (2 
samples)
X
X
X
X
Samples to be 
collected at home 
for all time points: 
First pre-dose
sample, collect 
any time in 
screening between 
7 and 4 days 
before C1D1; 
second pre-dose 
sample collect at 
least 2 days after 
first pre-dose 
sample; Post-dose 
samples collected
2-5 days after
dosing at C1, C2, 
C4 & C12, if 
clinically feasible
Tumor Tissue
X
Known PD-L1 
status should be 
reported. 
If archival tissue 
is not available, 
newly obtained 
tumor tissue is 
required.
08SHQR


Product:  MK-1308 
38
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Efficacy Expansion 
Arms F and G
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screening Crossover 
Screening*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-
up
*For crossover: 
screening 
participants 
assessments do 
not need to be 
repeated if they 
have been 
performed within 
the last 4 weeks. 
Visit Timing / Cycle 
Day
Up to 28 
days prior
to first
dose
Up to 28
days prior
to first
dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Blood for TCR
X
X
X
Collected 
pre-dose on 
dosing days.
Blood for ctDNA
X
X
X
X
Collected pre-
dose (C1D1, 
C2D1, C3D1 and 
EOT)
a) Efficacy expansion phase: In Arm F, MK-1308 will be co-administered as an admixture with pembrolizumab every 6 weeks for a total of up to 24 months (ie, 18 cycles). 
In Arm G, MK-1308 will be given as monotherapy every 6 weeks for a total of up to 24 months (ie, 18 cycles). Participants in Arm G with radiographically confirmed progressive 
disease will be allowed to crossover to Arm F (Section 5).
08SHQR


Product:  MK-1308 
39
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Coformulation Phase: Arm I (MK-1308A Q6W)
Arm I (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 
days prior
to first dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
ICF and ICF for Future
Biomedical Research
X
Inclusion/Exclusion
Criteria
X
Participant Identification
Card
X
X
Update at C1D1
Demographics and 
Medical History 
X
Medical, Oncology
Disease Status and Prior
Oncology Treatment
History
X
Concomitant Medication
Review
X
X
X
X
X
X
X
X
X
Full Physical
Examination
X
X
X
X
X
X
X
X
X
X
Directed Physical
Examination
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
Required once 
per cycle
Vital Signs
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
Collected at pre-
dose and at the 
end of infusion.
08SHQR


Product:  MK-1308 
40
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm I (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 
days prior
to first dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
ECOG Performance
Status
X
X
X
X
X
X
X
X
X
X
Must be 
performed 
within 3 days of 
beginning C1,
and prior to each 
treatment.
12-Lead ECG
X
Repeat if 
clinically 
indicated
MK-1308A Q6W Dosing
X
X
X
X
X
X
AE/SAE Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous 
Reporting
Tumor Imaging and 
RECIST Response 
Assessment
X
X
X
Every 9 weeks
(±7 days) from 
first dose of 
study. 
After 54 weeks,
every 12 weeks
(±7 days)
MRI brain
X
X
X
See Section 
9.2.1.1. 
Survival Status
X
Refer to 
Sections 9.10.5 
& 9.10.6.
Hematology/Chemistry 
(blood glucose)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collected pre-
dose. For C1D1, 
collect within 72 
hours prior to 
the first dose.
Urinalysis
X
X
X
X
X
X
X
X
X
08SHQR


Product:  MK-1308 
41
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm I (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 
days prior
to first dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
PT/INR/aPTT
X
Equivalent type 
testing is 
permissible.
LDH
X
Thyroid Function Testing 
(T4, T3, TSH), ACTH and 
cortisol
X
X
X
X
X
X
X*
X
X
X
* After C6,
samples
collected every 
other cycle.
Samples for 
cortisol and 
ACTH should 
be collected in 
the morning at 
the earliest 
feasible time.
Pregnancy Test for 
WOCBP
X
X
X
X
X
X
X
X
X
Hepatitis Screen
X
08SHQR


Product:  MK-1308 
42
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm I (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 
days prior
to first dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
MK-1308 PK
X
X*
X
X
X
X
X
X
X
X
X
Collect within 
24 h pre-dose
and within 30 
minutes after
end of infusion 
on C1D1, C2D1, 
C3D1, and 
C4D1. 
Additional PK
on C1D8*, 
C1D21, C2D21, 
C3D21 and 
C4D21.
*Optional
Anti-MK-1308 Ab
(ADA)
X
X
X
X
X
X
Collect within 
24 h pre-dose on 
C1D1, C2D1, 
C3D1, and 
C4D1. 
Exploratory Sample for 
T-cell Response
X
Whole blood 
collected at EoT. 
08SHQR


Product:  MK-1308 
43
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm I (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 
days prior
to first dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
MK-3475 PK
X
X*
X
X
X
X
X
X
X
X
X
Collected within 
24 h pre-dose 
and within 30 
minutes after
end of infusion 
on C1D1, C2D1, 
C3D1, C4D1. 
Additional PK 
on C1D8*,
C1D21, C2D21, 
C3D21 and 
C4D21.
*Optional
Anti-MK-3475 Ab (ADA)
X
X
X
X
X
X
Collect within 
24 h pre-dose on 
C1D1, C2D1, 
C3D1, and 
C4D1. 
Blood for genetic analysis
X
Collect pre-dose. 
See Section 
9.9.1.
Tumor Tissue
X
If archival tissue 
is not available, 
newly obtained 
tumor tissue is 
required. For 
participants 
providing 
additional 
biopsies, 
archival tissue is 
also requested.
08SHQR


Product:  MK-1308 
44
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm I (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment Cycle
Screening
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 Cycles ≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow-
up
Survival 
Follow-up
Visit Timing / Cycle Day
Up to 28 
days prior
to first dose
1
8
21
1
21
1
21
1
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Blood for TCR
X
X
X
Collect predose 
Peripheral Blood for 
Immunophenotyping 
Biomarker Analyses
X
X
Collect pre-dose 
Blood for ctDNA
X
X
X
X
Collect pre-dose, 
except EOT
08SHQR


Product:  MK-1308 
45
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Coformulation Phase in China: Arm K (MK-1308A Q6W)  
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
ICF 
X
Inclusion/
Exclusion
Criteria
X
Participant
Identification
Card
X
X
Update at 
C1D1
Demographics and 
Medical History 
X
Medical, Oncology
Disease Status and
Prior Oncology 
Treatment History
X
Concomitant
Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical
Examination
X
X
X
X
X
X
X
X
X
X
Directed Physical
Examination
X
X
X
X
Height
X
08SHQR


Product:  MK-1308 
46
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Weight
X
X
X
X
X
X
X
X
X
X
Required 
once per 
cycle
Vital Signs
X
X
X
X
X
X
X
X
X
X
Pre-dose 
and end of 
infusion
and if 
clinically 
indicated
ECOG
Performance
Status
X
X
X
X
X
X
X
X
X
X
Must be 
performed 
within 3 
days of 
beginning 
C1, and 
prior to 
each 
treatment.
12-Lead ECG
X
Repeat if 
clinically 
indicated
MK-1308A Q6W
Dosing 
X
X
X
X
X
X
AE/SAE 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous 
Reporting
08SHQR


Product:  MK-1308 
47
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Tumor Imaging and 
RECIST Response 
Assessment
X
X
X
Every 9 
weeks (±7 
days) from 
first dose 
of study. 
After 54 
weeks, 
every 12 
weeks (±7 
days)
MRI brain
X
X
X
See 
Section 
9.2.1.1.
Survival Status
X
Refer to 
Sections 
9.10.5 & 
9.10.6.
Hematology/Chem
istry (blood 
glucose)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collected 
pre-dose. 
For C1D1, 
collect 
within 72 
hours prior 
to the first 
dose.
Urinalysis
X
X
X
X
X
X
X
X
X
08SHQR


Product:  MK-1308 
48
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
PT/INR/aPTT
X
Equivalent 
type testing 
is 
permissible
.
LDH
X
Thyroid Function 
Testing (T4, T3,
TSH), ACTH and 
cortisol
X
X
X
X
X
X
X*
X
X
X
* After C6,
samples
collected 
every other 
cycle.
Samples 
for cortisol 
and ACTH 
should be 
collected 
in the 
morning at 
the earliest 
feasible 
time
Pregnancy Test for 
WOCBP
X
X
X
X
X
X
X
X
X
08SHQR


Product:  MK-1308 
49
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Hepatitis Screen
X
HBsAg 
and HBV-
DNA. Hep 
C Ab, 
quantitativ
e HCV 
RNA
08SHQR


Product:  MK-1308 
50
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
MK-1308 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For C1, 
C2, and 
C4, collect 
within 24 h
pre-dose,
within 30 
min, and at
6 h after 
end of 
infusion as 
well as 
anytime on 
Days 2, 8, 
15, and 21.
For C3D1, 
collect 
within 24 h
pre-dose
and within 
30 min 
after end of 
infusion.  
On C3D21, 
collect one 
PK sample
anytime. 
After C4,
collect PK 
within 24 h
pre-dose 
every 2 
cycles.
08SHQR


Product:  MK-1308 
51
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Anti-MK-1308 Ab
(ADA)
X
X
X
X
X
X
X
Collect 
within 24 h
pre-dose 
on D1 for 
C1, C2, 
C3, and 
C4. After 
C4, collect 
ADA 
within 24 h
pre-dose
every 2 
cycles.
08SHQR


Product:  MK-1308 
52
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
MK-3475 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
For C1, 
C2, and 
C4, collect 
within 24 h
pre-dose,
within 30 
min, and at
6 h after 
end of 
infusion as 
well as 
anytime on 
Days 2, 8, 
15 and 21.
For C3D1,
collect 
within 24 h
pre-dose
and within
30 min 
after end of 
infusion.  
On C3D21, 
collect one 
PK sample 
anytime.  
After C4, 
collect PK 
within 24 h
pre-dose 
every 2 
cycles.
08SHQR


Product:  MK-1308 
53
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
Arm K (MK-1308A Q6W)
Treatment Period Cycle = 42 days
Post-Treatment Period
Notes
Visit / Treatment 
Cycle
Screen-
ing
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycles 
≥6
End of 
Treatment
Safety 
Follow-up
Disease 
Status 
Follow
-up
Survival 
Follow-
up
Visit Timing / 
Cycle Day
Up to 28 
days 
prior
to first
dose
1
2
8
15
21
1
2
8
15
21
1
21
1
2
8
15
21
1
1
Treatment 
discon-
tinuation
30 days 
after the 
last dose
90 days 
after the 
last dose
Every 9 
weeks
Every 12 
weeks
Visit Window 
(Days)
-28 to -1
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+14
+14
+14
+14
Anti-MK-3475 Ab
(ADA)
X
X
X
X
X
X
X
Collect 
within 24 h
pre-dose 
on D1 for 
C1, C2, 
C3, and 
C4. After 
C4, collect 
ADA 
within 24 h
pre-dose 
every 2 
cycles.
08SHQR


Product:  MK-1308 
54
Protocol/Amendment No.: 001-12
MK-1308-001-12 Final Protocol
02-Dec-2022
Confidential
3.
Introduction
MK-1308 (quavonlimab, but will be referred to as MK-1308 throughout the protocol) is a 
humanized, antagonist monoclonal antibody that binds Cytotoxic T-Lymphocyte-Associated 
Antigen 4 and blocks its interaction with its ligands, CD80 (B7.1) and CD86 (B7.2). This 
human immunoglobulin G1 antibody is being developed to combine with Keytruda®
(pembrolizumab/anti-PD-1) to increase anti-tumor efficacy in participants with various tumor 
indications.
Study Rationale 
Clinical studies utilizing the combination of Yervoy® (ipilimumab/anti-CTLA4 mAb) and 
Opdivo® (nivolumab/anti-PD1 mAb) have demonstrated improved efficacy over 
monotherapy in advanced melanoma. The Yervoy/Opdivo combination was initially 
approved by the FDA as a treatment for patients with BRAF V600 wild-type unresectable or 
metastatic melanoma, based on findings from the Phase 2 CheckMate-069 study [Postow, M. 
A., et al 2015] then expanded to include patients, regardless of BRAF mutational status, 
based on data from the Phase 3 CheckMate-067 trial, in which PFS and OS were co-primary 
endpoints [U.S. Prescribing Information 2017] [Larkin, J., et al 2015]. Additionally, 
combination treatment with lower dose ipilimumab (1 mg/kg) and pembrolizumab (2 mg/kg) 
in advanced melanoma in a Phase 1 study (KEYNOTE-029) demonstrated an estimated 1-
year PFS of 69% (95% CI 60–75) and an estimated 1-year OS of 89% (95% CI 83–93)
[Long, G. V., et al 2017]. Moreover, a single institution Phase 2 study in patients with 
PD-1/L1-refractory advanced melanoma recently showed a 50% ORR with ipilimumab 
combined with pembrolizumab [Olsonm, D., et al 2018].
This combination has also shown promising efficacy in NSCLC based on data from the 
Phase 1 CheckMate-012 study, prompting initiation of the Phase 3 CheckMate-227 study. 
The CheckMate-012 study suggested that lower and less frequent dosing of ipilimumab
provided an acceptable safety profile with improved efficacy over nivolumab alone in 1L 
NSCLC [Hellmann, M. D., et al 2016]. Evidence for combination efficacy in the 2L SCLC 
population has also been reported from the Phase 1 CheckMate-032 study [Antonia, S. J., et 
al 2016], prompting the initiation of Phase 3 studies for nivolumab and nivolumab plus 
ipilimumab as maintenance therapy after first-line chemotherapy (CheckMate 451) and for 
nivolumab versus chemotherapy as second-line therapy (CheckMate 331) in SCLC.
Based on the results of these promising studies, MK-1308 is being developed in combination 
with pembrolizumab for the treatment of solid tumors. This is the first-in-human trial of 
MK-1308 and it is designed to assess the safety, tolerability, pharmacokinetics, 
pharmacodynamics, and preliminary efficacy of escalating doses of MK-1308 when used in 
combination and in coformulation (MK-1308A) with pembrolizumab in participants with 
advanced solid tumors. In the dose confirmation phase, Arms A, B, C and E will explore 
different dosing schedules of the MK-1308 plus pembrolizumab combination and include 
only participants newly diagnosed with Stage III/IV NSCLC. Arm D will explore this 
combination in 2L SCLC. Arms F and Arm G will explore the anti-tumor activity of 
MK-1308 with or without pembrolizumab in participants with advanced melanoma that is 
refractory to anti-PD-1/PD-L1. Arms I and K will explore the new coformulated product,
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MK-1308A (25 mg MK-1308 + 400 mg pembrolizumab), in participants with advanced solid 
tumors. Arm K will study PK in participants from China.
Details regarding specific benefits and risks for participants participating in this clinical trial 
may be found in the IB and informed consent documents.
Background
Refer to the MK-1308 and pembrolizumab IBs for detailed background information.
Pharmaceutical and Therapeutic Background
In recent years, the field of cancer immunotherapy has developed a better understanding of 
mechanisms by which tumors can limit an immune response. The tumor microenvironment 
can escape immunosurveillance by possessing various immunosuppressive effects, allowing 
escape from immune detection and elimination. In particular, T-cells are kept from 
achieving activation when cell surface inhibitory receptors are engaged, prohibiting T-cell 
function. The most notable of these receptors are PD-1 and CTLA4, both of which have 
been demonstrated to be viable therapeutic targets through clinical investigation.
MK-1308 Background
MK-1308 is a humanized, antagonist mAb that binds Cytotoxic CTLA4 and blocks its 
interaction with both of its ligands, CD80 (B7.1) and CD86 (B7.2). This human IgG1 
antibody is being developed to combine with Keytruda® (pembrolizumab/anti-PD-1) and 
other therapies to increase anti-tumor efficacy in patients with various tumor indications.
Cytotoxic T-Lymphocyte-Associated Antigen-4 is a negative regulator of T-cell function and 
proliferation. It is found on the surface of activated T-cells and regulatory T-cells (Tregs) as a 
single-pass transmembrane protein belonging to the immunoglobulin superfamily. Cytotoxic 
T-Lymphocyte-Associated Antigen-4 was identified as a second receptor for both CD80 and 
CD86 and shares some structural homology with the activating co-receptor, CD28. Unlike 
CD28, which is expressed on naïve T-cells, the cell surface expression of CTLA4 is both 
transient and tightly regulated. The opposing responses mediated by these 2 receptors are 
capable of coordinating the strength of the immune system’s response.
As part of the adaptive immune response, T-cells are central to mounting a defense against 
tumor growth. Activation of T-cells is achieved via the dual engagement of both the T-cell 
receptor and CD28 receptor on the T-cell to mount a full immunogenic response. CD28 binds 
to either CD80 or CD86 molecules expressed on antigen presenting cells, leading to T-cell-
specific expression and presentation of CTLA4, which then competes with CD28 to bind 
either of these activating molecules, thereby dampening the activation signal for the T-cell, 
moving it to a more tolerogenic state. Therefore, blocking this immunomodulatory 
checkpoint, allowing T-cells to remain active, would allow the immune system to mount a 
more competent and durable anti-tumor response.
Cytotoxic T-Lymphocyte-Associated Antigen-4 suppression is thought to be primarily at 
sites of T-cell activation, eg, secondary lymph organs rather than within the tumor 
microenvironment. However, inhibition of CTLA4 results in substantial increases of T-cell 
infiltrates within tumor tissues. This contrasts with the presumed inhibition of T-cell function 
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via PD-1 engagement which occurs within the tumor microenvironment between T-cells 
interacting with both antigen presenting cells and the tumor cells themselves. Differences in 
mechanism and expression of these receptors and their ligands suggest that these differential 
mechanisms of action may underlie the observed clinical benefit when utilized as 
combination therapy above their respective monotherapies.
The humanized anti-human CTLA4 antibody is being proposed for development in 
combination with MSD’s anti-PD-1 mAb, pembrolizumab. Two human mAbs targeting 
CTLA4, ipilimumab (IgG1) and tremelimumab (IgG2) have been and continue to be 
evaluated in the clinic for the treatment of various oncology indications. Ipilimumab is 
approved for melanoma patients alone and in combination with the anti-PD-1 antibody. 
Ipilimumab demonstrates efficacy with doses from 1 to 10 mg/kg, with lower toxicity rates at 
lower doses. In Checkmate 227, the Phase 3 study of the combination in NSCLC, ipilimumab 
is being administered at a 1 mg/kg dose every 6 weeks (Q6W) [ClinicalTrials.gov 2017]. The 
combination of ipilimumab and nivolumab is being actively pursued in multiple cancer types.
MSD has conducted a Phase 1b study of pembrolizumab at 2 mg/kg every 3 weeks (Q3W) in 
combination with ipilimumab at 1 mg/kg Q3W x 4 doses in participants with advanced 
melanoma (KN-029) [Long, G. V., et al 2016]. Results of a melanoma expansion cohort 
(N=153) showed that the combination was reasonably well tolerated with 38% treatment-
related Grade 3/4 AEs and highly efficacious with a 57% ORR. This study has demonstrated 
that CTLA4 blockade in combination with pembrolizumab is potentially beneficial to 
patients.
MK-1308A Background
MK-1308A is a novel coformulation of 25 mg MK-1308 and 400 mg pembrolizumab, 
17.5-mL fill in a 20-mL single vial. The rationale to develop this single entity product as a 
FDC includes the following points:
1. There is an advantage to using FDCs when there is an identifiable patient population 
for whom treatment with a specific combination of agents in a fixed ratio of doses has 
been shown to be safe and effective, and when all of the agents contribute to the 
overall therapeutic effect [World Health Organization 2005].
2. As other anti-CTLA4 agents have not shown significant efficacy when administered 
as monotherapy, the Sponsor does not plan to develop MK-1308 as a monotherapy 
agent.
3. Data from the dose confirmation phase of this trial (MK-1308-001) show that only 
12 (6.7 %) of the 179 patients enrolled to Arms A, B, C and E discontinued the 
combination regimen of MK-1308 + pembrolizumab due to toxicity and subsequently 
started pembrolizumab monotherapy. Moreover, most of these patients had recurrent 
toxicities of equal or worse grade following resumption of pembrolizumab 
monotherapy, suggesting holding the combination and restarting only pembrolizumab
is not protective. 
4. Pembrolizumab is available as a marketed product and can be used as on-label or 
off-label if MK-1308A requires discontinuation due to toxicity.
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5. An FDC product is formulated in a single vial, which will result in time-conservation 
and reduced medication error in comparison to preparation of two independent 
products. 
The objective in the coformulation phases of the study is to evaluate the safety, efficacy, and 
PK of the coformulated product, and to compare these data to that of the single, 
co-administered products given at the same dose and schedule.
Pembrolizumab (MK-3475) Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA4, which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Talmadge, J. E., et al 2007] [Usubütün, A., et al 1998]. 
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. 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 ITIM, 
and an immunoreceptor tyrosine-based switch motif. After T-cell stimulation, PD-1 recruits 
the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such 
as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase 
(ZAP70), which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] 
[Chemnitz, J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism 
by which PD-1 down-modulates T-cell responses is similar to, but distinct from that of 
CTLA4 as both molecules regulate an overlapping set of signaling proteins [Nobili, C., et al
2008] [Hiraoka, N. 2010]. As a consequence, the PD-1/L1 pathway is an attractive target for 
therapeutic intervention in a variety of cancers.
Preclinical and Clinical Trials
MK-1308
MK-1308 was found to behave comparably to clinical standards as assessed through various 
biochemical and cellular assays. The monovalent affinities of MK-1308 against human 
CTLA4 were comparable to one another and ~2-3-fold tighter compared to ipilimumab. 
MK-1308 showed comparable binding to human and cynomolgus CTLA4 as compared to 
ipilimumab.
The ability of the antibodies to block binding of human CTLA4 to its natural ligands, CD80 
and CD86, was assessed by cell-based enzyme-linked immunosorbent assay (ELISA) using 
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CHO cells expressing human CTLA4. The determined mean inhibitory concentration (IC50)
values for binding inhibition of MK-1308 were comparable to ipilimumab. Both ipilimumab 
and tremelimumab induced dose-dependent up-regulation of IL-2 production from Jurkat 
T-cells. MK-1308 also induced the up-regulation of IL-2 in a dose-dependent manner with a 
comparable potency to either clinical standard. Consistent with this finding, both ipilimumab 
and tremelimumab induced dose-dependent IFN-gamma production from CD4+ T-cells in a 
mixed lymphocyte reaction (MLR) based assay, utilizing activated CD4+ T-cells and 
allogenic differentiated monocytes to serve as DCs. MK-1308 induced the up-regulation of 
IFN-gamma in a dose-dependent manner with observed efficacy between ipilimumab and 
tremelimumab. The inclusion of pembrolizumab in combination with either MK-1308 or 
ipilimumab resulted in a substantial and synergistic increase in IFN-gamma production in the 
current MLR format.
In a humanized mouse model implanted with the Panc 08.13 pancreatic adenocarcinoma cell 
line, MK-1308 showed comparable single-agent anti-tumor efficacy to ipilimumab.
Refer to the current IB for more information.
Pembrolizumab (MK-3475)
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor responses 
as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of interferon-gamma, granzyme B, and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell (Teff) function in vivo [Okazaki, T., et al 2001] [Pölcher, M., et al 2010] [Ropponen, 
K. M., et al 1997] [Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008] [Greenwald, R. J., 
et al 2005]. In-house experiments have confirmed the in vivo efficacy of PD-1 blockade as a 
monotherapy, as well as in combination with chemotherapy in syngeneic mouse tumor 
models.
Pembrolizumab has shown clinical activity in multiple tumor types. Please refer to the 
current label.
Ongoing Clinical Trials
MK-1308
The first human clinical trial with MK-1308 is MK-1308-001.
Additional ongoing trials evaluating MK-1308 include KEYNOTE-495, which is evaluating 
MK-1308 in combination with MK-3475 in participants with 1L NSCLC who have specific 
biomarkers and Substudy 02A: Safety and Efficacy of Pembrolizumab in Combination With 
Investigational Agents in Participants With Programmed Cell-death 1 (PD-1) Refractory 
Melanoma (MK-3475-U02A). 
Please see the IB for the description of clinical data from these trials.
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Pembrolizumab (MK-3475)
Over 300 interventional clinical studies involving pembrolizumab are currently ongoing in a 
number of advanced solid tumor indications as well as in hematological malignancies. For 
further details, please refer to the IB. 
Benefit/Risk Assessment
As discussed in Section 3.2 and the IB, both MK-1308 and pembrolizumab, in combination, 
have shown promising efficacy in participants with solid tumors, and preliminary safety data 
of the combination of MK-1308 and pembrolizumab suggest toxicity is manageable. 
The beneficial effects of pembrolizumab have been seen in several melanoma trials to date. 
Publications of a significantly positive benefit/risk ratio have been reported for melanoma in 
single-arm and randomized studies as monotherapy (KEYNOTE-001, KEYNOTE-002, 
KEYNOTE-006). The beneficial effects of pembrolizumab in combination with CTLA-4 
blockade [ipilimumab] have been seen in several melanoma trials to date. Significantly 
positive benefit/risk ratio has been reported for melanoma in the Phase 1b study of 
pembrolizumab in combination with ipilimumab (KEYNOTE-029). 
Given the relevance of improving and expanding treatment options for patients with 
advanced melanoma, there is an unmet medical need for novel combinations in this setting. 
The existing data suggest that CTLA4 blockade, in combination with PD-1 blockade, is a 
promising therapeutic strategy and the benefit: risk assessment for participants included in 
this study is considered to be favorable. 
It cannot be guaranteed that participants in clinical trials will directly 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 participants participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
4.
Objectives/Hypotheses and Endpoints
In male and female participants who are at least 18 years of age with advanced solid tumors:
Objective
Endpoint
Primary

