A Phase 1 Trial of MK-7684 as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors
Phase: PHASE1
Conditions: Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 1 Trial of MK-7684 as Monotherapy
and in Combination with Pembrolizumab in
Subjects with Advanced Solid Tumors
NCT02964013
06-June-2022

Product:  MK-7684 
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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).
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 1 Trial of MK-7684 as Monotherapy and in Combination with Pembrolizumab in 
Subjects with Advanced Solid Tumors
IND NUMBER:  131789
EudraCT NUMBER:  Not Applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Part A (Dose Escalation and Confirmation) ....................................................... 16
Part B (Dose Expansion)..................................................................................... 18
Trial Diagram........................................................................................................ 21
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 23
Primary Objective(s) & Hypothesis(es).............................................................. 23
Secondary Objective(s) & Hypothesis(es)........................................................... 23
Exploratory Objectives......................................................................................... 24
4.0
BACKGROUND & RATIONALE.......................................................................... 25
Background ........................................................................................................... 25
Pharmaceutical and Therapeutic Background .................................................... 25
MK-7684 Background ................................................................................. 25
Pembrolizumab (MK-3475) Background .................................................... 26
Lung Cancer: Epidemiology and Current Therapeutic Options .................. 27
NSCLC.................................................................................................. 27
.............................................................................................. 27
.............. 30
Preclinical and Clinical Trials............................................................................. 30
MK-7684 Preclinical and Clinical Trials..................................................... 30
Pembrolizumab (MK-3475) Preclinical and Clinical Trials........................ 33
Ongoing Clinical Trials....................................................................................... 34
MK-7684 Ongoing Clinical Trials............................................................... 34
Pembrolizumab Ongoing Clinical Trials ..................................................... 34
Information on Other Trial-related Therapy....................................................... 34
Rationale................................................................................................................ 34
Rationale for the Trial and Selected Subject Population .................................... 34
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Rationale for Dose Selection/Regimen/Modification......................................... 36
Rationale for MK-7684 Dose....................................................................... 36
Rationale for Preliminary MK-7684 RPTD (200 mg)................................. 39
Rationale for Pembrolizumab Dose............................................................. 40
..................... 41
.................... 41
42
Rationale for Endpoints ...................................................................................... 42
Efficacy Endpoints....................................................................................... 42
Safety Endpoints.......................................................................................... 43
Pharmacokinetic Endpoints ......................................................................... 43
Bio-comparability Endpoints................................................................ 44
Pharmacodynamic Endpoints....................................................................... 44
...... 44
.................................................................... 44
.................................................................. 44
Planned Exploratory Biomarker Research................................................... 44
Future Biomedical Research........................................................................ 46
Benefit/Risk ........................................................................................................... 46
5.0
METHODOLOGY ................................................................................................... 46
Entry Criteria........................................................................................................ 46
Diagnosis/Condition for Entry into the Trial...................................................... 46
Subject Inclusion Criteria.................................................................................... 46
Subject Exclusion Criteria .................................................................................. 52
Trial Treatment(s) ................................................................................................ 55
Dose Selection .................................................................................................... 60
Dose Selection (Preparation) ....................................................................... 60
Dose Escalation and Confirmation .............................................................. 60
Expansion Phase .......................................................................................... 63
Definition of Dose-limiting Toxicity........................................................... 65
Timing of Dose Administration.......................................................................... 66
Dose Modification (Escalation/Titration/Other)................................................. 66
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Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 66
Toxicity Management of Infusion Reactions Related to Pembrolizumab 
and MK-7684/MK-7684A........................................................................... 71
Dose Modification for Chemotherapy ......................................................... 72
Management Guidelines for Overlapping Toxicities................................... 76
Trial Blinding...................................................................................................... 77
Randomization or Treatment Allocation............................................................ 77
Stratification.......................................................................................................... 78
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 78
Acceptable Concomitant Medications/Procedures ............................................. 79
Prohibited Concomitant Medications.................................................................. 79
Rescue Medications & Supportive Care............................................................. 80
Antiemetic Use............................................................................................. 80
Colony-stimulating Factors.......................................................................... 80
Pemetrexed Premedication........................................................................... 81
Diet/Activity/Other Considerations..................................................................... 81
Diet...................................................................................................................... 81
Contraception...................................................................................................... 81
Use in Pregnancy ................................................................................................ 83
Use in Nursing Women....................................................................................... 83
Subject Withdrawal/Discontinuation Criteria................................................... 83
Discontinuation of Treatment ............................................................................. 83
Withdrawal from the Trial .................................................................................. 84
Subject Replacement Strategy............................................................................. 85
Beginning and End of the Trial ........................................................................... 85
Clinical Criteria for Early Trial Termination ................................................... 85
6.0
TRIAL FLOW CHART ........................................................................................... 86
Cross-over Flow Chart ......................................................................................... 95
 
........................................................................................... 99
 
................................................................... 105
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.................................................................................................... 110
7.0
TRIAL PROCEDURES ......................................................................................... 116
Trial Procedures ................................................................................................. 116
Administrative Procedures................................................................................ 116
Informed Consent....................................................................................... 116
General Informed Consent.................................................................. 116
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................. 117
Inclusion/Exclusion Criteria ...................................................................... 117
Subject Identification Card ........................................................................ 117
Medical History ......................................................................................... 117
Disease Details and Treatments................................................................. 117
Oncology Disease Details................................................................... 117
Prior Oncology Treatment History ..................................................... 117
Prior and Concomitant Medications Review............................................. 118
Prior Medications................................................................................ 118
Concomitant Medications................................................................... 118
Assignment of Screening Number............................................................. 118
Assignment of Treatment/Randomization Number................................... 118
Trial Compliance (Medication).................................................................. 119
Clinical Procedures/Assessments...................................................................... 119
Full Physical Examination......................................................................... 119
Height, Weight, and Vital Signs ................................................................ 119
Eastern Cooperative Oncology Group Performance Status....................... 119
Electrocardiogram...................................................................................... 119
Administration of Study Treatment ........................................................... 119
Disease Assessments.................................................................................. 120
Brain Imaging ............................................................................................ 122
Prophylactic Cranial Irradiation................................................................. 122
Adverse Event Monitoring......................................................................... 122
Laboratory Procedures/Assessments ................................................................ 123
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 123
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Other Laboratory Evaluations.................................................................... 124
Pharmacokinetic/Pharmacodynamic Evaluations...................................... 124
Blood Collection for MK-7684........................................................... 124
Blood Collection for Pembrolizumab (Arms 2, 3, 4, and 5 only)....... 125
Sample Collection for Exploratory Biomarkers ................................. 125
Tumor Tissue Collection............................................................................ 125
Planned Genetic Analysis Sample Collection............................................ 125
Future Biomedical Research Sample Collection ....................................... 125
Other Procedures............................................................................................... 125
Withdrawal/Discontinuation...................................................................... 125
Withdrawal From Future Biomedical Research ................................. 126
Lost to Follow-up................................................................................ 126
Blinding/Unblinding .................................................................................. 126
Calibration of Equipment........................................................................... 127
Visit Requirements............................................................................................ 127
Screening Period ........................................................................................ 127
Treatment Period Visits ............................................................................. 127
Post-treatment Period................................................................................. 128
Survival Status ........................................................................................... 128
Assessing and Recording Adverse Events ........................................................ 128
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor........................................................................................................ 129
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 130
Immediate Reporting of Adverse Events to the Sponsor.................................. 130
Serious Adverse Events ............................................................................. 130
Events of Clinical Interest.......................................................................... 131
Evaluating Adverse Events............................................................................... 132
Sponsor Responsibility for Reporting Adverse Events .................................... 135
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 135
Statistical Analysis Plan Summary ................................................................... 135
Responsibility for Analyses/In-house Blinding ................................................ 137
Trial Objectives................................................................................................... 137
Analysis Endpoints ............................................................................................. 137
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Efficacy/Pharmacokinetic Endpoints................................................................ 137
Safety Endpoints ............................................................................................... 138
Analysis Populations........................................................................................... 138
Safety Analysis Population............................................................................... 138
Pharmacokinetic Analysis and Target Engagement Populations...................... 138
Efficacy Analysis Populations .......................................................................... 139
Statistical Methods.............................................................................................. 139
Statistical Methods for Efficacy Analyses........................................................ 139
Statistical Methods for Safety Analyses ........................................................... 139
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 140
Demographic and Baseline Characteristics ............................................... 140
Population Pharmacokinetic/Pharmacodynamic Analyses........................ 140
Interim Analyses ................................................................................................. 140
Multiplicity .......................................................................................................... 140
Sample Size and Power Calculations ................................................................ 141
Subgroup Analyses and Effect of Baseline Factors ......................................... 141
Compliance (Medication Adherence)................................................................ 142
Extent of Exposure.............................................................................................. 142
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 142
Investigational Product ...................................................................................... 142
Packaging and Labeling Information ............................................................... 143
Clinical Supplies Disclosure............................................................................... 144
Storage and Handling Requirements................................................................ 144
Discard/Destruction/Returns and Reconciliation ............................................ 144
Standard Policies................................................................................................. 144
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 144
Confidentiality..................................................................................................... 144
Confidentiality of Data ..................................................................................... 144
Confidentiality of Subject Records................................................................... 145
Confidentiality of Investigator Information...................................................... 145
Confidentiality of IRB/IEC Information........................................................... 145
Compliance with Financial Disclosure Requirements..................................... 145
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Compliance with Law, Audit and Debarment ................................................. 146
Compliance with Trial Registration and Results Posting Requirements...... 148
Quality Management System............................................................................. 148
Data Management............................................................................................... 148
Publications ......................................................................................................... 148
11.0
LIST OF REFERENCES....................................................................................... 150
12.0
APPENDICES......................................................................................................... 157
Code of Conduct for Clinical Trials.................................................................. 157
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 160
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 164
ECOG Performance Status................................................................................ 175
Cockcroft-Gault Formula .................................................................................. 176
Abbreviations ...................................................................................................... 177
MASCC 2016 Guidelines.................................................................................... 181
Country-specific Requirements......................................................................... 182
Japan-specific Requirements............................................................................. 182
13.0
SIGNATURES......................................................................................................... 185
Sponsor's Representative ................................................................................... 185
Investigator.......................................................................................................... 185
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LIST OF TABLES
Table 1
Chemotherapy Dose Level Definitions for Arm 3............................................. 41
Table 2
Chemotherapy Dose Level Definitions for Arm 5............................................. 42
Table 3
Adequate Organ Function Laboratory Values ................................................... 51
Table 4
Trial Treatment .................................................................................................. 58
Table 5
Dose Escalation and Confirmation Rules Based on the Modified Toxicity 
Probability Interval Design................................................................................ 62
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ................................................................. 68
Table 7
Pembrolizumab and MK-7684/MK-7684A Infusion Reaction Treatment 
Guidelines .......................................................................................................... 71
Table 8
Recommended 
Dose 
Modifications 
for 
Chemotherapy-related 
Hematological Toxicities................................................................................... 74
Table 9
Recommended 
Dose 
Modifications 
for 
Chemotherapy-related 
Non-hematological Toxicities............................................................................ 75
Table 10
Laboratory Tests .............................................................................................. 123
Table 11
Evaluating Adverse Events.............................................................................. 133
Table 12
Product Descriptions........................................................................................ 143
Table 13
Japan-specific MK-7684 Dose Modification and Treatment Discontinuation 
Guidelines for Treatment-related Adverse Events........................................... 182
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
Title Page
Section 12.1 
Throughout
Code of Conduct for Clinical Trials
Throughout
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.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase 1
Trial of MK-7684
as Monotherapy and in Combination with 
Pembrolizumab in Subjects with Advanced Solid Tumors
Sponsor Product 
Identifiers
MK-7684 (N/A)
MK-3475 (Pembrolizumab)
MK-7684A (N/A)
Trial Phase
Phase 1/1b
Clinical 
Indication
Part A (dose escalation and confirmation phase): The treatment of subjects with 
advanced solid tumors
Part B (expansion phase): The treatment of subjects with non-small cell lung 
cancer (NSCLC), 
 
Trial Type
Interventional
Type of control
None
Route 
of 
administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment 
Groups
There are 5 treatment arms in this trial:
Arm 1: MK-7684
Arm 2: MK-7684 + pembrolizumab
During Part A (dose escalation and confirmation phase):
Subjects with advanced solid tumors will be allocated to either Arm 1 or Arm 2.
During Part B (expansion phase):
Subjects with NSCLC will be allocated to either Arm 1 or Arm 2.
Number of trial 
subjects
Approximately up to 492 subjects will be enrolled.
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Estimated duration 
of trial
The Sponsor estimates that the trial will require approximately 9 years from the 
time the first subject (or the subject's legally acceptable representative) provides 
documented informed consent until the last subject’s last study-related contact.
Duration 
of 
Participation
Each subject will participate in the trial from the time the subject (or the subject’s 
legally acceptable representative) provides documented informed consent through 
the final protocol-specified contact. During Part A (dose escalation and 
confirmation phase) and Part B (expansion phase), after a screening period of up to 
28 days, each subject will be allocated to a treatment arm (MK-7684 monotherapy
[Arm 1], MK-7684 in combination with pembrolizumab [Arm 2], 
 
 
 
 Study 
treatment in all arms will be given on Day 1 of each 3-week cycle, 
 
 In Arms 1 
and 2, subjects may receive up to 35 cycles of study treatment with MK-7684
and/or pembrolizumab. 
 
 
 
 
 
 
 
 
 
 
 
Study treatment will continue until disease progression, unacceptable adverse 
event(s) (AEs), intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw treatment, subject withdrawal of
consent, pregnancy of the subject, noncompliance with trial treatment or procedure 
requirements, subject completes treatment, or administrative reasons requiring 
cessation of treatment. Subjects who discontinue MK-7684 in the monotherapy 
arm due to disease progression may, at the investigator’s discretion and after 
consultation with the Sponsor, switch to combination treatment (Arm 2).
After treatment discontinuation, subjects will be monitored for AEs and serious 
adverse events (SAEs) for 90 days. Subjects who initiate new anticancer therapy 
less than 30 days after study treatment discontinuation will be monitored for 
AEs/SAEs for 30 days. Subjects who initiate new anticancer therapy between 
30 days and 90 days after study treatment discontinuation will be monitored for 
AEs/SAEs until the day new anticancer therapy is initiated. Subjects who 
discontinue treatment for reasons other than confirmed disease progression will 
have post-treatment follow-up for disease status until disease progression, 
initiating a new anticancer therapy, withdrawing consent for trial participation, or 
becoming lost to follow-up, whichever occurs first. After confirmed disease 
progression, each subject will be contacted by telephone every 12 weeks for 
survival until withdrawal of consent to participate in the trial, becoming lost to 
follow-up, death, or the end of the trial, whichever occurs first.
Randomization Ratio
All subjects in Part A, and all subjects in Part B 
, 
will be allocated to treatment without randomization.
 
 
A list of abbreviations used in this document can be found in Section 12.6.
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2.0 TRIAL DESIGN
Trial Design
This is a first-in-human, multi-site, open-label trial of MK-7684 as monotherapy, in 
combination with pembrolizumab, or in combination with pembrolizumab and standard of 
care (SOC) chemotherapy in subjects with a histologically or cytologically confirmed 
diagnosis of a solid tumor. The trial will include 2 parts: Part A will be a dose escalation and 
confirmation phase to examine safety, tolerability, and identify a preliminary recommended 
Phase 2 dose (RPTD; [Section 5.2.1.2]) and Part B will be an expansion phase to further 
examine 
safety 
and 
exploratory 
efficacy 
in 
specific 
tumor 
types/populations 
(Section 5.2.1.3). Part A will test MK-7684 as monotherapy (Arm 1) and combination 
therapy with pembrolizumab (Arm 2) in subjects with advanced solid tumors, 
 
 
 
 
 
 
Part B will assess the safety and antitumor efficacy of MK-7684 monotherapy
(Arm 1) in subjects with NSCLC, the safety and antitumor efficacy of MK-7684 in 
combination with pembrolizumab (Arm 2) in subjects with NSCLC, 
 
 
 
 
 
 
 
 
 
Part A (Dose Escalation and Confirmation)
Advanced Solid Tumors (Part A, Arms 1 and 2)
Subjects with advanced solid tumors of all types will be allocated by non-random assignment 
to receive escalating doses of MK-7684 as monotherapy (Arm 1) or in combination with 
pembrolizumab (Arm 2) centrally using an interactive voice response system/integrated web 
response system (IVRS/IWRS). Details of the enrollment process are described in 
Section 5.3. A modified toxicity probability interval (mTPI) design [1] with a target 
dose-limiting toxicity (DLT) rate of approximately 30% will be applied to identify a 
preliminary RPTD of MK-7684 in Arm 1 and Arm 2. Five pre-determined dose levels of 
MK-7684 will be explored independently in each arm: 2.1 mg, 7 mg, 21 mg, 70 mg, and 
210 mg. A single additional dose level of 700 mg may be added after the completion of the 
DLT period for 210 mg and provided that the DLT rate at 210 mg based on Table 5 grants 
the decision to “escalate”. Intermediate doses may be explored if one of the pre-planned 
doses is deemed unacceptably toxic and the immediate lower dose is deemed too low.
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During dose escalation, a minimum of 3 subjects are required at each dose, and up to 
6 subjects may be enrolled in the same cycle at each new dose. As outlined in Table 5, based 
on the mTPI design, the number of subjects who are enrolled at a dose but are not yet fully 
evaluable for DLT assessment may not exceed the number of remaining subjects who are at 
risk of developing a DLT before the dose would be considered unacceptably toxic. Dose 
escalation and confirmation in Arms 1 and 2 will end after 14 subjects have been treated at 
any of the selected doses (including intermediate doses) as long as the decision based on 
Table 5 is to “stay” or “escalate”. The pool-adjacent-violators algorithm [1] will be used to 
estimate the DLT rates across doses in each treatment arm under the assumption of 
monotonicity between DLT rates and dose levels. The dose with an estimated DLT rate 
closest to 30% may be treated as a preliminary RPTD. The totality of the data will be 
considered before deciding on the dose(s) to carry forward to Part B. The preliminary RPTD 
in Arm 2 will not exceed, but may equal, the preliminary RPTD in Arm 1.
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Part B (Dose Expansion)
Part B, Arms 1 and 2 will use the preliminary RPTDs identified for MK-7684 using the 
mTPI design in Part A.
 
PD-1/PD-L1 inhibitor treatment-refractory NSCLC (Part B, Arms 1 and 2)
Subjects with PD-1/PD-L1 inhibitor treatment-refractory NSCLC will be allocated by 
non-random assignment to receive MK-7684 at the preliminary RPTD as monotherapy 
(Arm 1) or in combination with pembrolizumab (Arm 2) centrally using IVRS/IWRS;
IVRS/IWRS will alternate assignment of subjects between Arm 1 and Arm 2 starting with 
Arm 1 until a maximum of 40 subjects are enrolled in each arm.
PD-1/PD-L1 inhibitor treatment-naïve NSCLC, 
 
Subjects with PD-1/PD-L1 inhibitor treatment-naïve NSCLC (n=14-40), 
 
 
 
will be allocated to receive MK-7684 at the preliminary RPTD in 
combination with pembrolizumab (Arm 2). Enrollment of subjects with NSCLC 
 
will use an adaptive design. In the adaptive design, if 3 or more objective responses are 
observed out of the first 14 subjects in a cohort based on Response Evaluation Criteria in 
Solid Tumors (RECIST), version 1.1, the corresponding cohort may continue enrolling up to 
a maximum of 40 subjects. If 3 objective responses are not observed in the first 14 subjects 
of these cohorts, the Sponsor will evaluate all available data to determine whether or not to 
expand enrollment.
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Each treatment arm will begin Part B once a preliminary RPTD for that arm is identified in 
Part A. To maximize enrollment efficiency, once a possible preliminary RPTD is reached, 
Part A enrollment of subjects with advanced solid tumors of all types will be restricted to the 
tumor indications specified in Inclusion Criterion 1 for Part B (Section 5.1.2), 
 
 
. Part A subjects eligible for the Part B tumor cohorts who receive the 
preliminary RPTD may be used toward enrollment caps in Part B. Data from subjects treated 
at the preliminary RPTDs in Part A will be included in the analysis of Part B if they meet the 
specifications described in Inclusion Criterion 1 (Section 5.1.2). Final RPTDs for MK-7684, 
both when used as monotherapy and in combination with pembrolizumab, will be determined 
using PK and pharmacodynamic (PD) endpoints, as well as all available safety data from 
subjects in Part A and Part B, including DLT rates and the cumulative incidence of late 
toxicities (i.e., toxicities that occur after the 21-day DLT observation period).
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The Sponsor may prematurely terminate enrollment into a cohort for administrative reasons; 
in such cases, the sites will be notified via an administrative letter. All subjects already 
enrolled or in the screening period will be allowed to continue in the study.
All study treatments in Parts A and B will be administered by intravenous (IV) infusion on 
Day 1 of each 21-day cycle with the exception of etoposide which will be given on Days 1, 2 
and 3 of each 21-day cycle. The dose of pembrolizumab in Arms 2, 3 and 5 will remain fixed 
at 200 mg.
Subjects in both parts of the trial may receive up to 35 cycles of treatment with MK-7684 
(Arms 1-5) and pembrolizumab (Arms 2-5),
 
 
 