To determine the safety and tolerability 
of MK-1308 in combination with 
pembrolizumab and to establish a 
preliminary recommended Phase 2 dose 
(RPTD) when used in combination 
with pembrolizumab (Dose Escalation
and Confirmation phases)

Number of participants with ≥1 DLT

Number of participants with ≥1 AE

Number of participants discontinuing 
study treatment due to an AE
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Objective
Endpoint

To determine the safety and tolerability 
of MK-1308 as monotherapy (Efficacy
Expansion phase)

Number of participants with ≥1 AE

Number of participants discontinuing 
study treatment due to an AE

To determine the safety and tolerability 
of MK-1308A (Coformulation phase)

Number of participants with ≥1 AE

Number of participants discontinuing 
study treatment due to an AE

Number of participants with ≥1 DLT 
(Arms I)

To evaluate ORR as assessed by BICR 
per RECIST 1.1 in the efficacy 
expansion phase (Arms F and G).
RECIST 1.1 is adjusted to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ 
(see Section 5.4.1.1)

Objective Response: CR or PR 
Secondary

To characterize the PK profiles and 
incidence of ADA, as appropriate, of
pembrolizumab, of MK-1308 as 
monotherapy, and of MK-1308 when 
used in combination and in 
coformulation with pembrolizumab in 
the dose escalation phase as well as in 
Arms A, B, C, D, E, F, G, and I.

To characterize PK profiles and 
incidence of ADA of both MK-1308 
and pembrolizumab in Chinese 
participants in Arm K when the study 
drugs are administered as a 
coformulated product (MK-1308A).

Pharmacokinetic parameters 
including AUC, Cmin, Cmax

Anti-drug antibody levels

To evaluate ORR as assessed by 
investigator per RECIST 1.1 in the dose 
escalation phase, the dose confirmation 
phase, and in Arms I and K in the 
coformulation phase

Objective response: CR or PR
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Objective
Endpoint

To evaluate DOR per RECIST 1.1 as 
assessed by BICR in the efficacy 
expansion phase (Arms F and G).