 
Study treatment will continue until disease progression, unacceptable AE(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
treatment, subject withdrawal of consent, pregnancy of the subject, noncompliance with trial 
treatment or procedure requirements, subject completes treatment, or administrative reasons 
requiring cessation of treatment. Arm 1 subjects with disease progression following treatment 
with MK-7684 monotherapy may be eligible to cross over to combination treatment. Subjects 
eligible for cross-over must have received at least 2 cycles of MK-7684 monotherapy and 
must have radiographic imaging to document disease progression by RECIST, version 1.1 
and to establish a new imaging baseline prior to cross-over. Subjects who permanently 
discontinue MK-7684 monotherapy for any reason other than radiologic disease progression 
are not eligible for cross-over.
After treatment discontinuation, subjects will be monitored for AEs and SAEs for 90 days. 
Subjects who initiate new anticancer therapy less than 30 days after study treatment 
discontinuation will be monitored for AEs/SAEs for 30 days. Subjects who initiate new 
anticancer therapy between 30 days and 90 days after study treatment discontinuation will be 
monitored for AEs/SAEs until the day new anticancer therapy is initiated.
Subjects who discontinue treatment for reasons other than confirmed disease progression will 
have post-treatment follow-up for disease status until disease progression, initiating a new 
anticancer therapy, withdrawing consent for trial participation, or becoming lost to follow-up, 
whichever occurs first.
After confirmed disease progression, each subject will be contacted by telephone every 
12 weeks for survival until withdrawal of consent to participate in the trial, becoming lost to 
follow-up, death, or the end of the trial, whichever occurs first.
The trial will be conducted in conformance with Good Clinical Practice (GCP). Adverse 
events will be evaluated according to criteria outlined in the National Cancer Institute’s 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
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Trial Diagram
The trial design is depicted in Figure 1.
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Figure 1
Trial Design
AUC = area under the curve; 
; IV = intravenous; mTPI = modified toxicity probability 
interval; NSCLC = non-small cell lung cancer; ORR = overall response rate; PD-1 = programmed death 1; 
RPTD = recommended 
Phase 2 
dose;
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male and female subjects with advanced solid tumors who are at least 18 years of age:
Primary Objective(s) & Hypothesis(es)
1) Objective: To determine the safety and tolerability of MK-7684 monotherapy and to 
establish an RPTD
2) Objective: To determine the safety and tolerability of MK-7684 in combination with 
pembrolizumab and to establish an RPTD for MK-7684 when used in combination 
with pembrolizumab
3)
 
Secondary Objective(s) & Hypothesis(es)
1) Objective: To characterize the pharmacokinetic (PK) profile of MK-7684 when used 
as monotherapy in Arm 1, in combination with pembrolizumab in Arm 2, 
 
 
 
2) Objective: To characterize the PK profile of pembrolizumab when used in
combination with MK-7684 in Arm 2, 
 
 
3) Objective: To evaluate the antitumor activity of MK-7684 when used as 
monotherapy in Arm 1, in combination with pembrolizumab in Arm 2, 
 
 
using Response 
Evaluation Criteria in Solid Tumors (RECIST), version 1.1 as assessed by 
investigator review and measured by overall response rate (ORR)
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Exploratory Objectives
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4.0 BACKGROUND & RATIONALE
Background
Refer to the MK-7684 Investigator’s Brochure (IB) and the pembrolizumab IB for detailed 
background information on MK-7684, MK-7684A, and pembrolizumab.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformation has been known for decades [2]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [3] [4] [5] [6] [7] [8] [9]. In particular, the presence of CD8+ T cells 
and the ratio of CD8+ effector T cells (Teffs)/FoxP3+ regulatory T cells (Tregs) seems to 
correlate with improved prognosis and long-term survival in solid malignancies such as 
ovarian, colorectal, and pancreatic cancers, hepatocellular carcinoma, malignant melanoma, 
and renal cell carcinoma (RCC). Tumor-infiltrating lymphocytes can be expanded ex vivo 
and re-infused, inducing durable objective tumor responses in cancers such as melanoma [10]
[11].
MK-7684 Background
MK-7684 is a humanized, antagonist monoclonal antibody (mAb) that binds to the immune 
checkpoint receptor, TIGIT, and blocks the interaction between TIGIT and its ligands. This 
human immunoglobulin G1 (IgG1)
antibody is being developed as a cancer
immunotherapeutic with the potential to be used as monotherapy or to be combined with 
pembrolizumab (a humanized anti-PD-1 receptor antibody) to increase benefit to patients 
with various tumor types.
TIGIT is an immunomodulatory receptor expressed primarily on activated CD4+ and CD8+ 
T cells, natural killer (NK) cells, and natural killer T (NKT) cells. Its structure reveals a 
single extracellular immunoglobulin domain, a transmembrane region, an immunoglobulin 
tail tyrosine (ITT)-like phosphorylation motif, and an immunoreceptor tyrosine-based 
inhibitory motif (ITIM). 
TIGIT forms part of a co-stimulatory network that consists of a positive (CD226) and 
negative (TIGIT) immunomodulatory receptor on T cells, and ligands (CD155 and CD112) 
expressed on tumor cells and antigen presenting cells [12]. Whereas CD226 is widely 
expressed on most immune cells, TIGIT is highly expressed on memory T cells, Tregs, 
NK cells, and NKT cells [13] [14]. CD155/PVR (poliovirus receptor) and CD112/PVRL-2 
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(poliovirus receptor-related 2) are two nectin family members that are widely expressed both 
on cells of the hematopoietic system and on fibroblasts and endothelial cells. Functionally, 
these receptor ligands are involved in cell adhesion and motility. CD155 is reported to be 
overexpressed in several tumor types, and has been found to be induced by Ras activation 
and genotoxic stress [15] [16] [17] [18] [19].
 
 
In addition, TIGIT is highly co-expressed with PD-1 on both CD4+ and CD8+ TILs 
including Tregs, in mouse and human tumors, and has been reported to be co-expressed with 
PD-1 and T-cell immunoglobulin and mucin domain containing-3 (Tim-3) on the TILs with 
the most exhausted phenotype [20] [21].
 