DOR: The time from first 
documented evidence of CR or PR 
until disease progression or death due 
to any cause, whichever occurs first 
(for responders only)
Tertiary/Exploratory
CCI
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5.
Study Design
Overall Design
This is a first-in-human, multicenter, multi-arm, open-label, non-randomized, Phase 1 / 2 study 
of MK-1308 in combination with pembrolizumab in participants with a histologically or 
cytologically-confirmed diagnosis of an advanced solid tumor. The trial design and guidance of 
decision rules for dose escalation, dose confirmation, and efficacy expansion are shown in
Figure 1 and Figure 2. The coformulation phase is presented in Figure 3.
This study will evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary 
efficacy of MK-1308 in combination and in coformulation with pembrolizumab. Participants
will be allocated to receive these agents using an interactive voice response system/integrated 
web response system (IVRS/IWRS).
After a screening period of up to 28 days, participants will be assigned to the dose escalation,
dose confirmation, efficacy expansion phase, or coformulation phase. Each treatment cycle 
for dose escalation and confirmation is 3 weeks and for efficacy expansion and 
coformulation is 6 weeks. In the efficacy expansion and coformulation phases, each 
participant will be treated for up to 18 cycles (approximately 24 months) after initiation of 
treatment. Clinical follow-up will be at 30 days in the dose escalation and at 30 and 90 days 
in the efficacy expansion and coformulation phases after the last dose.
Details of all phases of the study are provided below.
For the purposes of making dose decisions from a safety perspective, participants will be 
considered evaluable for DLT if they have completed the following:
1. Dose escalation phase: DLT observation period of 6 weeks without a DLT or experienced 
a DLT during this period.
2. Dose confirmation phase: DLT observation period of 3 weeks without a DLT or 
experienced a DLT during this period.
3. Efficacy expansion phase: (Arm F only, up to 14 participants): DLT observation period 
of 6 weeks without a DLT or experienced a DLT during this period.
4. Coformulation phase (Arm I): DLT observation period of 6 weeks without a DLT or 
experienced a DLT during this period.
The dose decision rules are provided for a target number of participants evaluable for DLT. 
When the actual sample size differs from the target size, a Go-decision for dose escalation or 
dose confirmation for MK-1308 in combination with pembrolizumab (Cohort 1, 2, and 3, 
Arm A, B, C, D, E and F) will require that no more than one-fourth of the participants have a 
DLT. The doses chosen for evaluation for the MK-1308 and pembrolizumab combination are 
expected to have a DLT rate ≤10%. This is based on the known DLT rate of 10.7% in the
KN-029 study (pembrolizumab combination with ipilimumab in melanoma) using a dose of 
ipilimumab of 1 mg/kg.
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Dose Escalation Phase for MK-1308 and Pembrolizumab
The projected dose levels are provided in Table 4. A staged dose escalation phase will be 
instituted whereby the available safety, PK, and pharmacodynamics data from the first
6 participants for each cohort after completion of the DLT period (first 2 cycles) will be 
evaluated and discussed with the investigators at dose escalation meetings prior to making 
dose escalation decisions and enrolling additional participants. Initiation of MK-1308 
treatment in participants enrolled within each new dose level will be staggered by at least 
24 hours for the first 3 participants at that dose level.
Based on the emerging safety and/or efficacy signals, an intermediate dose level may be 
explored in consultation and agreement with the investigators and Sponsor. 
Cohort 1 (n = 6 to 14) will enroll participants with advanced/metastatic solid tumors. On 
Cycle 1, Day 1, participants will receive a single monotherapy dose lead-in with MK-1308 at 
25 mg by intravenous route of administration. On Cycle 2, Day 1, and for 3 subsequent 
cycles on Day 1 (Cycles 3 to 5), these participants will receive MK-1308 at 25 mg in 
combination with pembrolizumab at 200 mg on a Q3W schedule. For all subsequent cycles 
(starting with Cycle 6), all participants will receive pembrolizumab monotherapy on a Q3W 
schedule. A total of 6 participants may be enrolled initially. If ≤ 1 participant of the first 6
DLT-evaluable participants has a DLT during the first 2 cycles, Cohort 1 may be expanded to 
a total of 14 participants in order to obtain additional safety, PK, and pharmacodynamic data;
a new cohort will be initiated at the next dose level; and 2 new dose confirmation arms 
(Arms A and B) at the same dose level will be initiated. If more than 1 DLT occurs in the 
first 6 DLT-evaluable participants, 6 new participants may be treated at a lower dose level 
consisting of a single monotherapy lead-in with MK-1308 at an estimated dose of 10 mg,
which will be determined by the available safety, PK, and pharmacodynamic data.
Cohort 2 (n = 6 to 14) will enroll participants with advanced/metastatic solid tumors except 
NSCLC. Non-small cell lung cancer participants will be excluded from this cohort based on 
data from the CheckMate-012 study that shows that these participants have unacceptable 
DLT and discontinuation rates at the equivalent ipilimumab dose of 1 mg per kg [Hellmann, 
M. D., et al 2016]. On Cycle 1, Day 1, participants will receive a single monotherapy dose 
lead-in with MK-1308 at 75 mg by intravenous route of administration. On Cycle 2, Day 1, 
and for 3 subsequent cycles on Day 1 (Cycles 3 to 5), these participants will receive MK-
1308 at 75 mg in combination with pembrolizumab at 200 mg on a Q3W schedule. For all 
subsequent cycles (starting with Cycle 6), all participants will receive pembrolizumab 
monotherapy on a Q3W schedule. A total of 6 participants may be enrolled initially. If ≤1 
participant of the first 6 DLT-evaluable participants has a DLT, Cohort 2 may be expanded to 
a total of 14 participants in order to obtain additional safety, PK, and pharmacodynamic data 
and 3 new dose confirmation arms (Arms C, D, and E) at the same dose level will be 
initiated. If more than 1 DLT occurs in the first 6 DLT-evaluable participants, 6 new 
participants may be treated at a lower dose level or at a different dosing interval which will
be determined by the totality of safety, PK, and pharmacodynamic data. 
Cohort 3 (n = 6) will enroll participants with advanced/metastatic solid tumors except 
NSCLC. Non-small cell lung cancer participants will be excluded from this cohort. On Cycle 
1, Day 1, participants will receive a single monotherapy dose lead-in with MK-1308 at 
200 mg by intravenous route of administration. On Cycle 2, Day 1, and for 3 subsequent 
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cycles on Day 1 (Cycles 3 to 5), these participants will receive MK-1308 at 200 mg in 
combination with pembrolizumab at 200 mg on a Q3W schedule. For all subsequent cycles 
(starting with Cycle 6), all participants will receive pembrolizumab monotherapy on a Q3W 
schedule. If more than 1 DLT occurs in the first 6 DLT-evaluable participants, 6 new 
participants may be treated at a lower dose level or at a different dosing interval which will 
be determined by the totality of safety, PK, and pharmacodynamic data. 
Dose Confirmation Phase for MK-1308 and Pembrolizumab
The purpose of dose confirmation is to gather additional safety, tolerability, PK, 
pharmacodynamic, and preliminary efficacy data of MK-1308 in combination with 
pembrolizumab. The dose confirmation phase will be initiated at selected dose levels once 
the safety profile of these dose levels in dose escalation has been characterized in the 
required number of participants specified above. A staged dose confirmation phase will be 
instituted for each arm whereby the safety, PK, and pharmacodynamic data from the first 14
participants for Arms A, B, C, and D and the first 6 participants of Arm E, and the safety 
profile beyond the DLT window for participants still on-therapy from the dose escalation 
phase will be evaluated and discussed with the investigators at dose escalation meetings prior 
to enrolling additional participants at that dose level. For subsequent dose levels (beyond 25 
mg), a dose between 25 mg and 75 mg may be selected, based on the totality of data.
As described in detail below and in Figure 1, the arms of the dose confirmation phase will 
include: first-line, advanced/metastatic NSCLC (Arms A, B, C, E,) and second-line (and 
beyond) advanced/metastatic SCLC (Arm D). With respect to PD-L1 status, any tumor 
PD-L1 expression level is eligible for enrollment. Known tumor PD-L1 status is not required 
for study enrollment. However, if there are less than 10 participants with a PD-L1 tumor 
proportion score (TPS) ≥50% in any arm (as determined by centralized testing), additional 
participants with PD-L1 expression ≥50% will be added at the discretion of the Sponsor, for
a total of 10 participants.
Arm A (n = 14 to 30) will enroll participants with a diagnosis of advanced/metastatic
NSCLC. On Cycle 1, Day 1 and during all subsequent cycles, participants will receive MK-
1308 at 25 mg in combination with pembrolizumab at 200 mg on a Q3W schedule. If ≤3 of 
the first 14 DLT-evaluable participants experience a DLT, after discussion of safety data with 
the Investigators, Arm A will be expanded to 30 participants. If more than 3 DLTs occur in 
the first 14 DLT-evaluable participants, enrollment of Arm A will not be expanded. Up to 
16 participants may be enrolled initially to achieve the desired sample size of 14 DLT-
evaluable participants.
Arm B (n = 14 to 30) will enroll participants with a diagnosis of advanced/metastatic
NSCLC. On Cycle 1, Day 1, participants will receive MK-1308 at 25 mg in combination 
with pembrolizumab at 200 mg. On all subsequent cycles, pembrolizumab will be given on a
Q3W schedule at a dose of 200 mg and MK-1308 will be given on a Q6W schedule at a dose 
of 25 mg. If ≤3 of the first 14 participants experience a DLT, after discussion of safety data 
with the investigators, Arm B will be expanded to 30 participants. If more than 3 DLTs occur
in the first 14 DLT-evaluable participants, enrollment of Arm B will not be expanded. Up to 
16 participants may be enrolled initially to achieve the desired sample size of 14 DLT-
evaluable participants.
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Arm C (n = 14 to 30) will enroll participants with a diagnosis of advanced/metastatic
NSCLC. On Cycle 1, Day 1, participants will receive MK-1308 at 75 mg in combination 
with pembrolizumab at 200 mg. On all subsequent cycles, pembrolizumab will be given on 
an every Q3W schedule at a dose of 200 mg and MK-1308 will be given on a Q6W schedule 
at a dose of 75 mg. If ≤3 of the first 14 participants experience a DLT, after discussion of 
safety data with the investigators, Arm C will be expanded to 30 participants. If more than 3
DLTs occur in the first 14 DLT-evaluable participants, enrollment of Arm C will not be 
expanded. Up to 16 participants may be enrolled initially to achieve the desired sample size 
of 14 DLT-evaluable participants.
Arm D (n = 14 to 30) will enroll participants with advanced/metastatic SCLC. On Cycle 1, 
Day 1, participants will receive MK-1308 at 75 mg in combination with pembrolizumab at 
200 mg. On all subsequent cycles, pembrolizumab will be given on a Q3W schedule at a 
dose of 200 mg and MK-1308 will be given on a Q6W schedule at a dose of 75 mg. If ≤3 of 
the first 14 participants experience a DLT, after discussion of safety data with the 
investigators, Arm D will be expanded to 30 participants. If more than 3 DLTs occur in the 
first 14 DLT-evaluable participants, enrollment of Arm D will not be expanded. Up to 16
participants may be enrolled initially to achieve the desired sample size of 14 DLT-evaluable 
participants.
Arm E (n = 6 to 14) will enroll participants with a diagnosis of advanced/metastatic
NSCLC. On Cycle 1, Day 1 and during all subsequent cycles, participants will receive MK-
1308 at 75 mg in combination with pembrolizumab at 200 mg on a Q3W schedule. If ≤ 1 of 
the first 6 DLT-evaluable participants experience a DLT, after discussion of safety data with 
the Investigators, Arm E will be expanded to 14 participants. If more than 1 DLT occur in the 
first 6 DLT-evaluable participants, enrollment of Arm E will not be expanded. Up to 8 
participants may be enrolled initially to achieve the desired sample size of 6 DLT-evaluable 
participants.
An efficacy interim analysis is planned for each arm in dose confirmation after the first 8 or 
14 participants (depending on the enrollment rate) have finished the first tumor assessment. 
An arm may have enrollment terminated early if there are zero responders out of the first 8 
evaluable participants in the arm, or less than 2 responders (CR, PR) out of the first 14 
participants in the arm, and if so, the remaining sample size yet to be enrolled for the arm 
may be used by one or more arms in the dose confirmation phase at the discretion of the 
Sponsor. 
Efficacy Expansion and Crossover Phases for MK-1308 and Pembrolizumab 
The purpose of the efficacy expansion phase is to gather preliminary anti-tumor efficacy data 
for MK-1308 in combination with pembrolizumab as well as for MK-1308 monotherapy in 
the specific target population of PD-1/PD-L1 refractory melanoma.
An adaptive design with one or more safety and efficacy interim analyses with potential to 
stop the enrollment early for futility will be implemented. Details of the interim analyses are 
described below. Whenever both the MK-1308 combination arm (Arm F) and the MK-1308 
monotherapy arm (Arm G) are open, 1:1 randomization will be implemented to facilitate the 
enrollment and reduce bias.
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Pre- and on-treatment biopsies are required for approximately 10 participants in each of 
Arms F and G. However, if there are less than 10 in each of these arms at the end of the 
planned enrollment period then additional participants will be added at the discretion of the 
Sponsor, for a total of up to 30 participants. 
Arms F and G is applicable only to sites in Australia, New Zealand, Israel, Canada, Chile, 
France, Poland, Italy, Greece, Sweden, Spain, and United States.
Arm F (n = up to 100): On Cycle 1, Day 1 and for all subsequent cycles, participants will 
receive MK-1308 at 25 mg in combination with pembrolizumab at 400 mg. Both MK-1308 
and pembrolizumab will be given on a Q6W schedule continuously for up to 18 cycles (up to 
24 months).
A safety interim analysis will be conducted when the first 6 DLT-evaluable participants have 
completed their DLT evaluation. Up to 8 participants may be enrolled initially to achieve the 
desired sample size of 6 DLT-evaluable participants. If the observed DLT rate is higher than 
25%, the 400 mg Q6W pembrolizumab dosing may be replaced with pembrolizumab 200 mg 
Q3W in the newly enrolled participants (Arm H; not activated). The decision to switch from 
pembrolizumab 400 mg Q6W to 200 mg Q3W will be based on the totality of the safety data 
and not limited to DLTs. If needed, up to 14 participants will be evaluated for DLT and 
additional safety interim analyses will be conducted after the first safety interim analysis of 
6 DLT-evaluable participants and before the final decision of the dose and frequency of the 
combination is determined. If the decision to switch from pembrolizumab 400 mg Q6W to 
200 mg Q3W is made, existing participants who have already been treated with 
pembrolizumab 400 mg Q6W plus MK-1308 25 mg Q6W may also be switched to
pembrolizumab 200 mg Q3W plus MK-1308 25 mg Q6W, after discussion with the Sponsor. 
As soon as the DLT and safety evaluation is complete and the dose and frequency are 
decided, randomization between Arm F and Arm G (described below) will begin. A total of 
100 new participants in the pembrolizumab 200 Q3W plus MK-1308 25 mg Q6W will be 
planned for enrollment, taking into consideration the efficacy interim analysis, if an alternate 
dosing regimen is chosen.
Note: The DLT period with the first 6 subjects concluded with no toxicity concerns. Arm H 
is not required and will not be activated.
Regardless of the dosing regimen chosen, an efficacy interim analysis will be conducted 
approximately 9 weeks after the first dose of the 20th participant. If at least 4 out of the first 
20 participants (ie, at least 20%) experience a response, Arm F will continue to enroll a 
maximum of 80 additional participants for a total of 100 participants at the same dose level. 
Enrollment to Arm F may not be paused to wait for results of the efficacy interim analysis. If 
fewer than 20% responses are observed, the totality of the data will be evaluated to decide 
whether or not to continue enrollment in Arm F.
Arm G (n = up to 40): On Cycle 1, Day 1 and for all subsequent cycles, participants will 
receive MK-1308 at 25 mg as monotherapy on a Q6W schedule continuously for up to 
18 cycles (up to 24 months). If after receiving at least 2 cycles of MK-1308 monotherapy, 
participants have radiographical-progressive disease that is centrally verified by BICR, they 
will be eligible to crossover to combination therapy with pembrolizumab.
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An efficacy interim analysis will be conducted approximately 9 weeks after the first dose of 
the 20th participant in Arm G. If at least one response is observed out of the first 20 
participants AND Arm F did not stop enrollment early at the efficacy interim analysis, 
Arm G enrollment will continue to enroll a maximum of 20 additional participants for a total 
of 40 participants. If there are zero responders out of the first 20 evaluable participants in 
Arm G OR a decision was made to stop the enrollment of Arm F, enrollment of Arm G will 
stop. Enrollment to Arm G may be paused to wait for results of the efficacy interim analysis. 
Crossover to Combination Therapy from Arm G
Participants who show BICR-verified radiographical-progressive disease in Arm G will be 
eligible to receive combination therapy with pembrolizumab after consultation with the 
Sponsor. The specific regimen into which participants will cross over will be determined by 
the safety analysis conducted after the first 6 participants in Arm F complete the DLT period. 
If the Q6W pembrolizumab dosing regimen is deemed safe, then Arm G participants will 
cross over to this regimen. 
Crossover to combination therapy will only be allowed after at least 2 treatments of 
monotherapy have been completed. Note: Disease progression must be assessed by imaging 
study using RECIST 1.1 and be sent to CIV for expedited central verification of progression 
by BICR. CIV will communicate the results to the study site and Sponsor via email. The 
imaging for BICR-verified progression will be used to establish a new baseline for the 
crossover phase if the imaging is performed within 28 days prior to first dose of combination 
therapy.
Participants who cross over to combination therapy will start with C1D1 activities per the 
SOA and should undergo all scheduled activities for the new Arm. 
Participants who crossed over to combination therapy will be eligible to receive a maximum 
of 24 months of treatment from the start of combination treatment.
Coformulation Phase for MK-1308A (Arms I and K)
The purpose of the coformulation phase is to evaluate safety, PK, and efficacy for
MK-1308A, a coformulation of 25 mg MK-1308 and 400 mg pembrolizumab, 17.5-mL fill in 
a 20-mL vial. The coformulation PK data will be compared to the data generated in the 
efficacy expansion phase when these drug products were individually co-administered at the 
same dose level and schedule. Arm I is applicable only to sites in Israel, New Zealand, and 
Australia. Arm K is applicable only to sites in mainland China.
Arm I (n= up to 20) will enroll participants with advanced/metastatic solid tumors. 
Participants will receive MK-1308A on a Q6W schedule starting on Cycle 1, Day 1 for up to 
18 cycles (~ 24 months).
Arm K (n= up to 20) will enroll participants who reside in China with advanced solid 
tumors. On Cycle 1, Day 1 and for all subsequent cycles, participants will receive 
MK-1308A on a Q6W schedule continuously for up to 18 cycles (up to 24 months).
Data from Arm K will be used to demonstrate acceptable safety and PK of MK-1308A in 
Chinese participants and will inform the use of MK-1308A in China in future studies, 
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independent of tumor type. Chinese participants who reside in China will only enroll in 
Arm K.
MK-1308A may be considered as tolerant if one or less participant of the first 3 experience a 
DLT, or if 2 or less participants of the first 6 experience a DLT (1/3 or ≤ 2/6) for each 
sub-cohort (Table 1).
Table 1
Toxicity Assessment
Number of Toxicities
Number of Participants Treated 
at Current Dose
n=3
n=6
0
S
S
1
S
S
2
DU
S
3
DU
DU
4
DU
5
DU
6
DU
S=stay at the same dose; DU=De-escalate; the current dose is unacceptable. 
Modified mTPI table based on target DLT rate of 30% and equivalent DLT interval of (0.25, 0.33).
Treatment Allocation
Treatment allocation for dose escalation, dose confirmation, and coformulation Arms I and K
will be accomplished by non-random assignment. During the dose confirmation phase when 
more than 1 treatment arm is open for enrollment of NSCLC participants, IVRS/IWRS will 
distribute successive participants across all open treatment arms in each phase to minimize 
selection bias. Each new arm (if applicable) will open for enrollment without delay once the 
DLT observation period of the previous dose cohort is completed and a dose escalation or 
cohort expansion decision is made. In the efficacy expansion phase, randomization by 
IVRS/IWRS will be implemented with equal randomization ratio whenever at least two of 
the Arms F and G are open for enrollment. (Note: this is a true randomization which is 
different from the assignment methodology in dose confirmation).
ORR as assessed by the investigator is a secondary objective in the dose escalation phase, 
dose confirmation phase, and coformulation phase (Arms I and K). The progression-free 
survival according to RECIST v1.1, as well as overall survival, will be evaluated as 
exploratory endpoints. In the efficacy expansion and coformulation phases, ORR and PFS 
will also be assessed by iRECIST.
In participants who have initial evidence of radiological progressive disease by RECIST 1.1, 
it will be at the discretion of the investigator whether to continue a participant on study 
treatment until repeat imaging is obtained. This clinical judgment should be based on the 
participant’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Participants may continue to receive study treatment until the tumor 
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assessment is repeated 4 to 8 weeks later in order to confirm progressive disease by iRECIST 
per site assessment.
Adverse events will be evaluated by the investigator, according to criteria outlined in the NCI 
CTCAE, Version 4.03, to establish the safety and tolerability of MK-1308 when 
administered as monotherapy, in combination with pembrolizumab, or in coformulation as 
per the primary objective of this study.
There will be no intra-participant dose escalation for participants enrolled in this study. The 
Sponsor will evaluate DLTs when at least 10 subjects have completed the DLT period to 
confirm the safety of Arm I. Enrollment will not be paused while this evaluation is 
performed. The definition of DLTs and criteria for dose modification of MK-1308 are 
outlined in Section 7.1.1 and Section 7.2.1. 
Participants may receive study treatment after initiation of combination treatment with 
MK-1308 plus pembrolizumab for up to 18 cycles (Q6W) or 35 cycles (Q3W), for a total of 
24 months. Participants will be treated until progressive disease, unacceptable toxicity, 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw treatment, participant withdrawal of consent, pregnancy of the participant, 
noncompliance with trial treatment or procedure requirements, participant completes 
treatment, or administrative reasons requiring cessation of treatment, at which point they will 
be discontinued from the study. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
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Trial Diagram
Figure 1
Trial Design for Dose Escalation and Dose Confirmation
In the dose escalation phase: dosing of pembrolizumab begins at Cycle 2 Day 1 following the monotherapy 
lead-in dose with MK-1308.
In the dose confirmation phase: dosing of pembrolizumab begins at Cycle 1 Day 1. 
*
A dose level of MK-1308 between 75 mg and 200 mg may be selected based on the totality of data.
†
An interim efficacy analysis will be performed after the first 8 or 14 participants. If there are 0 responses 
(CR, PR) in the first 8 evaluable participants, or if there is ≤1 response (CR, PR) in the first 14 evaluable
participants, enrollment of the arm may be stopped early (if the enrollment is not yet complete). A decision will 
be made at the Sponsor’s discretion whether the remaining sample size originally planned for the arm may be 
allocated to one or more arms in dose confirmation phase if the enrollments are open.
Figure 2
Trial Design for Efficacy Expansion Phase (Arm F and G)
*If participants have PD, they may cross over to Arm F, depending on the rules outlined in Section 5.1.
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Figure 3
Trial Designs for Coformulation Arms I and K
Number of Participants
This study is expected to enroll approximately 348 participants.
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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 participants

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 decision to no longer supply MK-1308 or 
pembrolizumab.
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Scientific Rationale for Study Design
Rationale for Endpoints
Efficacy Endpoints
For the efficacy expansion (Arms F and G) phase, ORR assessed by BICR based on 
RECIST 1.1 is the primary efficacy endpoint. The DOR based on RECIST 1.1 as assessed by 
BICR is a secondary efficacy endpoint for Arms F and G. The ORR assessed by investigator 
based on RECIST 1.1 is a secondary efficacy endpoint for the rest of the study. Exploratory 
endpoints include PFS and OS. In addition, ORR and PFS based on irRECIST (in the dose 
escalation phase and the dose confirmation phase) and iRECIST (in the efficacy expansion 
and coformulation phases) are exploratory endpoints.
Tumor responses are evaluated using RECIST 1.1, adjusted to follow a maximum of 
10 target lesions and a maximum of 5 target lesions per organ followed by irRECIST or 
iRECIST. Response confirmation per RECIST 1.1 is required. 
The irRECIST accounts for the unique tumor response characteristics seen with 
immunotherapeutic agents. Immunotherapeutic agents such as MK-1308 and pembrolizumab 
may produce anti-tumor effects by potentiating endogenous cancer-specific immune 
responses. The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents and can manifest a clinical response after 
an initial increase in tumor burden or even the appearance of new lesions. Standard RECIST 
may, thus, not provide an accurate response assessment of immunotherapeutic agents. These 
findings support the need to apply a modification to RECIST that takes into account the 
unique patterns of atypical response in immunotherapy and enables treatment beyond initial 
radiographic progression. irRECIST will be used by BICR and investigators to assess tumor 
response and progression and make treatment decisions in the dose escalation phase and the 
dose confirmation phase.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [Seymour, L., et 
al 2017]. The unidimensional measurement of target lesions, qualitative assessment of non-
target lesions, and response categories are identical to RECIST 1.1, until progression is seen 
by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. For the efficacy expansion phase, iRECIST 
will be used by investigators to assess tumor response and progression and make treatment 
decisions, as per current health authority guidance.
Safety Endpoints
The primary safety objectives of this trial include characterizing the safety and tolerability of 
MK-1308 when used in combination with and in coformulation with pembrolizumab in 
participants with advanced solid tumors. The primary safety analyses will be based on 
participants who experience toxicities as defined by CTCAE, Version 4.03. 
The attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. Safety data will include, but is not 
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limited to, AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific events will 
be collected and designated as events of clinical interest (ECIs) as described in Section 9.3.7.
Pharmacokinetic Endpoints
A secondary objective of this trial is to characterize the PK profile of MK-1308 and 
pembrolizumab. The serum concentrations of each antibody will be used to determine PK 
parameters (eg, Cmax, AUC) for MK-1308 and pembrolizumab. Furthermore, the results of 
these analyses will be used in conjunction with pharmacodynamics, safety, and ADA 
endpoints to help assess dosing strategies for MK-1308.
Pharmacodynamic Endpoints
A direct receptor occupancy assay to measure target engagement cannot be used as CTLA4
expression on the cell surface of T-cells is transient and tightly regulated. Therefore, post-
treatment changes in absolute leukocyte counts (ALC) and expression of T-cell activation 
markers (for example Ki67, ICOS, and HLA-DR) will be assessed in peripheral blood based 
on the proposed effect of CTLA4 blockade in the immune priming phase to increase 
activation and proliferation of T-cells.
5.4.1.4.1 Anti-Drug Antibody Assessment
Formation of ADAs can potentially confound drug exposures at therapeutic doses, and prime 
for subsequent infusion-related toxicity. Anti-drug antibody response at the beginning of 
each cycle will be determined to understand drug metabolism, exposure, and safety.
Anti-drug antibody response to MK-1308 and pembrolizumab will be evaluated in validated 
immunogenicity assays.
5.4.1.4.2 Exploratory Sample for T-cell Response
A whole blood sample will be collected at the end of treatment to perform an exploratory 
analysis to assess reactivity of T-cells to MK-1308 and pembrolizumab sequences. The 
procedure for collecting and shipping the blood to MSD will be provided in the Procedures
Manual. This will not be performed for Arm K.
5.4.1.4.3 Serum for Cytokine Testing
Because treatment with MK-1308 can result in immune stimulation and resulting potential 
for cytokine release, serum cytokines may be monitored as needed to provide supplementary 
information to assist in the evaluation of any safety events. This will not be performed for 
Arm K.
Planned Exploratory Biomarker Research
(This is not applicable for Arm K.)
Cancer immunotherapies represent an important and novel class of anti-tumor agents. The 
mechanism of action of these exciting new therapies is, however, not completely understood 
and much remains to be learned regarding how best to leverage these new drugs to treat 
patients. To aid future patients, it is important to investigate the determinants of response or 
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resistance to cancer immunotherapy, as well as determinants of AEs in the course of our 
clinical trials. These efforts will identify novel predictive/ pharmacodynamic biomarkers and 
generate information that will better guide single agent and combination therapy with 
immuno-oncology drugs. To identify novel biomarkers, this study will collect biospecimens 
(blood components, tumor material, etc.) to support analyses of cellular components (eg, 
protein, DNA, RNA, metabolites) and other circulating molecules. Investigations may 
include but are not limited to:

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 (mutations, methylation status, microsatellite instability [MSI], etc.). Key 
molecular changes of interest to immune-oncology drug development include, for 
example, 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. 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. Microsatellite instability may also 
be evaluated as this is an important biomarker for some cancers (ie, colorectal cancer). 
Circulating tumor DNA and/or RNA may also be evaluated from blood samples.

Germline (blood) genetic analyses (eg, Single Nucleotide Polymorphism (SNP) analyses, 
whole exome sequencing, whole genome sequencing):  This research will evaluate 
whether genetic variation within a clinical trial population correlates with response to the 
treatment(s) under evaluation. If genetic variation is found to predict efficacy or AEs, the 
data might inform optimal use of therapies in the patient population. Furthermore, it is 
important to evaluate germline DNA variation across the genome in order to interpret 
tumor-specific DNA mutations. In addition to studying variation across the human 
genome, gene variants of CTLA4 may be investigated for SNP analysis and correlation 
with various endpoints. Finally, MSI may be evaluated as this is an important biomarker 
for some cancers (ie, colorectal cancer).

Tumor and blood RNA analyses:  Both genome-wide and targeted messenger RNA 
(mRNA) expression profiling and sequencing in tumor tissue and in blood may be 
performed to define gene signatures that correlate with clinical response to treatment with 
MK-1308, pembrolizumab, or other immunotherapies. Immunotherapies induce a 
response in tumors that likely reflects an inflamed/immune phenotype. Specific immune-
related gene sets (such as those capturing interferon-gamma 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 as well as exosomal profiling.

Proteomics, metabolomics and IHC using blood or tumor: Tumor and blood samples 
from this study may undergo proteomic analyses (eg, PD-L1 IHC). PD-L1 protein level 
in tumor sections, assessed by IHC, has been shown to correlate with response to 
pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device has 
been developed for use with pembrolizumab in NSCLC. Preliminary data indicate that 
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this association may also be true in additional cancer types (ie, triple-negative breast 
cancer, head and neck cancer, and gastric cancer). Additional tumor or blood-derived 
proteins may also correlate with response to pembrolizumab. Tumor tissue may, 
therefore, be subjected to proteomic analyses using a variety of platforms that could 
include but are not limited to immunoassays and liquid chromatography/mass 
spectrometry. This approach could identify novel protein biomarkers that could aid in 
patient selection for pembrolizumab therapy.

Blood for immunophenotyping: Real-time biomarker analysis of Ki67, HLA-DR immune 
activation markers on CD4/CD8 T-cells will be performed to aid RPTD analysis. 
Analysis of peripheral blood for mononuclear cells will employ higher dimensional
cytometry panel(s) for more in-depth analysis of additional activation markers. The 
procedure for collecting and shipping the blood to MSD will be provided in the
Procedures Manual.

Other blood-derived biomarkers: In addition to expression on tumor tissue, PD-L1 and 
other tumor-derived proteins RNA and/or DNA can be shed from tumors and released 
into the blood. Assays such as enzyme-linked immunoassay that measure proteins, those 
assessing circulating tumor DNA, RNA and/or exosomes may also be evaluated from 
blood samples. Correlation of these biomarkers with response to pembrolizumab therapy 
may identify new approaches for predictive biomarkers in blood, representing a major 
advance from today’s reliance on assessing tumor biomarkers. This research would serve 
to develop such assays for future clinical use. 
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.

Recent research suggests that the diversity of bacteria in the GI tract (microbiome) might 
be associated with response to checkpoint inhibition therapy and development of irAEs
[Vetizou, M., et al 2015] [Carbonnel, F., et al 2017] [Lynch, S. V. 2016] [Dubin, K., et al 
2016]. For example, members of Bacteroides phylum may be protective against drug-
induced colitis. To evaluate the potential for such association in this study, stool will be 
collected during the Dose Escalation and Dose Confirmation phases and the diversity and 
strains of bacteria comprising the gut microbiome may be evaluated in the context of
irAEs, clinical response to MK-1308, and changes to the diversity of the microbiome that 
result from the study treatment.
Planned Genetic Analysis
Genetic variation may impact a participant’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, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
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). 
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Genetic research may consist of the analysis of one or more candidate genes or the analysis 
of genetic markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that they may help further the understanding of 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.
In addition to studying variation across the human genome, HLA will specifically be 
investigated for MK-1308 in combination with pembrolizumab and other treatments.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented 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, depending on which specimens are consented for future 
biomedical research.
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 participants. The objective of collecting/retaining 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 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of Future Biomedical Research are presented in Appendix 6 – Collection and 
Management of Specimens for Future Biomedical Research.
Justification for Dose
Starting Dose for This Trial
The first-in-human dose projection for MK-1308 was developed using an integrated 
approach based on the experimental no-observed-adverse-effect-level (NOAEL) from 
nonclinical Good Laboratory Practice (GLP) safety studies in cynomolgus monkeys (a 
relevant species), data obtained from various in vitro experiments, PK studies in cynomolgus 
monkeys (a relevant species), and using recent FDA guidelines for antibody-based 
immunotherapies [Saber, H., et al 2016]. Data and sources used for the comparison and 
analyses include: (1) the protein sequence of human and cynomolgus monkey CTLA4; (2) 
mRNA expression profiles in human and cynomolgus monkey; (3) the binding affinity of
MK-1308 to human and cynomolgus monkey CTLA4; (4) the in vitro bioactivity of MK-
1308 in human and cynomolgus monkey CTLA4; (5) the in vitro evaluation of cytokine
release; (6) PK (exposure) in cynomolgus monkeys following administration of MK-1308;
and (7) the results from the nonclinical safety studies in cynomolgus monkeys. MK-1308 
was also found to be comparable to ipilimumab in biochemical and cellular assays, as 
detailed in Section 3.2, and had similar PK to ipilimumab in cynomolgus monkeys.
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Predicted human MK-1308 exposure following administration of doses ranging from 
0.1 to 10 mg/kg Q3W are shown in Figure 4. It is anticipated that the maximum 
concentration at steady-state (Cmax, ss) following administration of the 0.3 mg/kg Q3W will 
not exceed ~8 µg/mL. This predicted steady-state concentration should provide an 
approximately 15-fold safety margin relative to the observed Cmax, ss of ~120 µg/mL at 
NOAEL (3 mg/kg MK-1308, Q1W) (Table 2). Additionally, based on the AUCτ,ss, the 
anticipated steady-state MK-1308 exposure at the FIH dose should provide an approximately 
6-fold safety margin to the observed AUC0-168h (approximately equivalent to AUCτ,ss) in 
cynomolgus monkey at the NOAEL (Table 2).
Figure 4
Predicted Serum Concentration-time Profiles of MK-1308 in the Proposed 
Clinical Study at Doses of 0.3 mg/kg to 10 mg/kg MK 1308 When Administered by 
Intravenous Infusion Once Every 21 Days
Conc. = concentration
Table 2
Predicted Pharmacokinetic Parameters in Humans and the Relative Fold 
Differences at the NOAEL in Cynomolgus Monkeys
PK parameter
Units
Human 
(0.3 mg/kg; Q3W)
Cynomolgus monkey 
NOAEL 
(3 mg/kg Q1W)
Fold increase of human 
predictions over 
NOAEL in cynomolgus 
monkeys
Cmax,ss
µg/mL
8.4
124
14.8
Cmin,ss
µg/mL
1.75
39.4
22.5
AUCτ,ss
µg/mL×h
1800
10,200
5.671
AUCτ,ss = area under the curve at steady-state; Cmax,ss = maximum concentration at stead state; 
Cmin,ss = minimum concentration at stead state; NOAEL = no-observed-adverse-effect-level; 
PK = pharmacokinetic(s); Q1W = every week; Q3W = every 3 weeks
1.The fold increase in AUCτ,ss was calculated as AUCτ,ss (cynomolgus monkey, at NOAEL) / AUCτ,ss
(human, at FIH dose).
0
21
42
63
84
105 126 147 168 189 210 231
0.01
0.1
1
10
100
1000
Days
MK-1308 Conc. (g/mL)
0.1 mg/kg
0.3 mg/kg
1 mg/kg
3 mg/kg
10 mg/kg
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Furthermore, in the cynomolgus monkey PK study, exploratory biomarker analysis revealed 
no impact on T-cell markers for MK-1308 serum concentrations ≤10 µg/mL with a single IV 
bolus dose of 0.5 mg/kg MK-1308.
In vitro activity assays performed using human and cynomolgus monkey cell-based assay 
systems revealed no apparent potency differences for MK-1308. Also, no signal was 
observed in the cytokine release assay for MK-1308 concentrations up to 1000 µg/mL.
In an exposure-response model of the safety of ipilimumab monotherapy in melanoma 
participants, the model-predicted probability of experiencing a Grade 2 or more immune-
related adverse events (irAEs) at the median Cmin,ss (5th, 95th percentiles) for the 0.3 mg/kg 
treatment group was approximately 9.8% (5.6, 14), and the corresponding probability of 
experiencing a Grade 3 or more irAE was approximately 3.3% (1.8, 4.9) [Feng, Y., et al 
2014].
Based on these assessments, the FIH starting dose of 0.3 mg/kg MK-1308 is proposed. This 
dose is equivalent to a fixed dose of 25.5 mg MK-1308 for an 85-kg participant. Based on 
these assumptions the proposed clinical trial dose will start at 25 mg.
A fixed-dose regimen is chosen to be used in this study because it is expected to simplify the 
dosing regimen and potentially reduce dosing errors, as well as be more convenient for 
physicians. A fixed dosing scheme will also reduce complexity in the logistical chain at 
treatment facilities as well as reducing waste. 
Given the similarity between ipilimumab and MK-1308, a published ipilimumab population 
PK model was used to identify a fixed-dose equivalent to 0.3 mg/kg MK-1308. The 
distribution of exposures from the 25 mg fixed-dose was predicted to considerably overlap 
those obtained with the 0.3 mg/kg dose. This comparison also demonstrated that the 25 mg 
fixed-dose regimen provided no substantive differences in PK variability (range of the 
distribution of individual exposures) as seen with weight-based dosing.
Similarly, the population pharmacokinetic model was used to identify that the 75 mg fixed-
dose regimen is approximately equivalent to 1 mg/kg MK-1308. The rationale for the
maximum dose studied in this trial is described in Section 5.5.2.
Maximum Dose/Exposure for This Trial
The maximum dose of MK-1308 will be determined based on the DLT rate during the dose 
escalation phase and data from the ongoing MK-1308 trial.
Rationale for Dose Interval and Trial Design
MK-1308 (Dose Escalation, Dose Confirmation, and Coformulation)
MK-1308 is being developed for the treatment of solid tumors. This is the first-in-human trial 
of MK-1308 and it is designed to assess the safety, tolerability, PK, and pharmacodynamics
of escalating doses of MK-1308 when used in combination with pembrolizumab in 
participants with advanced/ metastatic solid tumors that have been refractory to conventional 
therapy, in first-line, treatment-naïve NSCLC, and in second-line SCLC. The effect of 
MK-1308 on tumor size will also be explored. First-line NSCLC participants are included in 
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this study in the dose confirmation phase based on the known excellent response rates and 
the US FDA approval of pembrolizumab monotherapy in participants with untreated NSCLC 
in the PD-L1 high population. This study will include participants with any PD-L1 tumor 
score based on the results of the Phase 1 CheckMate-012 study suggesting that participants
with any tumor PD-L1 score may benefit from combination treatment with ipilimumab and 
nivolumab [Hellmann, M. D., et al 2016]. Second-line SCLC participants are included in this 
study in the dose confirmation phase based on the improved response rates observed in the 
Phase 1 CheckMate-032 study [Antonia, S. J., et al 2016], prompting the initiation of Phase 3 
studies for nivolumab and nivolumab plus ipilimumab as maintenance therapy after first-line 
chemotherapy (CheckMate 451), and for nivolumab versus chemotherapy as second-line 
therapy (CheckMate 331) in SCLC.
It is reasonable to expect MK-1308 to be consistent with that of other humanized mAbs that 
typically have a low clearance and a limited volume of distribution. Using a population PK 
model of ipilimumab, distribution of exposures from the 25 mg MK-1308 fixed-dose 
considerably overlap that obtained with the 0.3 mg/kg weight-based ipilimumab dose and 
exposures from the 75 mg MK-1308 fixed-dose considerably overlap those obtained with the 
1.0 mg/kg weight-based ipilimumab dose [Feng, Y., et al 2014]. Similar to pembrolizumab, a 
fixed-dose regimen of MK-1308 is expected to reduce complexity in the logistical chain at 
treatment facilities and reduce waste. The goal in introducing the lower doses of 25 mg 
MK-1308 at the schedule of either Q3W or Q6W is to determine if a similar response rate
can be achieved at lower doses, which would be expected to result in a reduction in immune-
related toxicities. The goal in evaluating the 75 mg MK-1308 dose at the Q6W interval is to 
achieve the expected response rates with similar acceptable toxicity and discontinuation rates
based on the Phase 1 CheckMate-012 results in the NSCLC population [Hellmann, M. D., et 
al 2016].
Details regarding specific benefits and risks for participants participating in this clinical trial 
may be found in the IB and informed consent documents.
MK-1308 (Efficacy Expansion Phase)
Participants with advanced melanoma that is refractory to PD-1/L1 are included in this study 
in the efficacy expansion phase based on the following evidence: 1) improved response rates 
after ipilimumab/nivolumab compared with ipilimumab monotherapy in treatment-naïve 
advanced melanoma in the CheckMate 067 study; 2) improved response rates after treatment 
with ipilimumab/pembrolizumab (Keynote-029); and 3) the results from an MSD -single 
institution collaborative study in a similar melanoma population [Wolchok, J. D., et al 2017] 
[Long, G. V., et al 2017] [Olsonm, D., et al 2018]. An interim analysis of MK-1308 safety, 
anti-tumor activity, PK and pharmacodynamic biomarker data was performed for the dose 
escalation and dose confirmation phases of the study based on an 07-NOV-2018 database 
lock. The ORR by BICR with confirmation of MK-1308 25 mg administered every 6 weeks 
in the advanced 1L NSCLC population (Arm B) was similar to the ORR at the 75-mg dose 
level given every 6 weeks (33% versus 22%) at this data cutoff date. The target dose-limiting 
toxicity rate was not reached in any of the Cohorts 1, 2, or 3; however, a higher toxicity rate 
correlated with a higher MK-1308 dose among several different AE characteristics including
drug-related AEs, Grade 3-5 AEs, serious AE (SAE), and AEs leading to treatment 
discontinuation or modification. The Grade 3-5 AE rate was 29% in Cohort 1, 71% in 
Cohort 2, and 100% in Cohort 3. In the dose confirmation phase, a lower MK-1308 dose and 
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a longer treatment interval had a more favorable toxicity profile (45% in Arm B, 48% in 
Arm A, 53% in Arm C and 86% in Arm E). Time to first Grade 3-5 AE was more rapid at a 
higher MK-1308 dose and with more frequent dosing (7 months in Arm B, 5.2 months in 
Arm A, 5.6 months in Arm C and 1.1 month in Arm E). The most common AEs were fatigue 
(24.9%), pruritus (24.4%), rash (23.5%), decreased appetite (22.5%), AST increased 
(19.2%), ALT increased (17.4%), diarrhea (16.4%), and hypothyroidism (16%). In totality, 
the efficacy, safety, and PK data indicated that a dose of 25 mg given every 6 weeks was 
most tolerable. 
MK-1308A (Coformulation Phase)
The dose composition and schedule of MK-1308A is 25 mg/400 mg 
(MK-1308/pembrolizumab) to be administered every 6 weeks. This formulation and dosing 
regimen were chosen after data analyses of 215 participants in the dose escalation and dose
confirmation phases of the study who were given varying dose levels of MK-1308 (25, 75, 
and 200 mg every 3 or 6 weeks) and a fixed dose of MK-3475 (200 mg every 3 weeks).
Evaluation of the safety, tolerability, PK, pharmacodynamics, and efficacy analysis of this 
part of the study showed that 25 mg MK-1308 every 6 weeks in combination with MK-3475 
every 3 weeks was equally efficacious but safer than the 75 mg and 200 mg MK-1308 dose 
levels. MK-1308A is being evaluated in this study in advanced solid tumors. 
Pembrolizumab (MK-3475)
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W) followed 
by 400 mg Q6W. The current approved dosing regimens of pembrolizumab for IV 
administration are 200 mg Q3W and 400 mg Q6W for adults.
200 mg Q3W
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W 
is an appropriate dose of pembrolizumab for adults across all indications. As outlined below, 
this dose is justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to
IB, Section 5.2.2)

Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
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400 mg Q6W
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings where 200 mg Q3W pembrolizumab is 
currently approved [Lala, M., et al 2020]. Specifically, the dosing regimen of 400 mg Q6W 
for pembrolizumab is considered adequate based on modeling and simulation analyses, given
the following rationale:

PK simulations demonstrating that in terms of pembrolizumab exposures:
o
Average concentration over the dosing interval (Cavg) [or area under the curve
(AUC)] at 400 mg Q6W are similar to the approved 200 mg Q3W dose, thus bridging 
efficacy between dosing regimens.
o
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W, in majority (>99%) of participants.
o
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.

Exposure-Response for pembrolizumab has been shown to be flat across indications, and 
OS predictions in melanoma and NSCLC show that efficacy at 400 mg Q6W is expected
to be similar to 200 mg or 2 mg/kg Q3W, given the similar exposures; thus 400 mg Q6W 
is expected to be efficacious across indications.
6.
Study Population
Male and female participants with advanced or metastatic solid tumors who are at least 18 
years of age on the day of signing consent will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
Male and female participants who are at least 18 years of age on the day of signing consent 
will be enrolled.
1.
For Dose Escalation Phase: Have any histologically- or cytologically-confirmed 
advanced/metastatic solid tumor (except NSCLC for Cohorts 2 and 3) by pathology 
report and have received, been intolerant to, been ineligible for or refused all treatment 
known to confer clinical benefit.
2.
For Dose Confirmation Phase, Arms A, B, C, and E: Have newly diagnosed
histologically or cytologically-confirmed Stage IIIB/Stage IV NSCLC:
The participant must not have received prior systemic treatment for advanced NSCLC 
or must have received previous neoadjuvant and adjuvant chemotherapies ≥6 months 
before dosing of study drug if prior systemic treatment was given for early-stage 
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disease. Diagnosis must be stated in a pathology report and pathologically confirmed at 
the study site by the investigator.
Note: Site must confirm that EGFR and ALK directed therapy is not indicated as
primary therapy (document absence of tumor activating (sensitizing) EGFR mutations
AND absence of ALK gene rearrangements).
If participant’s tumor is known to have a predominantly squamous histology, molecular 
testing for EGFR mutation and ALK translocations is not required, as this is not part of 
current diagnostic guidelines.
3.
For Dose Confirmation Phase, Arm D: Have histologically- or cytologically-
confirmed metastatic (Stage III/IV) SCLC with progressive disease after at least one 
platinum-based chemotherapy regimen. Participants with platinum-sensitive (relapse 
≥90 days after chemotherapy) or platinum-resistant (relapse <90 days after or during 
chemotherapy) disease are eligible. Diagnosis must be stated in a pathology report and
pathologically confirmed at study site by the investigator.
4.
Have measurable disease by RECIST 1.1 as assessed by the local site 
investigator/radiology. Target lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions.
5.
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
Performance Scale.
6.
Demonstrate adequate organ function as defined by the following table (Table 3). All 
screening labs should be performed within the screening period.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL
Platelets a
>100,000/mcL 
Hemoglobin a
≥9 g/dL or ≥5.6 mmol/L without a red blood cell 
transfusion within 2 weeks of randomization
Renal
Serum Creatinine or 
CrCl (measured or calculated b) or
GFR in place of CrCl
≤1.5 X ULN or 
≥30 mL/min for participant with creatinine levels >1.5 X 
ULN
Hepatic c
Total bilirubin (serum) 
≤1.5 X ULN or 
Direct bilirubin ≤1.5 X ULN for participants with total 
bilirubin levels >1.5 X ULN If there is no institutional 
ULN, then direct bilirubin must be <40% of total bilirubin 
to be eligible. Note: In no case can the total bilirubin 
exceed 3 x ULN.
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN or ≤5 X ULN for participants with liver 
metastases
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System
Laboratory Value
Coagulation
International Normalized Ratio (INR) or Prothrombin 
Time (PT)
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy 
Activated Partial Thromboplastin Time (aPTT)
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range 
of intended use of anticoagulants
Note:  This table includes eligibility-defining laboratory value requirements for treatment. All screening lab tests must be 
reviewed by the Investigator or qualified designee and be acceptable prior to randomization.
ALT (SGPT) = alanine aminotransferase (serum glutamic-pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic-oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper limit of 
normal.
a Criteria must be met without packed red blood cell (pRBC) transfusion within last 2 weeks. Participants can be on 
stable dose of erythropoietin (≥ approximately 3 months).
b Creatinine clearance (CrCl) should be calculated per institutional standard. If no local guideline is available,creatinine 
clearance should be calculated using the Cockcroft-Gault Method: CrCl = [(140-age) * weight (kg) * (0.85 for females 
only)] / (72 * serum creatinine)
c An exception to this criteria is Gilbert’s Syndrome
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 

Is not a WOCBP
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year) or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long-term and persistent basis), as described in
Appendix 5 during the intervention period and for at least 120 days after the last dose 
of pembrolizumab or MK-1308A, whichever comes last. The investigator should 
evaluate the potential for contraceptive method failure (ie, noncompliance, recently 
initiated) in relationship to the first dose of study intervention.
o
A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum as required by local regulations) within 24 hours for urine and within 
72 hours for serum before the first dose of study intervention. 
o
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
in Section 9.5.5.