 
 We hypothesize, therefore, that combining MK-7684 with pembrolizumab will 
offer substantially augmented antitumor efficacy.
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 programmed cell death ligand 2 
(PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent 
receptor blocking activity for PD-1.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated antigen-4
(CTLA-4), which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [22] [23].
The structure of murine PD-1 has been resolved [24]. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig variable-type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 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 [25] [26] [27] [28]. The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins [29] [30].
As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in a variety of cancers.
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Lung Cancer: Epidemiology and Current Therapeutic Options
The global incidence of lung cancer was 1.8 million in 2012, resulting in an estimated 
1.6 million deaths [31]. In the United States (US), the 2018 estimated incidence of new 
diagnoses was 234,030, and the estimated number of deaths was 154,050 [32].
NSCLC
NSCLC represents approximately 80% to 85% of all lung cancers. Of the patients with 
NSCLC, tumor histology is approximately 40% to 60% adenocarcinoma, 10% to 15% 
squamous, 5% neuroendocrine, and the rest, “not otherwise specified” [33].
Approximately 70% of patients with NSCLC have advanced disease not amenable to surgical 
resection at the time of diagnosis. From 2006 to 2012, the overall 5-year relative survival rate 
for lung cancer in the US was 17.7%. Five-year relative survival rates were 55% for 
localized, 28% for regional, 4.3% for distant, and 7.4% for unstaged [34].
In the open-label Phase 3 study KEYNOTE-024, treatment with pembrolizumab resulted in
statistically significant increases in overall survival (OS) and PFS in treatment-naïve 
participants with metastatic NSCLC whose tumors expressed high levels of PD-L1 (tumor 
proportion score [TPS] ≥50%) with no epidermal growth factor receptor (EGFR) or 
anaplastic lymphoma kinase (ALK) genomic tumor aberrations compared to treatment with 
SOC platinum-based chemotherapy [35]. Furthermore, in the pembrolizumab treatment arm, 
treatment-related AEs of any grade were less frequent (occurring in 73.4% vs 90.0% of 
patients), as were Grades 3, 4, or 5 treatment-related AEs (26.6% vs 53.3%). Data from this 
study led to regulatory approval of pembrolizumab for this indication in the US and other 
countries around the world.
In the randomized Phase 2 cohort, Cohort G, of the open-label study, KEYNOTE-021, 
pembrolizumab plus pemetrexed and carboplatin showed statistically significant increases in 
objective response rate ([ORR]; 55% vs 29%) and PFS (8.9 vs 13.0 months, HR 0.53 [95% 
confidence interval [CI] 0.31 to 0.91]) compared to pemetrexed and carboplatin alone in 
participants with advanced non-squamous NSCLC, regardless of PD-L1 status [36]. The 
incidence of Grades ≥3 treatment-related AEs was similar between groups. Moreover, a 
recent update of data from KEYNOTE-021 showed that an OS benefit has also been seen 
when pembrolizumab is added to chemotherapy (hazard ratio [HR] 0.59; 95% CI 0.34 to 
1.05; p=0.03) [37]. These findings were confirmed in a randomized Phase 3, double-blinded 
study, KEYNOTE-189, that showed that treatment with pembrolizumab plus pemetrexed and 
either carboplatin or cisplatin significantly prolonged OS (HR 0.49; 95% CI 0.38 to 0.64; 
p<0.001) and PFS (HR 0.52; 95% CI 0.43 to 0.64; p<0.001) compared with SOC
chemotherapy as first-line treatment of metastatic, non-squamous NSCLC [38]. Adverse 
events of Grades ≥3 occurred in 67.2% of the patients in the pembrolizumab-containing arm 
and in 65.8% of patients in the placebo treatment arm. These results established 
pembrolizumab plus chemotherapy as an efficacious option for first-line treatment in patients 
with non-squamous NSCLC.
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Pembrolizumab (MK-3475) Preclinical and Clinical Trials
Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor 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 Teff
function in vivo [54] [55] [56] [57] [25] [58]. 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 an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA™ (pembrolizumab) is 
indicated for the treatment of patients across a number of indications.
No hematology changes have been observed in non-human primate safety studies of 
pembrolizumab; however, slight focal mononuclear cell infiltrates in multiple tissues that 
were considered an exacerbation of spontaneously occurring background mononuclear 
changes were detected in individual animals. Based on clinical experience with 
pembrolizumab, immune-mediated adverse effects may occur in patients. In clinical trials, 
the main immune-mediated adverse effects associated with pembrolizumab included low 
grade and low incidence of immune-mediated endocrinopathies, pneumonitis, colitis, 
hepatitis, and nephritis. Most immune-mediated adverse effects were reversible and managed 
with interruptions of pembrolizumab and administration of corticosteroids and/or supportive 
care. Immune-mediated adverse effects affecting more than one body system can occur 
simultaneously. While these immune-mediated adverse effects are not unexpected based on 
the mechanism of action of anti-PD-1 activity, they are fundamentally different in nature 
from phenotypes developed in PD-1 KO mice. In those models, PD-1 deficiency is 
associated with the onset of progressive autoimmune diseases. An immune-mediated dilated 
cardiomyopathy can be detected as early as 5 weeks of age in PD-1-/-mice on a BALB/c 
background [59] while lupus-like proliferative arthritis and glomerulonephritis developed in 
aging PD-1-/-C57BL/6 mice [60]. Also, earlier onset of diabetes and inflammatory insulitis 
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were observed in PD-L1/PD-L2-/-non-obese diabetic mice, which indicates that the loss of 
the PD-1 pathway leads to an accelerated disease course [61].
Ongoing Clinical Trials
MK-7684 Ongoing Clinical Trials
This trial represents the first-in-human use of MK-7684.
Pembrolizumab Ongoing Clinical Trials
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.
Rationale
Rationale for the Trial and Selected Subject Population
MK-7684 is being developed for treatment of solid tumors. This is the first-in-human trial of 
MK-7684 and is designed to assess the safety, tolerability, PK, and PD of escalating doses of 
MK-7684 when used as monotherapy and in combination with pembrolizumab in subjects 
with advanced solid tumors that have not responded to conventional therapy. The effect of 
MK-7684 on tumor size will also be explored.
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Overall, the Part B tumor types were selected based on expression of TIGIT and its receptors
CD155 and CD112, known susceptibility of tumor types to immune checkpoint therapies, 
unmet medical need, and/or preliminary signs of clinical activity in the Part A portion of the 
study.
The NSCLC cohort was chosen based on its high expression of TIGIT and known 
responsiveness to PD-1 blockade. Both PD-1/PD-L1 inhibitor treatment-refractory and 
treatment-naïve populations are being assessed.
PD-1/PD-L1 inhibitor treatment-refractory NSCLC is an indication with a high unmet 
medical need, with reported objective response rates of ~10% for second-line chemotherapies
[65]. There is scientific evidence that the expression of alternate immune checkpoints 
including TIGIT may increase after PD-1 blockade, suggesting that TIGIT could function as 
an escape mechanism to PD-1 therapy. TIGIT blockade may, therefore, reverse PD-1 
resistance in some cases [20]. Since further PD-1/PD-L1 inhibitor monotherapy is not 
expected to benefit patients who have radiographic progression on a PD-1/PD-L1 inhibitor 
agent, both Arm 1 (MK-7684 monotherapy) and Arm 2 (MK-7684 and pembrolizumab 
combination therapy) will be tested. The intention is to assess preliminary efficacy in this 
population, and to compare the clinical efficacy of MK-7684 monotherapy to MK-7684 and 
pembrolizumab combination therapy in a uniform population.
The PD-1/PD-L1 inhibitor treatment-naïve Arm 2 cohort will assess activity of MK-7684 in 
combination with pembrolizumab. The intention is to determine whether adding MK-7684 to 
pembrolizumab provides added efficacy benefit to pembrolizumab alone, since a 
chemotherapy-free treatment option is preferable for some patients including those that are 
elderly, frail, or those with significant co-morbidities.
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Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the IB and informed consent documents.
Rationale for Dose Selection/Regimen/Modification
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0
20
40
60
80
100
0.00001
0.0001
0.001
0.01
0.1
1
10
100
1000
Time (days)
Predicted MK-7684
Concentration (g/mL)
Cmax @ NOAEL
10 mg/kg MK-7684
3 mg/kg MK-7684
1 mg/kg  MK-7684
0.3 mg/kg MK-7684
0.1 mg/kg MK-7684
0.03 mg/kg MK-7684
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Rationale for Preliminary MK-7684 RPTD (200 mg)
Based on the totality of available data, a preliminary MK-7684 RPTD of 200 mg was defined 
for Part B in select tumor types. The dosing recommendation was based on preliminary PK, 
safety, and efficacy data.
Preliminary PK profiles of MK-7684 suggested that target-mediated drug disposition of 
MK-7684 was saturated at the 200-mg dose. Saturation of target-mediated drug disposition 
reflects saturation of the target (TIGIT).
Available clinical safety data indicate that MK-7684 was well tolerated at doses up to and 
including 700 mg, both when used as monotherapy and in combination with pembrolizumab. 
No DLTs were observed at any of the MK-7684 doses tested either as monotherapy or in 
combination with pembrolizumab during dose escalation and confirmation, and the MTD 
was not reached. Reported AEs were consistent with those observed in subjects treated with 
pembrolizumab monotherapy in previous studies [71] and with those expected for patients 
with advanced cancers. No obvious dose-dependency of AE severity or frequency was 
observed.
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Clinical efficacy was observed at the 200-mg dose level both during dose escalation and 
confirmation in subjects with advanced solid tumors of all types and during dose expansion 
in subjects with specific tumor types. Responses observed in PD-1/PD-L1 inhibitor 
treatment-refractory NSCLC, especially in subjects treated with MK-7684 monotherapy, 
demonstrate clinical antitumor activity at the 200-mg dose.
Rationale for Pembrolizumab Dose
The planned dose of pembrolizumab for this study is 200 mg given once every 3 weeks. 
Based on the totality of data generated in the Keytruda development program, 200 mg given 
once every 3 weeks is the appropriate dose of pembrolizumab across all indications and 
regardless of tumor type. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose-efficacy and 
exposure-efficacy relationships from doses of 2 mg/kg given once every 3 weeks to 
10 mg/kg given once every 2 weeks;
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg given once every 3 weeks across multiple indications; and
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK analysis) 
at 200 mg given once every 3 weeks.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects with either 
melanoma or NSCLC were enrolled, covering different disease settings (i.e., treatment-naïve, 
previously treated, PD-L1-enriched, and all-comers) and different treatment settings (i.e., 
monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg given 
once every 3 weeks with 10 mg/kg given once every 3 weeks (KN001 B2, KN001 D, 
KN002, KN010, and KN021), and 3 studies compared 10 mg/kg given once every 3 weeks
with 10 mg/kg given once every 2 weeks (KN001 B3, KN001 F2, and KN006). All of these 
studies demonstrated flat dose-response and exposure-response relationships across the doses 
studied representing an approximate 5-fold to 7.5-fold difference in exposure. The 2-mg/kg 
(or 200-mg fixed dose) given once every 3 weeks provided similar responses to the highest 
doses studied. Subsequently, flat dose-response and exposure-response relationships were 
also observed in other tumor types including head and neck cancer, bladder cancer, gastric 
cancer, and classical Hodgkin’s lymphoma, confirming 200 mg given once every 3 weeks as 
the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and 
not by direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg given once every 
3 weeks. First, PK data in KN001 evaluating target-mediated drug disposition conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
given once every 3 weeks. Second, a physiologically-based PK analysis was conducted to 
predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expressions. 
This evaluation concluded that pembrolizumab at 200 mg given once every 3 weeks achieves 
full PD-1 saturation in both blood and tumor.
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Finally, population PK analysis of pembrolizumab which characterized the influence of body 
weight and other subject covariates on exposure, has shown that fixed dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200-mg given once every 3 weeks dose and the 2-mg/kg 
given once every 3 weeks dose. Supported by these PK characteristics, and given that fixed
dose has advantages of reduced dosing complexity and reduced potential of dosing errors, the 
200-mg given once every 3 weeks fixed dose was selected for evaluation across all 
pembrolizumab protocols.
No dose reduction is allowed for pembrolizumab in this trial.
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Rationale for Endpoints
Efficacy Endpoints
Overall response rate is a secondary efficacy endpoint for this trial. Exploratory endpoints 
include DOR and PFS. Tumor response will be assessed by investigators using RECIST, 
version 1.1.
 
 
RECIST guidelines, initially published in 2000 (version 1) and updated in 2009 (version 1.1), 
were established by the RECIST working group, a collection of academic investigators, 
cooperative groups, industry, and government authorities. These guidelines are widely 
considered the gold standard for quantitative assessment of changes in tumor burden in 
response to anticancer therapeutic agents.
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Safety Endpoints
The primary objectives of this trial include characterizing the safety and tolerability of 
MK-7684 when used as monotherapy and in combination with pembrolizumab
 
in subjects with 
advanced solid tumors. 
 
 
 
 
 
 
The primary safety analyses will be based on subjects who experience toxicities as defined 
by CTCAE, version 4.0. Safety will be assessed by quantifying the toxicities and grades of 
toxicities experienced by subjects who receive MK-7684 or 
.
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 
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 7.2.3.2.
Pharmacokinetic Endpoints
Secondary objectives of this trial are to characterize the PK profiles of MK-7684 when used 
as monotherapy in Arm 1, in combination with pembrolizumab in Arm 2
 
 
 
 
 
 
The concentrations of these agents will serve as the primary readout for the PK, and this data 
will be used to derive PK parameters of MK-7684 alone and in combination. Furthermore, 
the results of these analyses will be used in conjunction with the PD, safety, and exploratory 
endpoints to help assess future dosing strategies for MK-7684.
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Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of Future Biomedical Research are presented in Section 12.2 - Collection and Management 
of Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
Benefit/Risk
It cannot be guaranteed that subjects 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(s).
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with advanced solid tumors who are at least 18 years of age will be 
enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. For Part A subjects enrolled prior to Amendment 7, must meet the following 
criterion:
Have a histologically or cytologically confirmed metastatic solid tumor for 
which there is no available therapy that is expected to convey clinical benefit.
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For Part B (and for Part A, once a decision is made to restrict the tumor types in 
Part A) – Have one of the following tumor types:
a.
Advanced metastatic non-small cell lung cancer (NSCLC) that meets the 
criteria described below. Subjects who have EGFR or ALK mutant tumors 
should have received an approved targeted therapy.
i. [Arm 1 & Arm 2] - PD-1/PD-L1 inhibitor treatment-refractory
subjects must have progressed on prior anti-PD-1/PD-L1 therapy 
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(Arms 1 and 2). PD-1/PD-L1 inhibitor treatment-refractory disease is
defined as (subjects must meet all of the following criteria):
a.
Have received at least 2 doses of anti-PD-1/PD-L1 mAb at a local 
regulatory agency-approved dose and schedule.
b. Have progressive disease after anti-PD-1/PD-L1 mAB defined 
according to RECIST, version 1.1. The initial evidence of PD is to 
be confirmed by a second assessment no less than 4 weeks from 
the date of the first documented PD, in the absence of rapid clinical 
progression. Note: This determination is made by the investigator. 
If PD is confirmed, the initial date of PD documentation will be 
considered the date of disease progression.
c.
Have documented disease progression within 24 weeks of the last 
dose of anti-PD-1/PD-L1 mAb. Subjects who were re-treated with 
anti-PD-1/PD-L1 mAb and subjects who were on maintenance 
with anti-PD-1/PD-L1 mAb will be allowed to enter the trial as 
long as there is documented PD within 24 weeks of the last 
treatment date (with anti-PD1/PD-L1 therapy).
ii. [Arm 2] - PD-1/PD-L1 inhibitor treatment-naïve subjects (Arm 2 only) 
may be untreated or could have received and progressed on 1 prior 
platinum-containing chemotherapy regimen, but must not have 
received prior anti-PD-1/PD-L1 therapy.
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The Sponsor may prematurely terminate enrollment into a cohort for administrative 
reasons; in such cases, the sites will be notified via an administrative letter. All 
subjects already enrolled or in the screening period will be allowed to continue in the 
study.
2. Have measurable disease by RECIST.
3. Be male or non-pregnant and non-breast feeding female, >18 years of age on the day 
of providing documented informed consent.
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
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5. Have adequate organ function as defined in Table 3 during screening. Screening 
laboratory specimens must be collected within 7 days prior to the start of study 
treatment.
Table 3
Adequate Organ Function Laboratory Values
System / Parameter
Laboratory Value
HEMATOLOGICAL
Absolute neutrophil count (ANC)
>1500/µL
Platelet count
>100 000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusions
within 2 weeks of treatment initiation
RENAL
Creatinine OR
Measured or calculated creatinine clearance 
(CrCl)1
NOTE: Glomerular filtration rate (GFR) can 
be used in place of creatinine or CrCl
≤1.5 × institutional upper limit of normal (ULN) 
OR
≥50 mL/min for subjects with creatinine levels 
>1.5 × institutional ULN (all cohorts except 
ES-SCLC)
≥60 mL/min for subjects with creatinine levels 
>1.5 × institutional ULN (subjects with ES-SCLC 
enrolled as part of Amendment 12)
HEPATIC
Total bilirubin
OR
Direct bilirubin
Total bilirubin ≤1.5 × ULN 
OR
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 × ULN
Alanine aminotransferase (ALT) or serum 
glutamic pyruvic transaminase (SGPT)
AND
Aspartate aminotransferase (AST) or serum 
glutamic oxaloacetic transaminase (SGOT) 
≤2.5 × ULN 
OR
≤5 × ULN for subjects with liver metastases
COAGULATION
International Normalized Ratio (INR) or
Prothrombin time (PT)
≤1.5 × ULN unless the subject is receiving 
anticoagulant therapy
Activated partial thromboplastin time
(aPTT) or Partial thromboplastin time (PTT)
≤1.5 × ULN unless the subject is receiving 
anticoagulant therapy
Note: Assessment of adequate organ function as measured by laboratory testing will be based on laboratory 
results obtained locally at the site. The ULN will be based on local laboratory normal ranges.
1. Creatinine clearance should be calculated using the Cockcroft-Gault Method; refer to Appendix 12.5 for the 
appropriate formula.
6. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior the first dose of study treatment. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
7. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for 
the course of the trial through 120 days after the last dose of MK-7684,
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pembrolizumab, or MK-7684A OR 180 days after the last dose of chemotherapeutic 
agents.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
8. Male subjects with a female partner(s) of childbearing potential must agree to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, 
starting with the first dose of study treatment through 120 days after the last dose of 
MK-7684, pembrolizumab, or MK-7684A OR 180 days after the last dose of 
chemotherapeutic agents.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
9. Be willing and able to provide documented informed consent/assent for the trial. The 
subject may also provide consent/assent for future biomedical research (FBR);
however, the subject may participate in the main trial without participating in FBR.
10. Have provided an archival tumor tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded 
tissue blocks are preferred to slides. Newly obtained biopsies are preferred to 
archived tissue.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior to 
the first dose of study treatment, or has not recovered to CTCAE Grade 1 or better 
from the adverse events due to cancer therapeutics administered more than 4 weeks 
prior to the first dose of study treatment (including subjects who had previous 
immunomodulatory therapy with residual immune-related adverse events [irAEs]). 
Subjects receiving ongoing hormone replacement therapy for endocrine irAEs will 
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not be excluded from participation in this trial. Subjects with Grade 2 or lower 
neuropathy may be eligible.
 