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.
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8.
Female participants of childbearing potential must be willing to use an adequate
method of contraception, as outlined in Appendix 5 – Contraceptive Guidelines, for the 
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle preferred contraception for 
the participant.
9.
Male participants with a female partner(s) of childbearing potential must agree to use
an adequate method of contraception as outlined in Appendix 5 – Contraception during 
the treatment period plus an additional 120 days after the last dose of study treatment 
and refrain from donating sperm during this period.
Note: Abstinence is acceptable if this is the usual lifestyle preferred contraception for 
the participant.
10.
Has voluntarily agreed to participate by giving documented informed consent for the 
trial. The participant may also provide consent/assent for Future Biomedical Research. 
However, the participant may participate in the main trial without participating in 
Future Biomedical Research.
11.
Must submit an evaluable baseline tumor sample for analysis (either a recent or archival 
tumor sample). Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. 
If submitting unstained cut slides, freshly cut slides should be submitted to the testing 
laboratory within 14 days from when the slides are cut (Details pertaining to tumor 
tissue submission can be found in the Procedures Manual).
12.
For Efficacy Expansion Phase Arms F and G (Applicable countries only): 
a.
Have histologically/cytologically-confirmed unresectable Stage III or Stage IV
melanoma per American Joint Committee on Cancer (AJCC) staging system 
version 8, not amenable to local therapy.
b. Have at least 1 measurable lesion by CT or MRI per RECIST 1.1 by BICR. 
Cutaneous lesions and other superficial lesions are not considered measurable 
lesions for the purposes of this protocol but may be considered as non-target 
lesions.
Note: Lesions that are in an area that has been previously irradiated should not be 
considered measurable unless there has been documented growth of the lesions 
since the completion of radiation.
c.
Participants with unresectable Stage III or IV disease must have progressed 
on-treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either 
as monotherapy, or in combination with other checkpoint inhibitors or other 
therapies (combinations with anti-CTLA-4 agents will not be allowed). 
PD-1 treatment progression is defined by meeting all of the following criteria:
1. Has received at least 2 doses of anti-PD-1/L1 mAb.
2. Has demonstrated disease progression after PD-1/L1 as defined by RECIST 
v1.1. 
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3. The initial evidence of disease progression is to be confirmed by a second 
assessment ≥4 weeks from the date of the first documented PD, in the absence 
of rapid clinical progression [Seymour, L., et al 2017].
o
Note: Progressive disease is confirmed according to iRECIST. 
4. Progressive disease must have been documented within 12 weeks from the last 
dose of anti-PD-1/L1 mAb.
5. Participants who have received targeted therapies as 1L treatment then 
progressed on anti-PD-1/ PD-L1 may enroll in this study.
6. Participants who have received prior neoadjuvant or adjuvant treatment may 
enroll in this study.
7. Early treatment discontinuation (prior to first response evaluation) on initial 
anti-PD-1/L1 therapy due to treatment intolerance will not be considered 
PD-1/PD-L1 refractory.
d. Participants who receive anti-PD-1 therapy as adjuvant treatment following
complete resection of Stage III or Stage IV melanoma (Stage II may be eligible
with Sponsor consultation) and have disease recurrence (unresectable loco-regional 
disease or distant metastases) while on active treatment or within 6 months of 
stopping anti-PD-1 are eligible. For these participants, the following applies: 1) a
second assessment to confirm disease progression beyond recurrence is not required
(eg, iRECIST is not required); 2) they must have received at least 2 prior doses of 
anti-PD-1/ PD-L1 mAb.
e.
Have submitted pre-trial imaging: The site’s study team must have reviewed pre-
trial images that are of diagnostic quality from at least 3 scans (only the first 2 scans
are needed for the recurrent adjuvant population and in the setting of rapid clinical 
progression after consultation with and approval from the Sponsor. The reason for 
rapid clinical progression must be documented in the participant's study record.) to 
determine that radiographic progression has occurred per RECIST 1.1 following 
initiation of an anti-PD-1/ PD-L1 agent (see Section 9.2.1 for further details). 
The visits for the 3 scans are as follows:
1.
First scan = baseline scan before previous anti-PD-1/ PD-L1 treatment was 
given
2.
Second scan = scan showing progression on prior anti-PD-1/ PD-L1 treatment
per RECIST 1.1
3.
Third scan = scan confirming progression (iCPD) on prior anti-PD-1/ PD-L1 
treatment per iRECIST
Note: The second scan indicating PD (for adjuvant participants) and the third
scan indicating iCPD (for all other participants) can be used as the baseline 
scan for the MK-1308 study, after consultation with and approval from the 
Sponsor. The reason for rapid clinical progression must be documented in the 
participant's study record.
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The site must have received confirmation that the pre-trial images are of 
acceptable diagnostic quality by central imaging prior to enrollment.
f.
BRAF V600 mutation-positive melanoma participants should have received 
targeted therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, 
alone or in combination) prior to enrolling on this study; however, they are not 
required to progress on this treatment prior to enrollment. Exceptions may be made 
only for countries where these inhibitors are not available, after Sponsor 
consultation.
g. Participants with BRAF V600E mutant melanoma who have NOT received a BRAF 
inhibitor (either as adjuvant therapy or in the metastatic disease setting) are eligible 
for the study ONLY if they meet the following criteria: 
1. LDH < local ULN  
2. No clinically significant tumor related symptoms in the judgment of the 
investigator    
3. Absence of rapidly progressing metastatic melanoma in the judgment of the 
investigator
h. Approximately 10 participants each from Arms F and G will have 2 mandatory 
biopsies; one prior to C1D1 and one on-treatment during Cycle 1 (Week 4, ±7 
days), as detailed in the Procedure Manual.
13.
For the Coformulation Phase - Arm I (Applicable countries only):
a.
Have any histologically- or cytologically-confirmed advanced/metastatic solid 
tumor by pathology report and have received, been intolerant to, been ineligible 
for or refused all treatment known to confer clinical benefit.
b. Must meet all requirements for Inclusion Criteria 4 through 11.
14.
For the Coformulation Phase - Arm K (China only):
a.
Have any histologically- or cytologically-confirmed advanced/metastatic solid 
tumor by pathology report and have received, been intolerant to, been ineligible 
for, or refused all treatment known to confer clinical benefit.
b.
Be a Chinese participant residing in China.
Note: Chinese participants residing in China are not eligible for any other study arm.
c.
Must meet all requirements for Inclusion Criteria 4 through 10.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
For all phases of the study: Has received previous treatment with another agent 
targeting CTLA4.
2.
For the Dose Confirmation Phase: Has received previous treatment with another agent 
targeting PD-1, PD-L1, or anti-PD-L2 agent or with an agent directed to another 
stimulatory or co-inhibitory T-cell receptor (eg, OX-40, CD137).
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3.
Has had chemotherapy, definitive radiation, or biological cancer therapy within 
4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy or has 
not recovered to CTCAE Grade 1 or better from any AEs that were due to cancer 
therapeutics administered more than 4 weeks earlier (this includes participants with 
previous immunomodulatory therapy with residual irAEs). 
Note: Participants receiving ongoing replacement hormone therapy for endocrine irAEs 
will not be excluded from participation in this study if the associated AE has recovered 
to CTCAE Grade 1 with replacement hormone therapy prior to the first dose of study 
therapy.
4.
Has received lung radiation therapy of >30 Gy within 6 months before the first dose of 
study treatment. 
Note: Participants must have recovered from all radiation-related toxicities to Grade 1 
or less, not require corticosteroids, and not have had radiation pneumonitis.
Note: If the participant has received prior lung radiation, the radiated lesion must not be 
included as a target lesion for RECIST 1.1 measurements or must show signs of 
progression before study start.
5.
Is currently participating and receiving study therapy in a study of an investigational 
agent or has participated and received study therapy in a study of an investigational 
agent or has used an investigational device within 28 days of administration of MK-
1308.
Note: Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
6.
Has a history of a second malignancy, unless potentially curative treatment has been
completed with no evidence of malignancy for 3 years.
Note: The time requirement does not apply to participants 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.
7.
For Cohorts 1-3 and Arms A through E ONLY: Has known untreated central 
nervous system (ie, brain and/or spinal cord) metastases. Has known carcinomatous 
meningitis.
Note: Participants with brain metastases may participate only if they satisfy all of the 
following:
Completed treatment (eg, whole brain radiation treatment [WBRT], stereotactic 
radiosurgery, or equivalent) at least 14 days prior to the first dose of trial treatment, 
Have no evidence of new or enlarging brain metastases confirmed by post-treatment 
repeat brain imaging (using the same modality) performed at least 3 weeks after pre-
treatment brain imaging, and 
Are neurologically stable without the need for steroids for at least 7 days before first 
dose of trial treatment as per local site assessment.
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Participants with small (<1 cm) asymptomatic brain metastases may participate 
without satisfying the above requirements however they must be followed with 
regularly scheduled brain MRI scans throughout the study.
8.
Has received any prior immunotherapy and was discontinued from that treatment due to 
a Grade 3 or higher irAE.
9.
Previously had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody or has a known sensitivity to any component of pembrolizumab.
10.
Has any active infection requiring therapy.
11.
Has a history of interstitial lung disease. 
12.
Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis. 
13.
Has a history of inflammatory bowel disease.
14.
Has an active autoimmune disease that has required systemic treatment in the past 2 
years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs) except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such 
as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed. 
Use of non-systemic steroids is permitted.
Note: Participants with asthma or chronic obstructive pulmonary disease that require 
intermittent use of bronchodilators, inhaled steroids, or local steroid injections are not 
excluded from the study. 
15.
Has clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study drug administration, or New York 
Heart Association Class III or IV congestive heart failure. Medically controlled 
arrhythmia stable on medication is permitted.
16.
Has received a live or live attenuated vaccine within 28 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted.
Refer to Section 7.7 for information on COVID-19 vaccines.
17.
Participants with known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies) and/or active hepatitis B or C, and/or positive HBsAg and HBV-DNA. 
Active hepatitis C is defined by a positive Hep C Ab result and quantitative HCV RNA 
results greater than the lower limits of detection of the assay. 
Note: Hepatitis B and hepatitis C testing is required at screening as indicated in Section 
2 –Schedule of Events.
18.
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s 
participation for the full duration of the study, make administration of the study drugs 
hazardous or make it difficult to monitor adverse effects such that it is not in the best 
interest of the participant to participate, in the opinion of the treating Investigator.
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19.
Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s ability to cooperate with the requirements of the trial.
20.
Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with screening and for up to 120 days following 
cessation of pembrolizumab or MK-1308A.
21.
Has not fully recovered from any effects of major surgery without significant detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study drug administration. Surgery requiring regional/epidural anesthesia 
must be completed at least 72 hours before first study drug administration and 
participants should be recovered.
22.
Is taking chronic systemic steroids in doses >10 mg daily of prednisone or equivalent 
within 7 days prior to the first dose of trial treatment.
23.
Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain). A 
participant who is clinically stable following treatment for these conditions (including 
therapeutic thoraco- or paracentesis) is eligible.
24.
For Arm F and G (Efficacy Expansion Phase) and Arm K (Coformulation Phase) 
ONLY:
a.
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 
4 weeks before the first dose of study treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases 
confirmed by repeat imaging, and have not required steroids for at least 14 days 
before study treatment.
Note: Participants with asymptomatic, previously untreated brain metastases may 
not participate.
b. Has not had resolution of anti-PD-1 antibody-related AEs, including immune-
mediated AEs back to Grade ≤1 or baseline (not applicable to Arm K).
c.
Has not discontinued steroid treatment for an irAE for at least 2 weeks prior to the 
first dose of study drug (not applicable to Arm K).
d. Has ocular melanoma (not applicable to Arm K).
e.
Has mucosal melanoma (not applicable to Arm K).
25.
Has had an allogenic tissue/solid organ transplant.
Lifestyle Restrictions
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea, or vomiting, detailed in Section 7.7.1.
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Caffeine, Alcohol, and Tobacco
There are no restrictions on caffeine, alcohol, and tobacco.
Activity
There are no restrictions on activity.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
Participants discontinuing within the DLT window due to reasons unrelated to study 
treatment will not be considered evaluable for DLTs and may be replaced. Participants with a 
DLT within the DLT window should not be replaced. Participants who receive less than 90% 
of the total MK-1308 (or pembrolizumab) infusion in Cycle 1 (eg, if the infusion had to be 
discontinued due to an infusion reaction) and did not experience a DLT may be replaced (not 
applicable for Arm I). See Section 10.5.1 for description of safety analysis population.
If a participant experiences a DLT, trial treatment should be discontinued. However, if 
the participant is deriving clinical benefit from the trial treatment, the participant may be 
allowed to continue after discussion between the Sponsor and the Investigator.
7.
Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment and replacement participants as required.  When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies.  Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Treatments Administered
The study treatment(s) to be used in this trial are outlined below in Table 4.
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Table 4
Study Treatments
Dose Escalation Phasea
Study 
Treatment 
Name
Dosage 
Formulation
Dose
Regimen/ Treatment 
Period
Dose 
Frequency
Route of 
Adminis-
tration
Sourcing
Unit 
Strength
MK-1308
Solution for 
infusion
25 mg
Escalation/ Day 1 of 
each cycle × 5 doses.
Q3W
IV infusion
Provided 
centrally by 
Sponsor
100 mg/
2 mL vial
Solution for 
infusion
75 mg
Escalation/Day 1 of 
each cycle × 5 doses.
Q3W
100 mg/
2 mL vial
Solution for 
infusion
200 mg
Escalation/Day 1 of 
each cycle × 5 doses.
Q3W
100 mg/
2 mL
vial
Pembrolizumab 
(MK-3475)
Solution for 
infusion
200 mg
Escalation/Day 1 of 
each cycle starting at 
Cycle 2a
Q3W
IV infusion
100 mg/
4 mL vial  
Dose Confirmation Phasea
Study 
Treatment 
Name
Dosage 
Formulation
Dose
Regimen/ Treatment 
Period
Dose 
Frequency
Route of 
Adminis-
tration
Sourcing
Unit 
Strength
MK-1308
Solution for 
infusion
25 mg
Confirmation/Arm A-
Day 1 of each cycle
Q3W
IV infusion
Provided 
centrally by 
Sponsor
100 mg/
2 mL vial
Confirmation/ Arm B-
Day 1 of every other 
cycle
Q6W
Solution for 
infusion
75 mg
Confirmation/Arms C 
and D- Day 1 of every 
other cycle
Q6W
IV infusion
100 mg/
2 mL vial
Confirmation/Arm E-
Day 1 of each cycle
Q3W
Pembrolizumab 
(MK-3475)
Solution for 
infusion
200 mg
Confirmation/ Day 1 of 
each cycle starting at 
Cycle 1a
Q3W
IV infusion
100 mg/
4 mL vial
Efficacy Expansion Phaseb
Study 
Treatment 
Name
Dosage 
Formulation
Dose
Regimen/ Treatment 
Period
Dose 
Frequency
Route of 
Adminis-
tration
Sourcing
Unit 
Strength
MK-1308 + 
pembro 
Co-
administration 
admixture
Solution for 
infusion
25 mg 
MK-1308
+ 
400 mg 
pembro
Efficacy expansion 
phase/ 
Arm F- Day 1 of every 
cycle, Option 1
Q6W 
IV infusion
Provided 
centrally by 
Sponsor
25 mg / 
0.5 mL vial
MK-1308 
+ 
100 mg/
4 mL vial 
pembro
MK-1308
Solution for 
infusion
25 mg MK-
1308
Efficacy expansion 
phase/ 
Arm G - Day 1 of every 
other cycle
Q6W
IV infusion
100 mg/
2 mL vial
or
25 mg/
0.5 mL vial
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Coformulation Phasec
Study 
Treatment 
Name
Dosage 
Formulation
Dose
Regimen/ Treatment 
Period
Dose 
Frequency
Route of 
Adminis-
tration
Sourcing
Unit 
Strength
MK-1308A
Solution for 
infusion
25 mg 
MK-1308 + 
400 mg 
pembro
Coformulation Phase
(Arms I, K)
Q6W
IV infusion
Provided 
centrally by 
Sponsor
25 mg MK-
1308 + 
400 mg 
pembro/ 
17.5 mL vial
Pembrolizumab 
(MK-3475)d
Solution for 
infusion
200 mg
Coformulation Phase 
(Arm I)
Q3W
IV infusion
Provided 
centrally by 
Sponsor
400 mg
Q6W
100 mg/ 
4 mLvial
IV = intravenous; pembro = pembrolizumab; Q3W = every 3 weeks; Q6W = every 6 weeks.
a
For dose escalation and dose confirmation, pembrolizumab will be administered as an IV infusion over 30 minutes. 
MK-1308 will be administered as an IV infusion over 30 minutes. MK-1308 will be administered 30 minutes after 
completion of pembrolizumab infusion on the days when pembrolizumab is administered. In the dose escalation phase 
of the study, pembrolizumab administration will start in Cycle 2 and in the dose confirmation phase pembrolizumab 
administration will start in Cycle 1. In addition to the dose levels detailed in this table, intermediate doses may also be 
evaluated in consultation and agreement with the investigators and Sponsor.
b
For the efficacy expansion phase, Arm F pembrolizumab and MK-1308 will be co-administered in the same infusion 
bag over 30 minutes. For Arm G, MK-1308 will be administered alone. Participants in Arm F or G who cross over 
will receive the doses of MK-1308 and MK-3475 as determined by interim analysis at the time of crossover.
c
For the coformulation phase, the solution will be infused over 30 minutes.
d
In cases where toxicity is attributed to MK-1308A, participants may be re-initiated with pembrolizumab monotherapy 
at either 200 mg Q3W or 400 mg Q6W, after communication and agreement with the Sponsor.
All supplies indicated in Table 4 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  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.
Refer to section 9.1.8 for details regarding administration of the study treatment.
Definition of Dose-limiting Toxicity
All toxicities will be graded using NCI CTCAE Version 4.03 based on the investigator 
assessment.
The DLT window of observation will encompass the first 2 cycles of treatment for dose 
escalation and the first 1 cycle for dose confirmation, efficacy expansion, and coformulation 
(Arm I only).
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The occurrence of any of the following toxicities during the DLT window will be considered 
a DLT, if assessed by the investigator to be possibly, probably or definitely related to study 
drug administration, excluding toxicities clearly not related to the drug, such as disease 
progression, environmental factors, unrelated trauma, etc.:
1. Grade 4 non-hematologic toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:

Grade 4 thrombocytopenia of any duration 

Grade 3 thrombocytopenia associated with bleeding that requires a platelet 
transfusion
3. Any non-hematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤ 3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per standard of care; Grade 3 rash 
without use of corticosteroids or anti-inflammatory agents per standard of care.
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if:

Clinically significant medical intervention is required to treat the participant, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week.

The abnormality results in a drug-induced liver injury (DILI) (see Section 9.3.7 for 
criteria)
5. 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 one hour

Grade 4 is defined as 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 one hour, with life-
threatening consequences and urgent intervention indicated.
6. Prolonged delay (>2 weeks) in initiating Cycle 2 or Cycle 3 in Dose Escalation due to 
treatment-related toxicity; Prolonged delay (>2 weeks) in initiating Cycle 2 in Dose 
Confirmation due to treatment-related toxicity.
7. Any treatment-related toxicity that causes the participant to discontinue treatment during 
the DLT observation period.
8. Grade 5 toxicity.
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Dose Modification (Escalation/Titration/Other)
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 an agreement by the Sponsor (not applicable to Arm K).
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.
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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. 
See Section 7.7.1 for supportive care guidelines, including use of corticosteroids.
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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 a
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 b or 4 c
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 d
   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 d
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 d
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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
Ophthalmologic
Uveitis, iritis, 
episcleritis
Grade 2
Withhold
   Administer corticosteroid 
eye drops to participants 
who develop uveitis, iritis, 
or episcleritis
   Permanently discontinue 
study drugs for immune-
mediated ocular disease that 
is unresponsive to local 
immunosuppressive therapy
   Monitor for signs and symptoms of ophthalmologic 
disorders
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 e
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
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a   AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b   AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 
10.0 x baseline if baseline abnormal
c   AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d    The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the 
investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e   Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis).
(See Appendix 12.7.1 for France-specific criteria)
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Dose modification and toxicity management of infusion reactions related to 
pembrolizumab, MK-1308, and MK-1308A
Pembrolizumab, MK-1308, and MK-1308A may cause severe or life-threatening infusion
reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion. Dose modification and toxicity management 
guidelines on pembrolizumab-, MK-1308-, and MK-1308A-associated infusion reactions are 
provided in Table 6. 
Table 6
Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg,
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h.
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/h to 50 mL/h). 
Otherwise, dosing will be held until symptoms resolve 
and the participant should be premedicated for the 
next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
MK1308/pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (eg,
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, refer to the Common Terminology Criteria for Adverse Events v4.03 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption or Dose Delay 
MK-1308, MK-1308A, or pembrolizumab may be interrupted/delayed for situations other 
than treatment-related AEs, ie, medical/surgical events or logistical reasons not related to 
study therapy. Participants should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the participant's study record. This also applies to 
site-related holidays or unexpected closures due to other reasons, such as inclement weather.
Method of Treatment Assignment
Treatment allocation will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 3 planned treatment cohorts 
(Cohorts 1, 2, and 3) in dose escalation and 5 planned treatment arms (Arms A, B, C, D, and
E) in dose confirmation, 2 planned treatment arms in efficacy expansion (Arms F and G), and 
3 planned treatment arms in the coformulation phase (Arms I and K). Participants will be 
allocated to 1 of 13 planned treatment cohorts/arms.
Treatment allocation will be accomplished by non-random assignment in dose escalation,
dose confirmation, and coformulation phase. When more than one treatment arm is open for 
enrollment of participants with NSCLC during dose confirmation, IVRS/IWRS will 
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distribute successive participants across all open treatment arms within each phase to 
minimize selection bias. Each new arm will open for enrollment without delay once the DLT 
observation period of the previous dose cohort is completed and a dose escalation or cohort 
expansion decision is made. In the efficacy expansion phase, participants will be randomly 
assigned to either Arm F or Arm G with 1:1 randomization ratio until Arm G reaches the 
total sample size of 40.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Blinding
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
treatment administered.
Preparation/Handling/Storage/Accountability
Dose Preparation
The rationale for selection of doses to be used in this trial is provided in Section 3.2 –
Background.  There are no specific calculations or evaluations required to be performed in 
order to administer the proper dose to each participant.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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.
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.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Interruptions from the protocol specified treatment for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
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 participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant.
Participants are prohibited from receiving the following therapies during the screening and 
treatment phases (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab, MK-1308, or MK-1308A

Radiation therapy 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion. 
For all NSCLC and SCLC participants: Targeted external beam irradiation should not 
be used in the primary lung field where assessment for tumor is indicated.

Live or live attenuated vaccines within 28 days before the first dose of study
intervention and while participating in the study. Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy. Investigational vaccines (ie, those not licensed or approved for 
Emergency Use) are not allowed.

Systemic glucocorticoids may be used for the following purposes:
o
To modulate symptoms of an AE that is suspected to have an immunologic 
etiology
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o
To modulate symptoms of non-immune-related AEs (If more than 10 mg 
prednisone equivalent, this treatment should be discussed with the Sponsor) 
o
Premedication for IV contrast allergies
o
Oral physiologic replacement (eg, prednisone < 10 mg/day) or treatment of 
COPD (standard dosing guidelines)
Note: Topical, ocular, intra-articular, or other local (non-systemic) use is allowed. 
Inhalation in the management of asthma or chronic obstructive pulmonary disease is also 
allowed.
Note: CBD oil and other THC-related medications are allowed, per institutional 
guidance.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned prohibited treatments for clinical management should be removed from the 
trial. Participants may receive other medications that the investigator deems to be medically 
necessary.
Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2.1 (Table 5). Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to MK-1308 or pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to MK-1308 or 
pembrolizumab, the investigator does not need to follow the treatment guidance. Refer to 
Table 5 in Section 7.2.1 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Systemic Corticosteroid Use:
Systemic corticosteroids are permitted in the following situations:

To mediate potential irAEs or non-immune AEs, as guided in Table 5

As pre- or post-medication to prevent AEs associated with IV contrast material

Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use 
is considered standard of care (eg, for chronic obstructive pulmonary disease 
exacerbation)
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
For chronic systemic replacement, not to exceed 10 mg/day prednisone equivalent

In addition, the following glucocorticoid use is allowed: 
-
For topical use or ocular use
-
For intra-articular joint use
-
For inhalation in the management of asthma or COPD
Physiologic replacement doses of steroids (for example, prednisone 5 to 10 mg daily) are 
permitted while on study, as is the use of local (non-systemic) steroids.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study treatment (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
Standard Policies
For trials using Controlled Substances, all Federal, State, Province, Country, etc. regulations 
must be adhered to in regard to the shipping, storage, handling and dispensing of controlled 
substances. Additionally, the investigator should have the appropriate controlled drug 
license(s) as mandated by Federal, State, Province, Country, etc. laws in which the trial is 
being conducted.
8.
Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - Schedule of Activities
(SoA) and Section 9.10.3 – Discontinued Participants Continuing to be Monitored in the 
Study.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
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A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
Unacceptable AE(s).
o
Intercurrent illness that prevents further administration of study treatment.
o
Confirmed radiographic disease progression outlined in Section 9.2.1 (exception if the 
Sponsor approves treatment continuation).
o
Investigator’s decision to discontinue the participant
o
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 7.2.
o
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment
o
The participant has a confirmed positive serum pregnancy test.
o
Noncompliance with trial treatment or procedure requirements.
o
The participant completes study treatment (ie, up to 24 months of
MK-1308/pembrolizumab/MK-1308A, as applicable).
o
Administrative reasons.
For participants who are discontinued from treatment but continue to be monitored in the 
trial, all visits and procedures, as outlined in the SoA, should be completed. 
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant, as well as 
specific details regarding withdrawal from Future Biomedical Research are outlined in 
Section 9.1.9 – Withdrawal/Discontinuation.
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Lost to Follow-Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (e.g. phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
Note:  A participant is not considered lost to follow up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines
9.
Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.

Furthermore, additional evaluations/testing may be deemed necessary by the 
investigator and or the Sponsor for reasons related to participant safety. In some 
cases, such evaluation/testing may be potentially sensitive in nature (eg, HIV, 
hepatitis C, etc.), and thus local regulations may require that additional informed 
consent be obtained from the participant. In these cases, such evaluations/testing will 
be performed in accordance with those regulations.
The maximum amount of blood collected from each participant including any extra 
assessments that may be required, will not exceed 550 mL over any 8-week period.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
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Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history including smoking 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 to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
Advanced Solid Tumor (ST), NSCLC, SCLC, and Melanoma History
The investigator or qualified designee will obtain information regarding the participant’s 
advanced ST, NSCLC, SCLC, and melanoma. This information will include but is not 
limited to the presentation at primary diagnosis, date of and stage at primary diagnosis, date 
of and stage at most recent recurrence and location of metastases at screening (if applicable).
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 28 days before the first dose of study treatment.
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9.1.5.1.1 Prior Treatment for Advanced Solid Tumor Cancer
The investigator or qualified designee will review and report all prior treatments for 
advanced solid tumor including systemic treatments, radiation, and surgeries.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant
during the trial.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 9.3.
All new anticancer therapy initiated after the study start must be recorded in the electronic 
case report form (eCRF). If a participant initiates another anticancer therapy other than the 
assigned study treatment(s), the study treatment(s) should be discontinued and the participant
will move into the survival follow-up phase; if a participant initiates a new anticancer therapy 
within 30 days after the last dose of the trial treatment, the Mandatory Safety Follow-up visit 
should occur before the first dose of the new therapy.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment.  Each participant will 
be assigned only one screening number.  Screening numbers must not be re-used for different 
participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/re-screening) are provided in 
Section 9.10.1.  
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Trial treatment should be administered on the day of treatment allocation/randomization or as 
close as possible to the date on which the participant is allocated/assigned. Administration of 
trial medication will be monitored by the investigator and/or trial staff at study visits. The 
total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
The instructions for preparing and administering MK-1308, pembrolizumab, and MK-1308A
will be provided in the Pharmacy Manual.
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Study Treatment should begin within 3 days of assignment of randomization number.
Timing of Dose Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual. Details of administering the individual 
components are discussed below.
9.1.8.1.1 Timing of Dose Administration of MK-1308/MK-1308A
MK-1308 will be administered at the dose specified in the specific arm of the study using 
30-minute IV infusion either every 3 weeks or every 6 weeks. MK-1308 will be administered 
30 minutes after completion of pembrolizumab infusion on the days when pembrolizumab is 
administered.
For Arm F, MK-1308 will be co-administered as an admixture with pembrolizumab over a 
30-minute time period.
For Arms I and K, MK-1308A will be administered over a 30-minute time period.
9.1.8.1.2 Timing of Dose Administration of Pembrolizumab
Pembrolizumab will be administered at a dose of 200 mg using a 30-minute IV infusion 
every 3 weeks during dose escalation and dose confirmation phase. In the efficacy expansion
phase, Arm F, pembrolizumab will be co-administered as an admixture with MK-1308 at a 
dose of 400 mg every 6 weeks. Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible. However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes -5 min/+10 min).
The Pharmacy Manual contains specific instructions for MK-1308, pembrolizumab, and 
MK-1308A reconstitution, preparation of the infusion fluid, and administration.
Every effort should be made to begin the first dose of study treatment on the day a participant 
is enrolled, but if this is not achieved, trial therapy should be initiated no later than 3 days 
from the date of allocation. All subsequent cycles of study treatment may be administered up 
to 3 days before or 3 days after the scheduled Day 1 of each cycle due to administrative 
reasons per the investigator’s judgment. All study treatments will begin on Day 1 of each 
cycle after all pre-dose study procedures and assessments have been completed as detailed in 
the SoA. The reason for any variability in administration outside of the protocol-specified 
window should be documented in the participant’s chart and recorded on the eCRFs.
Trial Communication Plan Summary
Safety data from individual participants will be closely followed by the principal investigator 
and the Sponsor on an ongoing basis and shared at regular safety teleconferences (typically
once per week). The safety and tolerability of all participants, including those undergoing 
DLT evaluation, as well as those who have completed DLT evaluation, will be reviewed 
prior to the start of the next cohort. The Sponsor and principal investigators will assess the
appropriateness of dose escalation/dose confirmation and assess safety and tolerability at the 
completion of each cohort/arm, and prior to the opening of enrollment for the next 
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cohort/arm. The subsequent dose level to be tested in the next cohort/arm of participants will 
be communicated to the investigator or designee following each dose escalation/dose 
confirmation decision meeting. A memorandum will be sent to each site to communicate the 
specified next dose level. Participants will be enrolled and allocated via IVRS according to 
the dose escalation and confirmation guidelines outlined in Section 5.1. The dose at each 
cohort will be specified via IVRS. Cohorts will be opened or closed through IVRS to assure 
correct dosing in each cohort.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final trial visit should be performed at the time of withdrawal.  Any adverse 
events which are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 9.3 - Adverse Events, Serious Adverse Events and 
Other Reportable Safety Events.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants 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).  Subsequently, the 
participant's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal.  Any analyses in progress 
at the time of request for withdrawal 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 (eg, 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 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and 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.
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Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion laboratory evaluations and trial 
assessments

Imaging equipment – as required for response assessments

Electrocardiogram (ECG) equipment – as required for trial assessments

Infusion pumps – as required for MK-1308, pembrolizumab administration

Refrigerators and freezers – as required to store study treatments and laboratory
samples
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual, and Site Imaging Manual.
Efficacy Assessments
Tumor Imaging and Assessment of Disease
In addition to survival, efficacy will be assessed based on imaging evaluation of changes in 
tumor burden over time, until the participant is discontinued from the trial or goes into 
survival follow-up. The process for image collection and transmission to the CIV can be 
found in the SIM. Tumor imaging should be acquired by CT (strongly preferred). Refer to 
the Imaging Manual for additional guidance. MRI should be used when CT is contraindicated 
or for imaging in the brain. For the abdomen and pelvis, contrast-enhanced MRI may be used 
when CT with iodinated contrast is contraindicated, or when mandated by local practice. The 
same imaging technique regarding modality and use of contrast should be used in a 
participant throughout the study to optimize the visualization of existing and new tumor 
burden. Required anatomical images as well as the process for image collection and 
transmission to the CIV can be found in the SIM. Note: for the purposes of assessing tumor 
imaging, the term “investigator” refers to the local investigator at the site and/or the 
radiological reviewer at the site or at an offsite facility.
All tumor imaging (scheduled and unscheduled) should be submitted to the CIV for analysis. 
In addition, if the investigator obtains additional imaging, including other modalities, that are 
obtained at an unscheduled time point to determine if the participant has progressed as well 
as imaging obtained for other reasons but captures radiologic progression, all of these 
imaging scans should be sent to the CIV. All scheduled images for all study participants from 
the sites will be submitted to the CIV. In addition, images (including via other modalities) 
that are obtained at an unscheduled time point to determine disease progression, as well as 
imaging obtained for other reasons, but which show radiologic progression, should also be 
submitted to the CIV.
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of first 
dose. The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1. For the efficacy expansion phase Arms F and G, BICR 
confirmation of measurable disease based on RECIST 1.1 is required prior to 
allocation/randomization.
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Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of first dose of study medication.
For SCLC, thyroid cancer, and melanoma participants: Brain MRI is required at Screening.
For efficacy expansion phase Arms F and G: Sites must submit 2 or 3 pre-trial scans to the 
CIV and receive a scan acceptance email from the CIV before randomizing the participant 
(See Inclusion criterion 12e for details).
Brain Imaging
Participants with previously treated brain metastases may participate provided they have 
stable brain metastases, ie, without evidence of progression by imaging (confirmed by MRI if 
MRI was used at prior imaging or confirmed by CT imaging if CT used at prior imaging) for 
at least 3 weeks (4 weeks for the melanoma participants) prior to the first dose of trial 
treatment. Any neurologic symptoms must have returned to baseline and participants must 
have no evidence of new or enlarging brain metastases and have not used steroids for brain 
metastases for at least 7 days (14 days for the melanoma participants) prior to trial initiation 
as per local site assessment. This exception does not include carcinomatous meningitis, as 
participants with carcinomatous meningitis are excluded regardless of clinical stability.
For participants with stable brain metastases enrolled in the trial, the baseline brain image 
must be submitted to the CIV to be held for possible future analysis. For any participant with 
known stable brain metastases at baseline and who achieves a CR during trial treatment, 
follow-up brain imaging is required for confirmatory assessment of CR. This image will be 
submitted for independent central radiologic review.
Participants with small cell lung, thyroid cancer, and melanoma (without a history of stable 
brain metastases) must undergo a brain scan within 28 days prior to the first dose of trial 
treatment, with local confirmation that no new or untreated brain metastases are present. For 
those participants with these tumor types subsequently enrolled in the trial, this baseline brain 
scan should be submitted to the CIV, but independent central radiologic confirmation of a 
lack of brain metastases is not required.
For all parts except Arms F and G: Participants with small (<1 cm) asymptomatic brain 
metastases must be followed with regularly scheduled brain MRI scans throughout the study. 
For Arms F and G: Participants with asymptomatic, previously untreated brain metastases 
may not participate. 
If a participant develops a new brain metastasis during treatment, the following steps will be 
taken:  

Participants with symptomatic brain metastases will be removed from study 
treatment.