 
2. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
Note: Subjects 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.
3. Has received previous treatment with another agent targeting the TIGIT receptor.
4. Has received previous treatment with an immunomodulatory agent (e.g., 
anti-PD-1/PD-L1 or CTLA-4) and was discontinued from that treatment due to a 
Grade 3 or higher irAE.
 
 
5. Has had a severe hypersensitivity reaction to treatment with another mAb.
6. Is expected to require any other form of antineoplastic therapy while participating in 
the trial.
7. Has had major surgery in the past 4 weeks.
8. Is on chronic systemic steroid therapy in excess of replacement doses (e.g., 
≥10 mg/day of prednisone equivalent), or on any other form of immunosuppressive 
medication. Subjects with reactive airway disease that require intermittent use of 
bronchodilators, inhaled steroids, or local steroid injections will not be excluded from 
the trial.
9. Has a history of a previous additional malignancy, unless potentially curative 
treatment has been completed with no evidence of malignancy for 5 years.
The time requirement of 5 years with no evidence of disease does not apply to:

The tumor for which the subject is enrolled in the trial;

Subjects who underwent successful definitive resection of basal cell carcinoma of 
the skin;

Superficial bladder cancer;

In situ cervical cancer; or

Other in situ cancers.
10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
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provided they are radiologically stable, i.e., without evidence of progression for at 
least 4 weeks by repeat imaging (note that the repeat imaging should be performed 
during study screening), clinically stable and without requirement of steroid treatment 
for at least 14 days prior to first dose of trial treatment.
11. Has an active autoimmune disease or a documented history of autoimmune disease, 
except vitiligo or resolved childhood asthma/atopy. Replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency) is not considered a form of systemic treatment. Subjects 
receiving ongoing hormone replacement therapy for previous PD-1 or CTLA-4 
inhibitor-related endocrine irAEs will not be excluded from participation in this trial.
 
12. Has an active infection requiring systemic treatment.
13. Has interstitial lung disease.
14. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
15. Has symptomatic ascites or pleural effusion. A subject who is clinically stable after
treatment of these conditions (including therapeutic thoracentesis or paracentesis) will 
not be excluded from participation in this trial.
16. Has previously had a stem cell or bone marrow transplant.
17. Has previously had a solid organ transplant.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might, in the opinion of the treating investigator, confound the results of the trial, 
interfere with the subject’s participation for the full duration of the trial, or make trial
participation not in the best interest of the subject.
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19. Is known to be human immunodeficiency virus (HIV)-positive (e.g., HIV 1/2 
antibodies) and/or known to have active chronic or acute hepatitis B (e.g., HBsAg 
reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).
20. Has a known psychiatric and/or substance abuse disorder that would make it difficult 
for the subject to cooperate with the requirements of the trial.
21. Is a regular user (including “recreational use”) of any illicit drugs at the time of
providing documented informed consent, or has a recent history (within the last year) 
of substance abuse (including alcohol), as determined by the treating investigator.
Subjects who use cannabis for medicinal purposes or to treat specific symptoms will 
not be excluded unless it is being abused in the opinion of the treating investigator.
22. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of MK-7684, pembrolizumab, or MK-7684A OR 180 days after the last 
dose of chemotherapeutic agents.
23. Has received a live-virus vaccine within 30 days prior to the first dose of study 
treatment. Seasonal flu vaccines that do not contain live virus are permitted.
24. Has had hormonal cancer therapy (e.g., tamoxifen, leuprolide). within 4 weeks prior 
to the first dose of study treatment.
Trial Treatment(s)
The treatment(s) to be used in this trial are outlined below in Table 4. Detailed instructions 
regarding study drug administration are provided in the Pharmacy Manual.
In the dose escalation and confirmation phase of Part A, an mTPI design with a target DLT 
rate of approximately 30% will be applied to identify a preliminary RPTD of MK-7684 
independently in Arm 1 (MK-7684 monotherapy) and Arm 2 (MK-7684 in combination with 
pembrolizumab). The starting dose of MK-7684 will be 2.1 mg and may proceed, based on 
safety events, to a dose of 700 mg. Intermediate doses may be explored if one of the 
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pre-planned doses is deemed unacceptably toxic and the immediate lower dose is deemed too 
low. The preliminary RPTD of MK-7684 in the combination treatment arm will not exceed, 
but may equal, the preliminary RPTD in the MK-7684 monotherapy treatment arm.
In Part B (expansion phase), the preliminary RPTDs identified for MK-7684 monotherapy 
and combination therapy with pembrolizumab using the mTPI design in Part A will be used
in subjects with NSCLC, 
 as described 
in Inclusion Criterion 1 (Section 5.1.2).
 
 
 
 
 
 If the dose confirmation portion of the Part A mTPI design calls for a 
de-escalation of one or more of these doses, the doses will be modified accordingly. The final 
decision for these doses will be communicated to sites via an administrative letter before 
enrollment into this cohort begins. Subjects in Part B with ES-SCLC will be treated with 
MK-7684 in combination with pembrolizumab, the investigator’s choice of platinum agent
(carboplatin or cisplatin), and etoposide for up to 4 cycles followed by MK-7684 and 
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pembrolizumab for up to an additional 31 cycles. The doses of chemotherapy will be those 
identified using the mTPI design in Part A.
In the combination treatment arms (Arms 2, 3, and 5), in both Part A and Part B (as 
applicable), the dose of pembrolizumab will remain constant at 200 mg. Pembrolizumab will 
be administered first on Day 1 of each cycle, with administration of MK-7684 occurring 
approximately 30 minutes after completion of the pembrolizumab infusion (Arms 2, 3, and 
5).
 
 
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Table 4
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
IMP/NIMP
Arms 1, 2, 3, 
and 5: 
MK-7684
Part A dose 
escalation and 
confirmation:
2.1 mg
7 mg
21 mg
70 mg
210 mg
700 mg 
(tentatively)
Part A non-
squamous 
NSCLC 
enrolled as part 
of 
Amendment 7:
200 mg
Part B 
expansion 
phase:
Preliminary 
RPTDs 
identified in 
Part A
 
 
Every 3 
weeks
IV infusion
Day 1 of each 
21-day cycle for 
up to 35 cycles
Experimental
IMP
Arms 2, 3, 
and 5:
Pembrolizumab
Part A and 
Part B: 200 mg
Every 3 
weeks
IV infusion
Day 1 of each 
21-day cycle for 
up to 35 cycles
Experimental
IMP
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Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
IMP/NIMP
AUC = area 
under 
the 
curve; 
IMP = investigational 
medicinal 
product; 
IV = intravenous; 
NIMP = non-investigational medicinal product; NSCLC = non-small cell lung cancer; RPTD = recommended 
Phase 2 dose; 
Trial treatments should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
All supplies indicated in Table 4 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will 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.
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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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale. There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Dose Escalation and Confirmation
In the dose escalation and confirmation phase of Part A of the trial, an mTPI design [1] with 
a target DLT rate of approximately 30% will be applied to identify a preliminary RPTD of 
MK-7684 in Arm 1 (MK-7684 monotherapy) and Arm 2 (MK-7684 in combination with 
pembrolizumab) in subjects with advanced solid tumors according to the rules outlined in
Table 5.
Five pre-determined dose levels of MK-7684 will be explored independently in each arm: 
2.1 mg, 7 mg, 21 mg, 70 mg, and 210 mg. The dose of 210 mg was chosen based on changes 
to hematology parameters in cynomolgus monkeys, including a transient reduction in 
T lymphocytes in the blood occurring within hours of dosing (see Section 4.0). If safety data 
demonstrate acceptable hematology parameters in humans, an additional cohort dosed at 
700 mg may be added after the completion of the DLT period for 210 mg and provided that 
the DLT rate at 210 mg grants the decision to “escalate”. If dose escalation proceeds to the 
700-mg dose, at least 6 subjects will be enrolled and complete the DLT observation period
with acceptable toxicity rates in each arm before enrollment into the 700-mg cohort of Part B 
begins for the respective arm. At least 3 subjects must enroll at 700 mg in Arm 1 and 
complete the DLT period with acceptable toxicity rates prior to enrollment of subjects at the 
700-mg dose level in Arm 2
Intermediate doses may be explored if one of the pre-planned doses is deemed unacceptably 
toxic and the immediate lower dose is deemed too low. All dose escalation decisions will be 
based on the occurrence of DLTs and will be made jointly by the investigators and the 
Sponsor. The dose of pembrolizumab in Arm 2 will remain constant at 200 mg.
Treatment allocation for Part A will be accomplished by non-random assignment. Enrollment 
into the MK-7684 + pembrolizumab combination treatment arm (Arm 2) will begin once 
2 dose levels of MK-7684 have been tested in the MK-7684 monotherapy arm (Arm 1) and a 
dose escalation decision has been made so that the starting dose of MK-7684 in Arm 2 will 
be at least 2 levels below the dose being tested in Arm 1. When both treatment arms are open 
for enrollment, IVRS/IWRS will alternate subject assignment between Arm 1 and Arm 2 
starting with Arm 1. For example, once the 21-mg dose cohort of Arm 1 (MK-7684 
monotherapy) and the 2.1-mg dose cohort of Arm 2 (MK-7684 + pembrolizumab) are open 
for enrollment, the first subject will be allocated to Arm 1, the second subject will be 
allocated to Arm 2, the third subject will be allocated to Arm 1, etc. An observation period of 
at least 24 hours will occur between treatment initiation in subjects enrolled within each dose 
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level. Each new dose cohort will open for enrollment without delay once the 21-day DLT 
observation period of the previous dose cohort is completed and a dose escalation decision is 
made.
In Table 5, the number of subjects treated is indicated in the columns and the number of 
subjects who experience at least 1 DLT is indicated in the rows. Dosing decisions include
escalate to the next higher dose (E), stay at the current dose (S), de-escalate to the next lower 
dose (D), and de-escalate to a lower dose and never test this dose again (i.e., unacceptably 
toxic dose; DU).
Based on the mTPI design, the number of subjects who are enrolled at a dose but are not yet 
fully evaluable for DLT assessment may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic
(denoted as DU in Table 5). To determine how many more subjects can be enrolled at a dose 
level, one can count steps in a diagonal direction (down and to the right) from the current cell 
to the first cell marked DU.
During dose escalation, a minimum of 3 subjects are required at each dose. Depending on 
accrual rate, 3, 4, 5, or 6 subjects may be enrolled at each new dose until the last of those 
subjects completes the 21-day DLT assessment period. For example, if 3 subjects are 
enrolled at a dose and none of them develops a DLT, then the dose can be escalated to the 
next level without further expansion. If 1 out of the first 3 subjects at a given dose level 
develops a DLT, no more than an additional 3 subjects may be enrolled at this dose level 
until additional DLT data are available since this dose would be considered unacceptably 
toxic if all 3 of the additional subjects experience a DLT (i.e., 4 out of 6 subjects). If 2 out of 
the first 3 subjects at a given dose level develop a DLT, the dose will be de-escalated to the 
next lower level. If 3 out of the first 3 subjects at a given dose level develop a DLT, this dose 
will be considered unacceptably toxic, i.e., the dose will be de-escalated and never 
re-escalated to that dose again. The same principle will be applied whether 3, 4, 5, or 
6 subjects are enrolled in the same dose cohort according to Table 5.
In total, 3 to 14 subjects may be enrolled at a given dose level. The dose of MK-7684 in the 
combination arm (Arm 2) may not be escalated to a dose that is higher than the MK-7684 
dose in the MK-7684 monotherapy arm (Arm 1); however, once dose escalation of MK-7684 
in Arm 1 is stopped, the dose of MK-7684 in Arm 2 may be escalated up to that dose.
To maximize enrollment efficiency, once a possible preliminary RPTD is reached, Part A 
will be restricted to the tumor indications specified in Inclusion Criterion 1 for Part B
(Section 5.1.2),
. These subjects may be used toward 
enrollment caps in Part B. For example, if dose escalation reaches the highest dose level and 
DLT data suggest ‘stay’ or ‘escalate’ based on the mTPI design (Table 5), the remaining 
subjects enrolled in Part A will be restricted to the tumor indications specified in Inclusion 
Criterion 1 for Part B (Section 5.1.2).
Dose escalation and confirmation will end after 14 subjects have been treated at any of the 
selected doses (including intermediate doses) as long as the decision based on Table 5 is to 
stay. The pool-adjacent-violators algorithm [1] that forces the DLT rate estimates to be 
non-decreasing with dose levels and pools adjacent violators for weighted estimates by 
sample size, will be used to estimate the DLT rates across doses in each treatment arm. The 
dose with an estimated DLT rate closest to 30% may be treated as a preliminary RPTD. The 
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totality of the data will be considered before deciding on the dose(s) to carry forward to 
Part B and the escalation schedule may be adjusted based on PD, PK, and safety data 
emerging throughout the trial. The preliminary RPTD of MK-7684 in the combination arm 
(Arm 2) will not exceed, but may equal, the preliminary RPTD in the MK-7684 monotherapy 
arm (Arm 1).
Note that while 30% was the target toxicity rate used to generate the guidelines in Table 5,
the observed rates of subjects with DLTs at any given dose level may be slightly above or 
below 30%.
Table 5
Dose Escalation and Confirmation Rules Based on the Modified Toxicity 
Probability Interval Design
Number of Subjects Treated at Current Dose
Number of Subjects 
with at Least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 30%
Flat non-informative prior Beta (1,1) is used as a prior and ε1=ε2=0.03 [1], [73], [74]
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Expansion Phase
In Part B of the trial, the preliminary RPTDs identified using the mTPI design in Part A will 
be used in subjects with NSCLC, 
 as described in Inclusion Criterion 1 (Section 5.1.2).
The preliminary MK-7684 RPTD(s) identified in Part A, Arm 1 will be tested in 
approximately 40 PD-1/PD-L1 inhibitor treatment-refractory subjects with NSCLC.
The preliminary MK-7684 RPTD(s) identified in Part A, Arm 2 in combination with a fixed 
dose of 200 mg of pembrolizumab will be tested as follows:

In approximately 40 PD-1/PD-L1
inhibitor treatment-refractory
subjects with 
NSCLC.
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
In 14 to 40 PD-1/PD-L1 inhibitor treatment-naïve subjects each with NSCLC 
 
, using an adaptive design. In the adaptive design, if 3 or more objective 
responses are observed out of the first 14 subjects in each indication based on 
RECIST, version 1.1, the corresponding tumor type will continue enrolling up to 
40 subjects. Enrollment will not be held after the first 14 subjects; data will be 
analyzed on an ongoing basis.

 
 
 
 
Each treatment arm will begin Part B once a preliminary RPTD for that arm is identified in 
Part A, 
 
. If a preliminary RPTD cannot be confidently identified in either 
or both of the treatment arms based on the totality of the data from the dose escalation and 
confirmation phase of the study (i.e., the MTD is not reached, high variability is observed for 
PK profiles, or target engagement cannot be confirmed), up to 2 doses of MK-7684 may be 
tested in a subset of the expansion phase at the Sponsor’s discretion.
Data from subjects treated at the preliminary RPTDs in Part A will be included in the 
analysis of Part B if they meet the specifications described in Inclusion Criterion 1 
(Section 5.1.2). Final RPTDs for MK-7684, both when used as monotherapy and in 
combination with pembrolizumab, will be determined using PK and PD endpoints, as well as 
all available safety data from subjects in Part A and Part B, including DLT rates and the 
cumulative incidence of late toxicities (i.e., toxicities that occur after the 21-day DLT 
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observation period). When both treatment arms are open for enrollment to PD-1/PD-L1 
inhibitor treatment-refractory NSCLC subjects in Part B, IVRS/IWRS will alternate subject 
assignment between Arm 1 and Arm 2 starting with Arm 1, until enrollment targets are met.
 
 
 
 
 
 
 
 
 
 
 
Definition of Dose-limiting Toxicity
The CTCAE, version 4.0 will be used to grade the severity of AEs in this trial.
Dose-limiting toxicities will be defined from toxicities observed during the first cycle of 
treatment (21 days) for each dose level explored. See Section 5.9 for rules on replacement of 
subjects who do not complete the DLT observation period.
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT if 
assessed by the investigator to be unrelated to the underlying disease:
1. Any Grade 4 non-hematological toxicity (not laboratory)
2. Any Grade 4 hematological toxicity lasting ≥7 days, except:

Thrombocytopenia

Grade 4 thrombocytopenia of any duration

Grade 3 thrombocytopenia associated with bleeding

Lymphopenia

Grade 4 lymphopenia lasting ≥21 days
3. Any Grade 3 non-hematological toxicity (not laboratory) lasting >3 days despite 
optimal supportive care
4. Any clinically significant Grade 3 or Grade 4 non-hematological
laboratory 
abnormality, if:

Medical intervention is required to treat the subject, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week
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5. Any Grade 3 or 4 febrile neutropenia
6. Any treatment-related AE that causes the subject to discontinue treatment during 
Cycle 1
7. Any treatment-related toxicity that causes a delay in Cycle 2 of >2 weeks
8. Any Grade 5 toxicity
Timing of Dose Administration
Study treatments in all arms will be given on Day 1 of each 3-week cycle, except etoposide 
which will be given on Days 1, 2, and 3 of each 3-week cycle.
In Arms 2, 3, and 5, pembrolizumab will be administered first on Day 1 of each cycle, with 
administration of MK-7684 occurring approximately 30 minutes after completion of the 
pembrolizumab infusion.
In Arm 3, the order of infusions will be as follows: pembrolizumab, MK-7684, pemetrexed, 
then carboplatin. Subjects should receive premedication per the approved product labels for 
pemetrexed and carboplatin.
In Arm 5, the order of infusions will be as follows: pembrolizumab, MK-7684, carboplatin or 
cisplatin, then etoposide. Subjects should receive premedication per the approved product 
labels for carboplatin/cisplatin and etoposide.
In Arm 1, Arm 2, and Arm 4, treatment in Cycle 2 may be administered up to 5 days after the 
scheduled Day 1. Beginning in Cycle 3, treatment may be administered up to 3 days before 
or 5 days after the scheduled Day 1 of each cycle. In Arm 3 and Arm 5, treatment in Cycles 2
through 4 may be administered up to 5 days after the scheduled Day 1. Beginning in Cycle 5, 
treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of 
each cycle. Etoposide must be administered on consecutive days (ie, Days 1, 2, and 3) 
without interruption.
Dose interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study treatment (e.g., elective surgery, unrelated medical events, subject 
vacations, and/or holidays). Subjects should be placed back on study treatment within 
3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The 
reason for interruption should be documented in the subject's case report form (CRF).
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 
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be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation.  
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
In these cases where the toxicity is attributed to pembrolizumab coformulations or IO 
combinations, re-initiation of pembrolizumab as a monotherapy may be considered after 
communication with and agreement by the Sponsor.
Holding Study Interventions: 
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions: 
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 6.
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Table 6
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 
2 or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic in participants 
with hyperglycemia
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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Toxicity Management of Infusion Reactions Related to Pembrolizumab and 
MK-7684/MK-7684A
Pembrolizumab and MK-7684/MK-7684A may cause severe or life-threatening infusion 
reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 
24 hours of completion of the infusion. Toxicity management guidelines for treatment-related
infusion reactions are provided in Table 7.
Table 7
Pembrolizumab
and 
MK-7684/MK-7684A 
Infusion 
Reaction 
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, 
non-steroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, 
IV fluids); prophylactic 
medications indicated 
for ≤24 hours
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 treatment
Participant may be 
premedicated 1.5 hours (± 30 
minutes) prior to infusion 
with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine)
Acetaminophen 
500-1000 mg PO (or 
equivalent dose of 
analgesic)
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 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 treatment
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of study treatment administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 at 
http://ctep.cancer.gov
Dose Modification for Chemotherapy
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 8
and Table 9. These serve only as a guide and do not replace investigator judgment and 
applicable local label recommendations, if more stringent. Please refer to Table 1 for 
definitions of the dose levels (DLs) for Arm 3 and Table 2 for definitions of the DLs for 
Arm 5.
For subjects in Arm 5, study drug-related toxicities must be resolved to baseline or Grade ≤1 
(with the exception of alopecia, Grade 2 fatigue, and endocrine-related AEs requiring 
treatment or hormone replacement, which may be Grade ≤2, and creatinine clearance, for 
which the guidelines provided below may be followed) prior to administering the next dose.
Subjects must not receive the next cycle of chemotherapy if any of the following apply:

Absolute neutrophil count (ANC) <1,500/mm3

Platelet count <100,000/mm3

Hemoglobin <8 g/dL

Total bilirubin >1.5 × ULN; and/or

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥2.5 × ULN, 
or ≥5 × ULN if liver metastases are present
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Subjects in Arm 5 are allowed to switch from cisplatin to carboplatin if they develop 
unexpected toxicities with the use of cisplatin (including hearing loss), become ineligible for 
further cisplatin therapy, and/or the investigator considers switching to carboplatin to be in 
the best interest of the subject. During dose escalation and confirmation, the dose of 
carboplatin will not be higher than the dose that is currently enrolling per the mTPI design. 
During dose expansion, the dose of carboplatin will not be higher than the dose that was 
carried forward from dose escalation and confirmation.
During Cycles 1 through 4 of Arm 5:

If etoposide dosing is delayed or interrupted, MK-7684, pembrolizumab, and 
carboplatin/cisplatin should also be delayed/interrupted. If etoposide and/or 
carboplatin/cisplatin delayed or interrupted during Cycles 1 through 4, subjects 
should be seen weekly until toxicity resolves.