Participants with asymptomatic brain metastases (no need for steroids, no symptoms 
and signs indicating clinically significant progression of disease, no decline in ECOG 
performance status) can continue on study treatment under the following conditions:
o
If no immediate WBRT, both systemic lesions and brain lesions, can be 
followed by iRECIST.
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o
If immediate WBRT is chosen, the brain lesions will be non-evaluable for 
iRECIST. 
o
Brain MRI will be required at each subsequent image assessment.
Imaging for Bone Metastases
For any participant with clinical symptoms suggesting bone metastases, bone imaging (eg, 
bone scan or PET scan) should be performed to identify possible bone metastases. If bone 
metastases are identified that have not been imaged on the CT/MRI performed for Initial 
Tumor Imaging (Section 9.2.1.1), then additional baseline and all subsequent tumor imaging 
studies should include such lesions in the imaging field.
Tumor Imaging During the Study
The first on-trial imaging assessment should be performed at 9 weeks (±7 days) from the date 
of first dose of study drug. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±7 days) or more frequently if clinically indicated. After 54 weeks, participants who 
remain on-treatment will have imaging performed every 12 weeks (84 days ±7 days), or 
sooner if clinically indicated, for all cohorts. Imaging timing should follow calendar days 
from treatment initiation and should not be adjusted for delays in cycle starts. Imaging should 
continue to be performed until disease progression is identified by the investigator, unless the 
investigator elects to continue treatment and follow irRECIST in the dose escalation phase 
and the dose confirmation phase (see Section 9.2.1.8) or iRECIST in the efficacy expansion 
and coformulation phases (see Section 9.2.1.9), the start of new anticancer treatment, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first. All 
supplemental imaging must be submitted to the CIV.
Per RECIST 1.1 (Section 9.2.1.7), PR and CR should be confirmed by a repeat imaging 
assessment. The tumor imaging for confirmation of response may be performed ≥4 weeks 
after the first indication of response or at the next scheduled scan (ie, 9 weeks later), 
whichever is clinically indicated. Participants will then return to regular scheduled imaging
every 9 weeks, starting with the next scheduled imaging time point. Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point. 
On-study brain imaging should be performed if clinically indicated or to confirm CR (if other 
lesions indicate CR and brain lesions existed at Screening).
Per iRECIST (Section 9.2.1.9), disease progression should be confirmed by the site 4 to 8 
weeks after site-assessed first radiologic evidence of progressive disease in clinically stable 
participants. Participants who have unconfirmed disease progression may continue on 
treatment at the discretion of the site investigator until progression is confirmed by the site. 
Participants who obtain a confirmation scan do not need to undergo the next scheduled tumor 
imaging if it is <4 weeks later; tumor imaging may resume at the subsequent scheduled 
imaging time point if clinically stable. Participants who have confirmed disease progression 
as assessed by the site will discontinue the treatment. Exceptions are detailed in Section 
9.2.1.9.
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For participants in Arm G, in order to be eligible to crossover, site-assessed radiographic PD 
must be verified by BICR. When the investigator identifies radiographic progression per 
RECIST 1.1 for participants in Arm G, the imaging should be submitted to CIV. Tumor 
imaging should be used as a new baseline for the participant for VOP by BICR. The CIV will 
perform expedited review and communicate the VOP results to the study site and Sponsor via 
email. In clinically stable participants, imaging should continue until PD has been verified by 
BICR (if initial site-assessed PD was not verified by BICR, each subsequent scan must be 
submitted to CIV with verification of PD request until PD has been verified by BICR).
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue trial treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. For participants who discontinue trial treatment due to documented disease
progression, this is the final required tumor imaging if the investigator elects not to 
implement irRECIST or iRECIST. 
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of first dose (see 
Section 9.2.1.4) until the start of a new anticancer treatment, disease progression, pregnancy, 
death, withdrawal of consent, or the end of the study, whichever occurs first.
Crossover Phase Tumor Imaging
For Arm G participants who are eligible to crossover to combination therapy (Arm F), the 
crossover screening imaging (new baseline) should be performed within 28 days prior to the 
first dose as new baseline imaging. The imaging for BICR-verified progression (while in 
Arm G) can be used as screening imaging if it’s performed within 28 days prior to first dose 
of combination therapy. Note: When the investigator identifies radiographic progression per 
RECIST 1.1 for participants in Arm G, the imaging should be submitted to CIV for VOP by 
BICR. The CIV will perform expedited review and communicate the VOP results to the 
study site and Sponsor via email. In clinically stable participants, imaging should continue 
until PD has been verified by BICR (if initial site-assessed PD was not verified by BICR, 
each subsequent scan must be submitted to CIV with verification of PD request until PD has 
been verified by BICR). In order to be eligible to crossover, PD must be verified by BICR.
Participants who crossed over to combination therapy will be eligible to receive a maximum 
of 24 months of treatment ,starting with C1D1 from the start of combination treatment and 
the imaging schedule will follow that described in Section 9.2.1.4.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study treatment). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
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irRECIST Assessment of Disease (Dose Escalation Phase and Dose 
Confirmation Phase)
The irRECIST accounts for the unique tumor response characteristics seen with 
immunotherapeutic agents. Immunotherapeutic agents such as MK-1308 and pembrolizumab 
may produce anti-tumor effects by potentiating endogenous cancer-specific immune 
responses. The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents and can manifest a clinical response after 
an initial increase in tumor burden or even the appearance of new lesions. Standard RECIST 
may, thus, not provide an accurate response assessment of immunotherapeutic agents. These 
findings support the need to apply a modification to RECIST that takes into account the 
unique patterns of atypical response in immunotherapy and enables treatment beyond initial 
radiographic progression.
Participants in the dose escalation phase and the dose confirmation phase who have initial 
evidence of radiological progressive disease by RECIST 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 progressive disease (irRECIST participant
management). This clinical judgment should be based on the participant’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Clinical 
stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values;

No decline in ECOG performance status;

Absence of rapid clinical progression of disease; and

Absence of progressive tumor at critical anatomical sites (eg, spinal cord
compression).
Any participant deemed clinically unstable should be discontinued from trial treatment and
is not required to have repeat imaging for progressive disease confirmation.
In determining whether or not the tumor burden has increased or decreased per
irRECIST, the local site investigator should consider all target and non-target lesions, as
well as any incremental new lesion(s).
Progressive disease will be confirmed at repeat imaging if ANY of the following occur by 
irRECIST:

Tumor burden remains ≥20% and there is at least a 5 mm absolute increase compared 
to the nadir;

Non-target disease resulting in initial progressive disease is qualitatively worse; 

New lesion resulting in initial progressive disease is qualitatively worse; 

Additional new lesion(s) are identified since the last evaluation; OR

Additional new non-target progression is identified since the last evaluation.
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If repeat imaging confirms progressive disease due to any of the scenarios listed above,
participants should be discontinued from study treatment. A participant with confirmed
radiologic progression may continue to receive study treatment, after consultation with the
Sponsor, if the investigator deems the participant is receiving clinical benefit or value from
treatment.
Progressive disease will not be confirmed at repeat imaging if ALL of the following occur
by irRECIST:

Tumor burden is <20% or there is a <5 mm absolute increase compared to the nadir;

Non-target disease resulting in initial progressive disease is stable or qualitatively
improved;

New lesion resulting in initial progressive disease is stable or qualitatively improved;

No incremental new lesion(s) are identified since the last evaluation; AND

No incremental new non-target progression is identified since the last evaluation.
If repeat imaging does not confirm progressive disease by irRECIST and the participant
continues to be clinically stable, treatment may continue and follow the regular imaging
schedule.
iRECIST Assessment of Disease (Efficacy Expansion Phase and Coformulation 
Phase)
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. During the efficacy expansion and the coformulation phases, 
iRECIST will be used by the investigator to assess tumor response and progression, and 
make treatment decisions instead of irRECIST, to be consistent with MSD’s newest standard. 
When clinically stable, participants in the efficacy expansion phase should not be 
discontinued until progression is confirmed by the investigator, working with local radiology, 
according to the rules outlined in Appendix 8. This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some participants can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. These data will be captured in the clinical database.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
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PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
CIV for potential retrospective BICR. In order to continue to receive study intervention after 
initial radiologic PD, the participant must sign an additional informed consent form (see 
Section 9.1.1.1).
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression as defined in Appendix 8, study 
treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 2.3 and 
submitted to the CIV.
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 7 and illustrated as a flowchart in Figure 5.
Table 7
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD
per iRECIST
May continue study 
treatment at the 
discretion of the 
investigator and 
after obtaining
participant’s consent
No additional 
imaging required
Discontinue treatment
Repeat tumor 
imaging confirms PD 
(iCPD) by iRECIST 
per investigator 
assessment.
No additional 
imaging 
required.
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor).
No additional 
imaging 
required.
Not applicable
Repeat tumor 
imaging shows iUPD 
by iRECIST per 
investigator 
assessment.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
Continue study 
treatment at the 
investigator’s 
discretion.
No additional 
imaging required
Discontinue treatment
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
treatment at the 
investigator’s 
discretion.
No additional 
imaging required
Discontinue treatment
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable 
disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response 
Evaluation Criteria in Solid Tumors 1.1; VOP=verification of progression.
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Figure 5
Imaging and Treatment for Clinically Stable Participants After First Radiologic 
Evidence of PD Assessed by the Investigator
Adverse Events, Serious Adverse Events and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE and other reportable safety event reports can be found in Appendix 4.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Adverse events will not be collected for participants during the pre-screening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention.  If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
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Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.

All AEs from the time of intervention allocation/randomization through 30 days for 
the dose escalation phase, and through 90 days for the efficacy expansion and 
coformulation phases, after cessation of study intervention must be reported by the 
investigator.

All AEs meeting serious criteria, from the time of intervention 
allocation/randomization through 90 days after cessation of study intervention or 30 
days after cessation of study intervention if the participant initiates new anticancer 
therapy, whichever is earlier, must be reported by the investigator.

All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through the time required to eliminate systemic exposure 
after cessation of study intervention as described in Sections 6.1 and 9.5.5, or 30 days 
after cessation of study intervention if the participant initiates new anticancer therapy 
must be reported by the investigator.

Additionally, any SAE brought to the attention of an investigator at any time outside 
the time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AE or SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and the event is considered to be reasonably 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 8.
Exception:
A positive pregnancy test at the time of initial screening is not a reportable 
event unless the participant has received study intervention.
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Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe to 
Report Event 
and Follow-up 
Information 
to SPONSOR:
Non-Serious Adverse 
Event (NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
Method of Detecting AE and SAE
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence.
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Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
o
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 
o
The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, 
IRB/IECs and investigators in accordance with all applicable global laws and 
regulations, ie, per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
o
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators, as necessary.
o
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (eg, summary or listing of SAE) from the 
sponsor will file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy Endpoints as outlined in this section will not be reported to the Sponsor, as 
described in Section 9.3.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
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Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
Treatment of Overdose
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-1308 or MK-1308A by ≥150% (eg, ≥1.5 times the indicated dose) based on the 
known dose-related toxicities of ipilimumab and for pembrolizumab ≥1000 mg. No specific 
information is available on the treatment of overdose of MK-1308, MK-1308A, or 
pembrolizumab. In the event of overdose, MK-1308, MK-1308A, or pembrolizumab should 
be discontinued and the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.
Safety
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 pre-trial to post-trial visits) can be found in Section 9.
Planned time points for all safety assessments are provided in the SoA.
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Physical Examinations
The investigator or qualified designee will perform a complete physical exam including 
neurologic assessment during the screening period. Clinically significant abnormal findings 
should be recorded as medical history. The time points for full physical exam and directed 
physical examination are described in Section 2 – Schedule of Activities (SoA). After the 
first dose of trial treatment new clinically significant abnormal findings should be recorded 
as AEs.
Vital Signs
The investigator or qualified designee will obtain vital signs at screening, prior to the dosing 
of each treatment (MK-1308, MK-3475, or combo admixture), and at the end of infusion.
Vital signs should also be collected at the End of Treatment Visit and Safety Follow-up 
(30-day and 90-day) Visits. Vital signs include temperature, pulse, respiratory rate, and blood 
pressure. Weight will be measured on Day 1 of each cycle (can be done at any time on Day 1 
of each cycle). Height will be measured at the Screening visit only.
Electrocardiograms
Standard 12-lead ECGs will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA in Section 2. Clinically significant abnormal findings at 
Screening should be recorded as medical history. Additional ECGs should be performed 
when clinically necessary.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study treatment, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator. 
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For dose escalation and dose confirmation only, laboratory safety tests (hematology and 
chemistries) for screening period should be performed within 14 days prior to the first dose 
of trial treatment. 
For efficacy expansion and coformulation phases, laboratory safety tests (hematology and 
chemistries only) should be performed and reviewed by the investigator or staff designee for 
eligibility within 72 hours prior to the first dose of trial treatment. All other required 
screening laboratory tests (including hepatitis, ACTH, cortisol, and thyroid function testing)
may be performed anytime within 28 days prior to first dose. If the participant has had prior 
anti-PD-1 or PD-L1 treatment, the ACTH, cortisol and thyroid test results must be reviewed 
prior to C1D1 dosing. Laboratory safety tests conducted within 72 hours of C1D1 do not 
need to be repeated prior to C1D1 dosing.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each subsequent dose of trial treatment. However, 
in the event thyroid function test results after Cycle 1 are not available prior to scheduled 
dosing, review of thyroid function tests (T3, T4, and TSH), ACTH and cortisol results after 
dosing is acceptable. Unresolved abnormal laboratory values that are drug-related AEs 
should be followed until resolution. Laboratory tests do not need to be repeated after the end 
of treatment if laboratory results are within the normal range.
Pregnancy Testing
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 6.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at every cycle (Q6W), prior to dosing, during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure.
-
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.
Pharmacokinetics
Sample collections are planned for PK and ADA analysis for MK-1308 and pembrolizumab 
according to the SoA described in Section 2. Blood samples will be obtained to measure the 
PK of serum MK-1308 given as monotherapy and in combination with and in coformulation
with pembrolizumab. If feasible, PK data of MK-1308 monotherapy and in combination and 
coformulation with pembrolizumab will be analyzed using nonlinear mixed effects modeling. 
A population PK analysis of MK-1308 may be performed to characterize PK parameters (ie,
clearance, volume of distribution [V]) and evaluate the effect of extrinsic and intrinsic factors 
to support the proposed dosing regimen. 
Pharmacokinetic data may also be used to explore the exposure-response relationships for 
MK-1308 anti-tumor activity/efficacy in combination with pembrolizumab, as well as safety 
in the proposed participant population. The results of these analyses, if performed, will be 
reported separately.
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PK and ADA samples may be disposed of in accordance with sample destruction procedures
once the PK and ADA data are finalized.
Blood Collection for Serum MK-1308
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures Manual. 
Pharmacokinetic samples should be drawn according to the PK collection schedule for all 
participants. Every effort should be taken to collect samples at 30 days after end of study 
intervention.
Blood Collection for Serum Pembrolizumab
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Procedures Manual.
Pharmacokinetic samples should be drawn according to the PK collection schedule for 
participants who receive pembrolizumab. Every effort should be taken to collect samples at 
30 days after end of study intervention.
Blood Collection for Anti-Pembrolizumab Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures Manual. Anti-pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for participants who receive pembrolizumab. Simultaneous PK 
sampling is required for interpretation of ADA analysis. Every effort should be taken to 
collect samples at 30 days after end of study intervention for ADA. Simultaneous PK 
sampling is required for interpretation of ADA analysis.
Blood Collection for Anti-MK-1308 Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures Manual. Anti-MK-1308 antibody samples should be drawn according to the 
ADA collection schedule for participants who receive MK-1308. Simultaneous PK sampling 
is required for interpretation of ADA analysis. Every effort should be taken to collect 
samples at 30 days after end of study intervention for ADA. Simultaneous PK sampling is 
required for interpretation of ADA analysis.
Pharmacodynamics
A direct receptor occupancy assay to measure target engagement cannot be used as CTLA4
expression on the cell surface of T-cells is transient and tightly regulated. Therefore, post-
treatment changes in ALC and expression of T-cell activation markers (for example Ki67, 
ICOS, and HLA-DR) will be assessed in peripheral blood based on the proposed effect of 
CTLA4 blockade in the immune priming phase to increase activation and proliferation of T-
cells. 
Sample collection, storage and shipment instructions for blood samples will be provided in 
the Procedures Manual.
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Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research (Not 
applicable for Arm K):

Leftover main study tumor

Leftover cells from mononuclear cells biomarker analysis

Leftover serum from serum cytokine

Leftover DNA from genetic analysis and T-cell repertoire

Leftover RNA

Leftover plasma from ctDNA

Leftover and/or derivative from stool for biomarker analysis (Dose Escalation and 
Confirmation phases only)
Biomarkers
(This is not applicable to Arm K in China.)
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA. Sample collection, storage and shipment instructions for these 
samples will be provided in the Procedures Manual:

Serum for cytokine measurements 

Blood for TCR repertoire

Blood for RNA analyses 

Peripheral blood for immunophenotyping biomarker analyses

Peripheral blood for mononuclear cells biomarker analysis

Whole blood for exploratory T-cell response

Blood for genetic analysis and HLA genotyping

Tumor tissue 

Blood for ctDNA

Stool microbiome collection (dose escalation, confirmation, and expansion phases 
only)
Pre- and on-treatment tumor tissue will be collected for additional biomarker analysis from 
approximately 10 participants each in Arms F and G.  For these participants, an archival 
tumor sample is also requested, if feasible, from a time point before receiving any prior 
immune-oncology treatment.  New biopsies of tumor tissue will be obtained from these 
participants at Screening (following confirmation of all other eligibility assessments) and at 
4 weeks after C1D1 (±7 days).  Tumor tissue from Screening should be accurately marked so 
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the same lesion site can be used for the on-treatment biopsy. If not possible, the Sponsor 
should be notified of the location.  
Planned Genetic Analysis Sample Collection
This sample should be drawn for HLA genotyping and for planned analysis of the association 
between genetic variants in DNA and drug response. Data analysis will be limited to HLA if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not 
approve the collection of the sample for these purposes. If the sample is collected, leftover 
extracted DNA will be stored for future biomedical research if the participant signs the FBR 
consent. 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.
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Approximately 28 days prior to treatment allocation/randomization, potential participants
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 participant signing consent as part of 
routine management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of trial treatment except for the following:

For dose escalation and dose confirmation, safety laboratory tests are to be performed 
within 14 days prior to the first dose of trial treatment. If these tests are performed 
within 72 hours of C1D1, they do not need to be collected earlier in screening.

For efficacy expansion and coformulation phases, laboratory safety tests (hematology 
and chemistries) should be performed and reviewed by the investigator or staff 
designee for eligibility within 72 hours prior to the first dose of trial treatment. All 
other required laboratory tests can be performed anytime within the 28-day 
screening period.

Evaluation of ECOG must be performed within 3 days (72 hours) prior to the first 
dose of trial treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 24 hours for urine and within 72 hours for serum prior to the first 
dose of trial treatment and prior to each subsequent dose. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed 
by the local study site laboratory).