If cisplatin/carboplatin dosing is delayed or interrupted, MK-7684, pembrolizumab, 
and 
etoposide 
should 
also 
be 
delayed/interrupted. 
If 
etoposide 
and/or 
carboplatin/cisplatin is delayed or interrupted during Cycles 1 through 4, subjects 
should be seen weekly until toxicity resolves.

If MK-7684 and/or pembrolizumab dosing is delayed or interrupted, etoposide and/or 
carboplatin/cisplatin 
can 
continue 
as 
scheduled. 
MK-7684/pembrolizumab 
administration should be attempted at the next cycle of therapy.

Each chemotherapy cycle may not be delayed by more than 3 weeks (>21 consecutive 
days) despite supportive treatment. If only 1 of the agents is thought to be causing the 
specified toxicity leading to a 21-day delay of administration of the next cycle, that 
chemotherapeutic agent can be stopped, and treatment can continue with MK-7684,
pembrolizumab and the remaining chemotherapy drug. MK-7684 and/or 
pembrolizumab dosing can continue with 1 chemotherapy agent or alone.
Use of colony-stimulating factors (CSFs) for primary prophylaxis is permitted at the 
investigator’s discretion. Refer to the American Society of Clinical Oncology (ASCO) 
guidelines for use of CSFs [75].
 
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Table 8
Recommended Dose Modifications for Chemotherapy-related Hematological 
Toxicities
a.  Arm 3
Platelets
ANC
Carboplatin
Pemetrexed
Dose level from Table 1
≥50,000/mcL
AND
≥500/mcL
DL 0
DL 0
≥50,000/mcL
AND
<500/mcL
DL -1
DL -1
<50,000/mcL without 
bleeding
AND
ANY
DL -1
DL -1
<50,000/mcL with 
Grade ≥2 bleeding
AND
ANY
DL -2
DL -2
ANY
AND
<1000/mcL + fever 
≥38.5°C (101°F)
DL -1
DL -1
b.  Arm 5
Drug Related Toxicitya
Carboplatin
Cisplatin
Etoposide
Dose Level from Table 2
Neutrophils (ANC) <500/mm3 without fever
DL -1
DL -1
DL -1
Febrile 
neutropenia 
(fever 
≥38.5C 
and 
ANC 
<1000/mm3)
DL -1
DL -1
DL -1
Platelets <50,000/mm3 without significant bleeding or 
requiring blood transfusion
DL -1
DL -1
DL -1
Platelets <50,000/mm3 with Grade ≥2 hemorrhage or 
requiring blood transfusion
DL -2
DL -2
DL -2
Grade 4 hemoglobin
DL -1
DL -1
DL -1
ANC=absolute neutrophil count; DL=dose level
Note: If toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the dose of one 
of the chemotherapy agents. Investigators may decide to use supportive measures/treatment and/or secondary 
prophylaxis as per institutional standards (eg, filgrastim, pegfilgrastim, transfusions) instead of dose reductions for the 
next cycle, if considered in the best interest of the subject.
a Should the hematologic toxicity recur, the dose of the agent could be reduced further; not more than 2 dose reductions 
per chemotherapy agent are permitted.
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Table 9
Recommended Dose Modifications for Chemotherapy-related Non-hematological 
Toxicities
a.  Arm 3
Event
CTCAE Grade
Carboplatin
Pemetrexed
Dose level from Table 1
Nausea or vomiting
Grade 3or 4
DL 0
DL 0
Diarrhea
Grade 3or 4
DL 0
DL -1
Mucositis
Grade 3or 4
DL 0
DL -2
Neurotoxicity
Grade 2
DL 0
DL 0
Grade 3or 4
DL -1
DL -1
Transaminase elevation
Grade 3
DL -1
DL -1
Grade 4
Discontinue treatment
Discontinue treatment
Other non-hematological
toxicities
Grade 3or 4
DL -1
DL -1
b.  Arm 5
Drug-Related Toxicitya
CTCAE 
Grade
Carboplatin
Cisplatin
Etoposide
Dose Level from Table 2
Nausea or vomiting
Grade ≥3b
DL -1
DL -1
DL 0
Mucositis
Grade ≥3b
DL -1
DL -1
DL -1
Diarrhea
Grade ≥3b
DL -1
DL -1
DL -1
Peripheral neuropathy
Grade 2
No modification
DL -1c
No modification
Grade 3
DL -1
Discontinued No modification
Grade 4
DL -1
Discontinue
No modification
Total bilirubin
Grade 2
No modificationNo modification
DL -2
Grade 3
No modificationNo modification
Discontinue
Grade 4
No modificationNo modification
Discontinue
Transaminase elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other non-hematological toxicities (except 
fatigue and transient arthralgia and myalgia)
Grade ≥3
DL -1
DL -1
DL -1
CTCAE=Common Terminology Criteria for Adverse Events; DL=dose level
Note: If considered in the best interest of the subject, and consistent with local practice, investigators may decide to use 
supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. Also, if 
toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the dose of one of the 
chemotherapy agents.
a Should the toxicity recur, the dose of the agent could be reduced further; not more than 2 dose reductions per 
chemotherapy agent are permitted.
b The first occurrence of Grade ≥3 nausea/vomiting, mucositis, and diarrhea should be managed symptomatically with 
optimal medical therapy, and improve to Grade ≤1 prior to proceeding with additional therapy. Should these events recur 
despite aggressive management, a dose modification can be employed once the AE improves to Grade ≤1.
c If Grade 2 neurotoxicity recurs after DL -1, drug will be given at DL -2 or switch can be made to the appropriate dose of 
carboplatin at the discretion of the investigator in consultation with the Sponsor. If Grade 2 neurotoxicity persists after 
2 dose level reductions and a 21-day hold, switch can be made to the appropriate dose of carboplatin at the discretion of 
the investigator in consultation with the Sponsor.
d If Grade 3 neurotoxicity occurs, cisplatin will be discontinued and, upon improvement, a switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor.
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Creatinine clearance (CrCl) for subjects in Arm 3: CrCl will be based on the original 
weight-based Cockcroft-Gault Method or institutional standard. CrCl must be ≥45 mL/min 
prior to the administration of chemotherapy. Carboplatin and/or pemetrexed may be delayed 
for up to 42 days to allow the participant time to recover from the toxicity. If a participant’s
CrCl value has not returned to ≥45 mL/min within 42 days after the previous dose, 
carboplatin and/or pemetrexed must be discontinued.
CrCl for subjects in Arm 5: CrCl will be based on the original weight-based
Cockcroft-Gault Method or institutional standard.
For subjects receiving cisplatin, the scheduled dose of cisplatin may only be administered if 
the calculated CrCl is ≥50 mL/min:

If CrCl falls to <50 mL/min, delay the start of that cycle for ≤21 days. In the interim, 
monitor renal function weekly and consider IV hydration. When CrCl improves to 
≥50 mL/min, decrease cisplatin to DL -1 (Table 2). Alternatively, if in the 
investigator’s judgment it is in the best interest of the subject, cisplatin can be 
switched to carboplatin if the calculated CrCl is appropriate, and in consultation with 
the Sponsor.

At the second occurrence of CrCl <50 mL/min, decrease cisplatin to DL -2 upon 
improvement of CrCl to ≥50 mL/min. Alternatively, if in the investigator’s judgment 
it is in the best interest of the subject, cisplatin can be switched to carboplatin if the 
calculated CrCl is appropriate, and in consultation with the Sponsor.

At the third occurrence of CrCl <50 mL/min, cisplatin should be discontinued. If in 
the investigator’s judgment it is in the best interest of the subject, cisplatin can be 
switched to carboplatin if the calculated CrCl is appropriate, at the discretion of the 
investigator and in consultation with the Sponsor.
For subjects receiving carboplatin, the scheduled dose of carboplatin may only be 
administered if the calculated CrCl is ≥40 mL/min:

If CrCl falls to <40 mL/min, delay the start of that cycle for ≤21 days. In the interim, 
monitor renal function weekly and consider IV hydration. When CrCl improves to 
≥40 mL/min, decrease carboplatin to DL -1 (Table 2).

At the second occurrence of CrCl <40 mL/min, decrease carboplatin to DL -2 upon 
improvement of CrCl to ≥40 mL/min.

At the third occurrence of CrCl <40 mL/min, carboplatin should be discontinued.
Management Guidelines for Overlapping Toxicities
For overlapping toxicities where it is unclear if the event is related to one or a combination of
drugs, it is recommended to hold all applicable drugs, and initiate management per Table 6. 
Standard of care should be followed for management of toxicities deemed related to 
chemotherapy.
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Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatments administered.
Randomization or Treatment Allocation
During the dose escalation and confirmation phase of Part A, subjects with advanced solid 
tumors of all types will be allocated to 1 of 2 treatment arms: MK-7684 monotherapy 
(Arm 1) or MK-7684 in combination with pembrolizumab (Arm 2) by non-random 
assignment using an IVRS/IWRS. Enrollment into the MK-7684 + pembrolizumab 
combination treatment arm (Arm 2) will begin once 2 dose levels of MK-7684 have been 
tested in the MK-7684 monotherapy arm (Arm 1) and a dose escalation decision has been 
made so that the starting dose of MK-7684 in Arm 2 will be at least 2 levels below the dose 
being tested in Arm 1. When both treatment arms are open for enrollment, IVRS/IWRS will 
alternate subject assignment between Arm 1 and Arm 2 starting with Arm 1. For example, 
once the 21-mg dose cohort of Arm 1 (MK-7684 monotherapy) and the 2.1-mg dose cohort 
of Arm 2 (MK-7684 + pembrolizumab) are open for enrollment, the first subject will be 
allocated to Arm 1, the second subject will be allocated to Arm 2, the third subject will be 
allocated to Arm 1, etc. An observation period of at least 24 hours will occur between 
treatment initiation in subjects enrolled within each dose level. Each new dose cohort will 
open for enrollment without delay once the 21-day DLT observation period of the previous 
dose cohort is completed and a dose escalation decision is made.
During Part B (expansion phase), subjects with PD-1/PD-L1 inhibitor treatment-refractory 
NSCLC will be allocated to MK-7684 monotherapy (Arm 1) or MK-7684 in combination 
with pembrolizumab (Arm 2) by non-random assignment using an IVRS/IWRS. Each 
treatment arm will begin Part B once a preliminary RPTD for that arm is identified in Part A. 
When both treatment arms are open for enrollment
to PD-1/PD-L1 inhibitor 
treatment-refractory NSCLC subjects, IVRS/IWRS will alternate subject assignment between 
Arm 1 and Arm 2 starting with Arm 1, until enrollment targets are met.
Part B subjects with PD-1/PD-L1 inhibitor treatment-naïve NSCLC,
 