Archival or newly obtained tumor sample collection is required to be submitted
within 28 days prior to the first dose of trial treatment. 
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
Participants may be re-screened up to 2 times with consultation and approval of the 
Sponsor.
Treatment Period
Visit requirements are outlined in Section 2.0 – Schedule of Activities (SoA). Specific 
procedure-related details are provided above in Section 9.1 – Administrative and General
Procedures.
Discontinued Participants Continuing to be Monitored in the Study
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. For the efficacy expansion and coformulation phases, a second mandatory Safety 
Follow-up Visit should be conducted approximately 90 days after the last dose of trial 
treatment or before the initiation of a new anticancer treatment, whichever comes first.
All AEs that occur prior to the Safety Follow-up visits should be recorded (up to 90 days 
following end of treatment). Participants with an AE of Grade > 1 will be followed until the 
resolution of the AE to Grade 0-1 or until the beginning of a new anticancer therapy, 
whichever occurs first. All AEs from the time of treatment allocation/randomization through 
90 days following cessation of study treatment must be reported by the investigator. All AEs 
meeting serious criteria, from the time of treatment allocation/randomization through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment if 
the participant initiates new anticancer therapy, whichever is earlier must be reported by the 
investigator.
Post-Study
Participants will be required to return to clinic approximately 30 days after the last dose of 
study treatment for the post-trial visit. If the post-trial visit occurs less than 30 days after the 
last dose of study treatment, a subsequent follow-up phone call should be made at 30 days 
post the last dose of study treatment to determine if any AEs have occurred since the post-
trial clinic visit.
For the efficacy expansion and coformulation phases, participants also will be required to 
return to clinic approximately 90 days after the last dose of study treatment for a post-trial 
visit. If the post-trial visit occurs less than 90 days after the last dose of study treatment, a 
subsequent follow-up phone call should be made at 90 days post the last dose of study 
treatment to determine if any AEs have occurred since the 30-day post-trial clinic visit.
Survival Follow-up
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone 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 eDMC 
review, interim and/or final analysis. Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor-defined time 
period will be contacted for their survival status (excluding participants who have previously 
recorded a death event in the collection tool).
10. Statistical Analysis Plan
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other non-confirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP). 
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report (CSR) for the 
study. 
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full details are 
in the Statistical Analysis Plan, Section 10.2 through Section 10.12.
Study Design Overview
Phase 1 / 2 trial of MK-1308 in combination with 
pembrolizumab in participants with advanced/metastatic 
solid tumors. 
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT), 
DLT-evaluable population for DLT analysis
PK (Secondary): Per-Protocol (PP)
Efficacy (Primary in the efficacy expansion phase, and 
secondary for the other phases): APaT population
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Primary Endpoint(s)
Safety: 
•
Number of participants with at least 1 DLT
•
Number of participants with ≥1 AE
•
Number of participants discontinuing study treatment 
due to an AE  
Efficacy (efficacy expansion phase): 
•
Objective Response Rate (ORR) defined as the portion 
of participants with CR or PR as assessed by BICR
based on RECIST 1.1, adjusted to follow a maximum 
of 10 target lesions and a maximum of 5 target lesions 
per organ)
Secondary Endpoints
ORR as assessed by the investigator based on RECIST 
1.1 (dose escalation phase, dose confirmation phase, and 
Arm I and K in the coformulation phase): 
DOR as assessed by BICR based on RECIST 1.1 
(efficacy expansion phase): 
•
The time from first documented evidence of CR or PR 
until disease progression or death due to any cause, 
whichever occurs first (for responders only)
PK profile and ADA of MK-1308 monotherapy and MK-
1308 in combination with pembrolizumab; PK parameters 
of pembrolizumab in combination with MK-1308; PK 
profiles of MK-1308 and pembrolizumab when drugs are 
sequentially administered, co-administered and 
coformulated as MK-1308A.
•
AUC, Cmin, Cmax
•
Anti-drug antibody levels
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
ORR will be summarized by treatment arm along with a 
95% confidence interval. 
Descriptive summary statistics will be provided for DOR.
Time-to-event analysis and Kaplan-Meier estimates may
be provided for DOR in addition to the descriptive 
summary statistics if there are at least 10 responders.
PK parameters of study medicines will be summarized by 
planned visit and time for each dose cohort.
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Treatment Assignment
Participants will be allocated to receive MK-1308 in 
combination with pembrolizumab (Arms A-F), or 
MK-1308 monotherapy (Arm G), or the coformulation 
product MK-1308A (Arm I and K) using an IVRS/IWRS.
Treatment assignments in the dose escalation phase, dose 
confirmation phase and coformulation phase are non-
random. Treatment assignments in the efficacy expansion 
phase will utilize random assignment whenever there is
more than 1 treatment arm open.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety 
endpoints as appropriate. 
Sample Size and Power 
The sample size in Cohorts 1, 2, 3 and Arms A, B, C, D, 
E of this study depends on the observed DLT profiles of 
MK-1308 in combination with pembrolizumab.
Maximum sample size will be 100 in Arm F and 40 in 
Arm G. Target sample size will be 20 in Arm I, and 20 in 
Arm K. A target sample size of 348 participants will be 
used for study planning purposes. 
Responsibility for Analyses/In-House Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, ie, participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned. 
Allocation to treatment in dose escalation, dose confirmation and coformulation phase will 
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not be randomized. Participants in the efficacy expansion phase will be randomized between 
Arms F and G.
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 4.
Analysis Endpoints
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
ORR per BICR based on RECIST 1.1 is the primary efficacy endpoint in the efficacy 
expansion phase. ORR per investigator based on RECIST 1.1 is a secondary endpoint for the 
dose escalation, dose confirmation, and Arms I and K in the coformulation phase. An 
objective response is a CR or PR with confirmation. ORR is defined as the portion of 
participants with CR or PR. 
DOR is a secondary endpoint in the efficacy expansion. For participants who demonstrate
CR or PR, DOR is defined as the time from first documented evidence of CR or PR until 
disease progression or death due to any cause, whichever occurs first.
PK endpoints include serum concentrations of MK-1308 and pembrolizumab, as well as 
derived PK parameters including AUC, Cmin, and Cmax. The primary PK parameters for the 
coformulation phase of MK-1308A would be AUC.
Incidence of ADA is a secondary endpoint.
Safety Endpoints
The primary safety endpoint is number of participants with at least one DLT.  In addition, 
safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
A description of safety measures is provided in Section 9.3.
Analysis Populations
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all participants who received at least 1 dose of study medicine.  
DLT-evaluable population: Participants in the APaT population who finished the DLT 
observation period in the dose escalation phase or DLT observation period in the dose 
confirmation phase, Arm F in efficacy expansion phase (first 14 participants only), or Arm I
without a DLT, or experienced a DLT during the DLT evaluation period will be included in 
the DLT evaluation. If a participant is replaced due to receiving less than 90% of MK-1308 
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(or pembrolizumab) in the first cycle, the participant will not be included in the DLT-
evaluable population.
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 analysis of PK and target engagement data in this 
study.  The PP population consists of the subset of participants who complied with the 
protocol sufficiently to ensure that their data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance includes such considerations as 
exposure to treatment, availability of measurements, and the absence of major protocol 
violations.  Any participants or data values excluded from the analyses will be identified, 
along with the reasons for exclusion, in the CSR.  At the end of the study, all participants
who were compliant with the study procedures and have available data from at least 1
treatment will be included in the PP analysis dataset.
Efficacy Populations
The APaT population will be the primary analysis population for ORR, PFS and OS. The 
APaT population consists of all participants who received at least 1 dose of study medicine. 
The Full Analysis Set (FAS) population will be a supportive analysis population for the ORR 
analyses. It consists of all participants with a baseline scan that demonstrated measurable 
disease, and who were administered at least 1 dose of study medicine. Efficacy data occurred 
during the crossover phase in Arm G will be excluded from the primary efficacy analyses of 
Arm G or F and may be used in exploratory analyses. For the primary analysis on group 
comparison between Arm F and Arm G, only the concurrent randomized participants from 
Arm G and Arm F will be included.  Exploratory analyses may be conducted by including all 
Arm G participants for the group comparison to support the use of pembrolizumab as part of 
the combination regimen. Detailed plans of the exploratory analyses will be summarized in 
the sSAP. 
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives.  
Statistical Methods for Efficacy Analysis
Objective response rate will be summarized by arm along with a 95% confidence interval. 
Confidence interval would be calculated using the Clopper–Pearson method. The Miettinen 
and Nurminen method [Miettinen, O. 1985] will be used for comparison of the ORR between 
Arm F and Arm G. 
Duration of Response will be summarized either using descriptive summary statistics or
Kaplan-Meier estimates, depending on the number of responders. 
Time to response and best overall response will also be summarized. 
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Statistical Methods for Safety Analysis
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.
Adverse events will be summarized by counts and frequencies for each arm.  Laboratory 
tests, vital signs, and other safety endpoints will be summarized as appropriate.
Dose-limiting toxicities will be listed and summarized for each arm.  
Summaries of Baseline Characteristics, Demographics and Other Analyses
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Pharmacokinetic and pharmacodynamic parameters of MK-1308 monotherapy and MK-
1308, administered in combination and in coformulation with pembrolizumab, will be 
summarized by planned visit and time for each dose cohort/arm.
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Sample Size and Power Calculations
The overall sample size in Cohorts 1 through 3, Arm A, B, C, D and E in this study depends 
on the observed safety profiles of MK-1308 in combination with pembrolizumab. The 
maximum sample size is 100 in Arm F and 40 in Arm G. For MK-1308A, the coformulated 
product, the target sample size is 20 in Arm I, and 20 in Arm K. A target total sample size of
348 participants will be used for study planning purposes.
 
 
 
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Subgroup Analyses
Subgroup analysis of ORR in PD-1/L1-refractory melanoma participants in the efficacy 
expansion phase will be conducted within each category of the following variables:
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Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial.  Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
11. References
[Antonia, S. J., et al 
2016]
Antonia SJ, Lopez-Martin JA, Bendell J, Ott PA, 
Taylor M, Eder JP, et al. Nivolumab alone and 
nivolumab plus ipilimumab in recurrent small-
cell lung cancer (checkmate 032): a multicentre, 
open-label, phase 1/2 trial. Lancet Oncol. 2016 
Jul;17(7):883-95.
[04MGJJ]
[Carbonnel, F., et al 
2017]
Carbonnel F, Soularue E, Coutzac C, Chaput N, 
Mateus C, Lepage P, et al. Inflammatory bowel 
disease and cancer response due to anti-CTLA-4: 
is it in the flora? Semin Immunopathol. 2017 
Apr;39(3):327-331.
[04QZ9M]
[Chemnitz, J. M., et al 
2004]
Chemnitz JM, Parry RV, Nichols KE, June CH, 
Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of 
programmed death 1 upon primary human T cell 
stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
[00VMPN]
[ClinicalTrials.gov 
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation/Term
Definition
1L
First-line
2L
Second-line
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug antibody
AE
Adverse event
ALC
Absolute leukocyte counts 
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
APaT
All-participants-as-treated
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the curve
BCG
Bacille Calmette Guerin
hCG
human chorionic gonadotropin
BICR
Blinded Independent Central Review
BRAF
proto-oncogene B-raf
BUN
Blood urea nitrogen
CBD
Cannabidiol
CD3ζ
CD3 zeta
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary
CIV
Central Imaging Vendor
Cmax
Maximum concentration
Cmax,ss
Maximum concentration at steady-state
Cmin
Minimum concentration
Cmin,ss
Minimum concentration at steady-state
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CrCl
Creatinine clearance
CRF
Case report form
CRP
C-reactive protein
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA4
Cytotoxic T-Lymphocyte-Associated Antigen-4
ctDNA
Circulating tumor deoxyribonucleic acid
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Abbreviation/Term
Definition
DILI
Drug-induced liver injury 
DLT
Dose-limiting toxicity
DOR
Duration of Response
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
End of treatment
FAS
Full Analysis Set
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAA
Food and Drug Administration Amendment Act
FDC
Fixed-dose combination
FIH
First-in-human
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-Stimulating Factor
GFR
Glomerular filtration rate
GGT
Gamma glutamyl transferase
GI
Gastrointestinal
GLP
Good Laboratory Practices
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HNSCC
Head neck squamous cell carcinoma 
HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
IC50
Mean inhibitory concentration
ICF
Informed consent form
ICH
International Council on Harmonisation
iCPD
iRECIST confirmed radiographic progression 
IEC
Independent Ethics Committee
IFNγ
Interferon-gamma
Ig
Immunoglobulin
IgV
Immunoglobulin variable
IHC
Immunohistochemistry
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Abbreviation/Term
Definition
IL
Interleukin
IND
Investigational New Drug application
INR
International normalized ratio
IO
Immune-oncology
irAE
Immune-related adverse event
IRB
Institutional Review Board
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITIM
Immunoreceptor tyrosine-based inhibition motif
IUD
Intrauterine device
IV
Intravenous
IVD
In vitro diagnostic
IVRS
Interactive voice response system
IWRS
Integrated web response system
KL-6
Sialylated carbohydrate antigen KL-6
LDH
Lactate dehydrogenase
mAb
Monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
chemotherapy, antiemetic therapy should follow Multinational 
Association of Supportive Care in Cancer (MASCC)
MLR
Mixed lymphocyte reaction
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MSI
Microsatellite instability
NCI
National Cancer Institute
NOAEL
No-observed-adverse-effect-level
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association 
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PBPK
Physiologically-based PK
PD
Progressive disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetic(s)
PKCθ
Protein kinase C-theta
PP
Per-protocol
PR
Partial response
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Abbreviation/Term
Definition
PT
Prothrombin time
Q1W
Every week / once per week
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q6W
Every 6 weeks
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RPTD
Recommended Phase 2 dose
SAE
Serious adverse event
SCLC
Small cell lung cancer
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SIM
Site Imaging Manual
SNP
Single nucleotide polymorphism
SoA
Schedule of Assessments
SP-D
Surfactant Protein D  
SpO2
Peripheral capillary oxygen saturation
sSAP
Supplementary Statistical Analysis Plan
SUSAR
Suspected unexpected serious adverse reactions
T3
Free triiodothyronine
T4
Free thyroxine
TCR
T-cell receptor 
Teff
Effector T-cell
TMDD
Target-mediated drug disposition
TPS
Tumor proportion score
Treg
Regulatory T-cell
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
US
United States
V
Volume of distribution
VOP
Verification of progression
WBC
White blood cell
WOCBP
Woman of childbearing potential
ZAP70
Zeta-chain-associated protein kinase
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Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 13 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 13
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Hemoglobin  
Hematocrit
WBC count with 
Differential: Absolute or
Percentage (%) 1, *
Neutrophils: Absolute
Lymphocytes
Monocytes
Eosinophils
Basophils
Platelet count
RBC Count 
RBC Indices:
MCV*
MCH*
MCHC
%Reticulocytes*
Chemistry
Albumin*
Calcium  
Lactate 
Dehydrogenase
(LDH)
Total Protein*
Alkaline phosphatase 
(ALP)
Chloride*
Magnesium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
CRP*
Phosphorous*
Uric Acid*
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-Oxaloacetic 
Transaminase (SGOT)
Creatinine
Potassium
Sialylated 
carbohydrate 
antigen KL-6 (KL-
6) (Japan only)
Bicarbonate (CO2)2
Gamma glutamyl 
transpeptidase
(GGT)*
Sodium
Surfactant Protein 
D (SP-D)(Japan 
only)
Blood Urea Nitrogen 
(BUN)3
Glucose 
[nonfasting]
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Routine 
Urinalysis

Specific gravity

pH

Bilirubin, blood, glucose, ketones, protein by dipstick

Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serum or urine human chorionic gonadotropin (hCG) pregnancy test (for women of 
childbearing potential)4

Follicle-stimulating hormone (FSH), if indicated

Hepatitis B surface antigen [HBsAg] and/or hepatitis B (HBV-DNA), hepatitis C 
antibody (HepCAb and/or HCV RNA)5

Prothrombin time/international normalized ratio and activated partial thromboplastin 
time (aPTT/PTT)6

Thyroid function testing (free T4, total T4/FT4, T3/FT3, TSH), ACTH and Cortisol7
Other Tests, if 
indicated

Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Testosterone, 
Prolactin, Thyroid peroxidase antibody (TPO), Thyroglobulin antibody (TGAb), 
Reverse T3

ACTH (Cosyntropin) Stimulation Test
*
Performed only if considered local standard of care.
1. Either absolute or percentage results may be reported at the initial visit. The same type of test results 
and normal ranges must be maintained for the remainder of the study.
2. If bicarbonate/CO2 is not done as part of standard of care in your region then these tests do not
need to be performed.
3. Blood urea nitrogen is preferred; if not available urea may be tested.
4. 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 is required.
5. Methodology of testing is at the discretion of the investigator. If the HBsAg and/or HepCAb is 
positive, this should be confirmed with specific RNA assays.
6. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all
participants. If aPTT is not available PTT is acceptable Any participant receiving anticoagulant
therapy should have coagulation factors monitored closely throughout the trial.
7. Total T3 is preferred; if not available free T3 or FT3 may be tested. 
Investigators must document their review of each laboratory safety report.
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Appendix 3: Study Governance Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A.
Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B.
Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II.
Scientific Issues
A.
Trial Conduct
1.
Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.
2.
Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3.
Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
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B.
Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A.
Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B.
Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C.
Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D.
Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A.
Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
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B.
Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C.
Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V.
Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
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except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy trial documents in
order to verify worksheet/case report form data.  By signing the consent form, the participant
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
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.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  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 FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants 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.  
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
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 this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical 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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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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 or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol-specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test result.  
An overdose without any associated clinical symptoms or abnormal laboratory results 
is reported using the terminology “accidental or intentional overdose without adverse 
effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to section 9.3.5 for protocol-specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical 
condition that is diagnosed prior to the use of an MSD product and is documented in 
the patient’s medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
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.
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Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse 
Events (CTCAE), version 4.03. 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.
●
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.
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Assessment of Causality
●
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 product 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:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to 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
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
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●
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 RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable.  
The AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each adverse event causality to the combination 
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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.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the EDC tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
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SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or secure 
email of the SAE paper CRF is the preferred method to transmit this information to the 
Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
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Appendix 5: Contraceptive Guidance
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantc,d

IUSc,e

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. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
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   Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c   Male condoms must be used in addition to female participant hormonal contraception.
d   If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation.
e   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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Appendix 6: 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 consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Sample Collection will be used in various experiments to 
understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology 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.
Participants for Enrollment
All participants 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 participants 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 participants on the visit designated in 
the trial flow chart.  If delayed, present consent at next possible Participant Visit.  
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Consent forms signed by the participant will be kept at the clinical trial site under 
secure storage for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant 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(s)
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 participant is having blood drawn for other trial purposes.
4. Confidential Participant 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 participant' 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 participant
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.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant
identifiers and this 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 Sponsor 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 a 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 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
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medical records for the main trial are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@msd.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/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 participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot 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 to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants 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 participants 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 participant have been minimized. No 
additional risks to the participant 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 participant
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
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Appendix 7: Country-specific Requirements
France Requirements
Patients should be permanently discontinued from study treatment if any of the following
AEs occur:
•
Guillain-Barre Syndrome
•
Encephalitis
•
Steven-Johnson Syndrome
•
Toxic-epidermal necrolysis
•
Recurrent Grade 3 Diarrhea / Colitis
France-specific additions to Table 5: Dose Modification and Treatment Discontinuation
Guidelines for Immune-Related Adverse Events Associated With Pembrolizumab, MK-1308, 
and MK-1308A (Section 7.2.1).
General instructions:
a.
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.
b.
Pembrolizumab, MK-1308A, and MK-1308 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 pembrolizumab 
treatment. 
c.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
d.
If pembrolizumab, MK-1308, and MK-1308A have been withheld, the study treatment may resume 
after the irAE decreased to ≤Grade 1 after corticosteroid taper. 
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAE
v5)
Action with 
pembrolizumab, 
MK-1308, and 
MK-1308A
irAE management 
with 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.

Add prophylactic 
antibiotics 
for 
opportunistic 
infections

Monitor 
participants for 
signs and 
symptoms of 
pneumonitis

Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment.

Add prophylactic 
antibiotics for 
opportunistic 
infections.
Recurrent Grade 2, 
3 or 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAE
v5)
Action with 
pembrolizumab, 
MK-1308, and 
MK-1308A
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
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
AST / ALT 
elevation or 
Increased 
Bilirubin
Grade 2 a
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 b or 4 c
Permanently 
discontinue

Administer 
corticosteroids 
(initial dose of 1-2 
mg/kg prednisone 
or equivalent) 
followed by taper.
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAE
v5)
Action with 
pembrolizumab, 
MK-1308, and 
MK-1308A
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
New onset T1DM 
or Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d

Initiate insulin 
replacement 
therapy for 
participants with 
T1DM. 

Administer 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 d
Hyperthyroidism 
Grade 2
Continue 

Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thioamides as 
appropriate. 

Monitor for signs 
and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grades 2, 3, 4
Continue 

Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care.

Monitor for signs 
and symptoms of 
thyroid disorders. 
Nephritis: grading 
according to 
increase creatine 
or acute kidney 
injury
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 or 2
Withhold

Based on severity 
of AE, administer 
corticosteroids.

Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes.
Grade 3 or 4
Permanently 
discontinue
Persistent Grade 2
Withhold
All Other 
immune-related 
AEs
Grade 3
Withhold or 
discontinue based 
on the type of 
event. e

Based on severity 
of AE, administer 
corticosteroids. 

Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes.
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAE
v5)
Action with 
pembrolizumab, 
MK-1308, and 
MK-1308A
irAE management 
with corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab, MK-1308, or MK-1308A is at the 
discretion of the investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab, MK-1308, 
or MK-1308A may be resumed.
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, 
Stevens-Johnson Syndrome, toxic-epidermal necrolysis, and recurrent Grade 3 diarrhea / colitis.
NOTE:
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab 
and/or MK-1308 is required, pembrolizumab and/or MK-1308 may be resumed when AE resolves to Grade ≤2 
and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
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Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study treatment 
until repeat imaging 4 to 8 weeks later is obtained (using iRECIST for participant 
management; see Table 7 and Figure 5). This decision by the investigator should be based on 
the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements,” but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ) may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥5 
mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:
o
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 
o
Visible growth of new non-target lesions 
o
The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
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Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 2 and submitted to the central imaging vendor.
Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
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
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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