 
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 will be allocated to MK-7684 in combination with pembrolizumab (Arm 2) 
using IVRS/IWRS until enrollment targets are met.
Each treatment arm will begin Part B once a preliminary RPTD for that arm is identified in 
Part A.
Stratification
No stratification based on age, sex, or other characteristics will be used in this trial. 
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the subject's primary physician.  However, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the investigator, the 
Sponsor and the subject.
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Acceptable Concomitant Medications/Procedures
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the trial; however, radiotherapy or procedures for symptom 
management is allowed. In cases of melanoma, local surgical excision may be allowed after 
discussion with the Sponsor.
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.
All concomitant medication will be recorded on the CRF including all prescription
medication, over-the-counter (OTC) medication, herbal supplements, and IV medications and 
fluids. Documentation of drug dosage, frequency, route, start/stop dates, and indication will 
be included on the CRF and all changes to these parameters will also be recorded. All 
concomitant medications received within 30 days before the first dose of study treatment 
through the Post-Treatment Safety Follow-Up visit should be recorded. After the Safety 
Follow-Up visit, only medications taken for reportable SAEs and ECIs as defined in 
Section 7.2 should be recorded.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phases of this trial:

Immunotherapy not specified in this protocol

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol

Investigational agents not specified in this protocol

Radiation therapy (radiotherapy for symptom management is allowed and PCI is 
permitted in Arm 5 subjects achieving CR or PR after Cycle 4.)

Hormonal cancer therapy (e.g., tamoxifen, leuprolide)

Live vaccines within 30 days before the first dose of study treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccines. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed. Intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed.

Glucocorticoids other than to modulate symptoms from an immune-mediated AE
and/or as pre/post-medication to prevent AEs associated with chemotherapy. Chronic 
systemic replacement doses of steroids and non-systemic steroids including inhaled 
steroids, topical steroids, intra-nasal steroids, intra-articular, and ophthalmic steroids 
are allowed. Systemic glucocorticoids are also allowed as required during and after 
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PCI in Arm 5 subjects; subjects requiring chronic glucocorticoid use (>7 days) after 
completion of PCI should be discontinued from study treatment.

Phenytoin during treatment with carboplatin

Subjects taking NSAIDs or salicylates will not take the NSAID or salicylate (other 
than an aspirin dose ≤1.3 g per day) for 2 days before, the day of, and 2 days after 
receiving pemetrexed. Subjects taking NSAIDs or salicylates with a long half-life (for 
example, naproxen, piroxicam, diflunisal, or nabumetone) will not take the NSAID or 
salicylates for 5 days before, the day of, and 2 days after pemetrexed.
Subjects who, in the opinion of the investigator, require the use of any of the prohibited 
therapies during the screening and treatment phases of this trial for clinical management 
should be removed from the trial. Subjects may receive other medications that the 
investigator deems to be medically necessary.  
The exclusion criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies after the Post-Treatment Safety Follow-Up visit.
Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined in Section 5.2.3.2, Table 6. 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 study treatment.
Note: If after evaluation of the event, it is determined not to be related to MK-7684 and/or 
pembrolizumab (or MK-7684A), the investigator does not need to follow the treatment 
guidance.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of the event.
Antiemetic Use
For participants receiving chemotherapy, antiemetic therapy should follow Multinational 
Association of Supportive Care in Cancer ([MASCC]; Section 12.7) or appropriate local 
guidelines and should, for the first 4 cycles, include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and aprepitant (or equivalent NK-1 receptor antagonist) as 
per the guideline followed.
Colony-stimulating Factors
For participants receiving chemotherapy, the ASCO guidelines for use of CSFs, or local 
equivalent, should be used for patient management [75]. Use of CSFs for primary 
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prophylaxis is permitted at the investigator’s discretion.
 
Pemetrexed Premedication
All participants must receive the appropriate supplementation of Vitamin B12, folic acid, and 
corticosteroid prophylaxis as listed below or per the local label:

Folic acid, 350 μg to 1000 μg orally: At least 5 doses of folic acid must be taken 
during the 7 days preceding the first dose of pemetrexed, through the full course of 
therapy, and for 21 days after the last dose of pemetrexed.

Vitamin B12, 1000 μg by intramuscular (IM) injection: Vitamin B12 must be given in 
the week preceding the first dose of pemetrexed and once every 3 cycles thereafter. 
Subsequent Vitamin B12 injections may be given on the same day as pemetrexed.

Dexamethasone prophylaxis, 4 mg
orally twice per day (or equivalent):
Dexamethasone may be taken the day before, day of, and day after pemetrexed 
administration. Higher or additional doses are permitted for antiemetic prophylaxis 
during Cycles 1 through 4 but are not to exceed doses in MASCC guidelines (or local 
equivalent).
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea, or vomiting.
Contraception
MK-7684, pembrolizumab, and MK-7684A may have adverse effects on a fetus in utero. 
Furthermore, it is not known if these drugs have transient adverse effects on the composition 
of sperm.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, starting with the first dose of study treatment (or 
14 days prior to the first dose of study treatment for oral contraception) through 120 days 
after the last dose of MK-7684, pembrolizumab, or MK-7684A OR 180 days after the last 
dose of chemotherapeutic agents by complying with one of the following:
1. Practice abstinence from heterosexual activity
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and IRBs/
Independent Ethics Committees (IECs). Periodic abstinence (e.g., calendar, ovulation, 
sympto-thermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception.
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OR 
2. Use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are:
•
Intrauterine device (IUD);
•
Vasectomy of a female subject’s male partner;
•
Contraceptive rod implanted into the skin; or
•
A combination of 2 of the following:
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male or female condom (cannot be used together)
•
hormonal contraceptive (oral contraceptive pill [estrogen/progestin pill or 
progestin-only pill], contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection)
If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in those countries/regions.
Note: Male subjects with pregnant partners must agree to use a condom; no additional 
method of contraception is required for the pregnant partner.
In addition, during treatment and up to 180 days after the last dose of treatment with 
chemotherapeutic agents, female participants must also agree not to donate eggs (ova, 
oocytes) to others or freeze/store eggs for their own use for the purpose of reproduction, and 
male participants must refrain from donating sperm and agree to use a male condom when 
engaging in any activity that allows for passage of ejaculate to another person of any sex.
If there is any question that a subject with reproductive potential will not reliably comply 
with the requirements for contraception, that subject should not be entered into the trial.
Female subjects will be considered of non-childbearing potential if they: 
1. Are postmenopausal 
Postmenopausal is defined as at least 12 months with no menses without an 
alternative medical cause. In women <45 years of age, a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
OR 
2. Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 
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OR 
3. Have a congenital or acquired condition that prevents childbearing.
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Use in Pregnancy
If a subject inadvertently becomes pregnant while on study treatment, study treatment will be 
immediately discontinued. The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy is completed or terminated. The outcome of the 
pregnancy will be reported to the Sponsor without delay and within 24 hours if the outcome 
is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling 
or life-threatening complication to the mother or newborn). The investigator will make every 
effort to obtain permission to follow the outcome of the pregnancy and report the condition 
of the fetus or newborn to the Sponsor. If a male subject impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy reported to the 
Sponsor and followed as described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether or not MK-7684, pembrolizumab, or MK-7684A are excreted in 
human milk. Since many drugs are excreted in human milk, and because of the potential for 
serious adverse reactions in the nursing infant, subjects who are breastfeeding are not eligible 
for enrollment into the trial.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
the Trial Flow Charts (Section 6) –and Section 7.1.5.3 – Post-Treatment Period.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
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The subject or subject’s legally acceptable representative requests to discontinue treatment.

Confirmed disease progression per response assessment criteria (see Section 7.1.2.6).

Clinical progression.

Unacceptable adverse event(s).

Intercurrent illness that prevents further administration of study treatment.

Investigator’s decision to withdraw the subject from treatment.

The subject has a confirmed positive serum pregnancy test.

Noncompliance with trial treatment or procedure requirements.

The subject completes study treatment (i.e., 35 cycles of MK-7684 monotherapy 
[Arm 1], 35 cycles of MK-7684 in combination with pembrolizumab [Arm 2],
35 cycles of MK-7684, pembrolizumab, and pemetrexed, and 4 cycles of carboplatin
[Arm 3], 35 cycles of MK-7684A
[Arm 4], or 35 cycles of MK-7684 and 
pembrolizumab, and 4 cycles of carboplatin or cisplatin and etoposide [Arm 5]as 
applicable).

Administrative reasons.
Subjects who discontinue MK-7684 in the monotherapy arm due to disease progression may, 
at the investigator’s discretion and after consultation with the Sponsor, cross over to 
combination treatment (Arm 2). Subjects eligible for cross-over must have received at least 
2 cycles of MK-7684 monotherapy and must have radiographic imaging to document disease 
progression by RECIST, version 1.1 and to establish a new imaging baseline prior to
cross-over. Subjects who permanently discontinue MK-7684 monotherapy for any reason 
other than radiologic disease progression are not eligible for cross-over. If cross-over is being 
considered, the subject must be re-consented and the risks and benefits of continuing 
treatment after disease progression should be reviewed
prior to performing any 
cross-over-related procedures. The subject will receive the dose of MK-7684 that has been 
determined to be safe in the combination arm (e.g., 1 dose level below the dose being tested
if in Part A) at the time of treatment cross-over. The MK-7684 dose will not exceed the dose 
the subject received in the monotherapy arm. The first dose of combination treatment must
occur no less than 21 days and no more than 42 days after the last dose of MK-7684 
monotherapy treatment. Any deviations from this time frame must be approved by the 
Sponsor. The total duration of treatment (monotherapy and combination therapy) will not 
exceed 35 cycles. Specific details regarding procedures to be performed are provided in the 
Cross-Over Flow Chart in Section 6.1.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
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Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
In order to evaluate safety and allow for dose escalation decisions, subjects who meet one or 
more of the following criteria will be replaced and will not be counted toward the cohort total 
for DLT evaluation:

Subjects who are enrolled but not treated;

Subjects who receive less than 75% of the total MK-7684, pembrolizumab, or 
MK-7684A infusion in Cycle 1 (e.g., because the infusion had to be discontinued due 
to an infusion reaction) and do not experience a DLT;

Subjects who discontinue from the trial before completing all the safety evaluations in 
Cycle 1 for reasons other than treatment-related AEs; or

Subjects who discontinue from the trial before completing Cycle 1 and do not 
experience a DLT before discontinuation.
Beginning and End of the Trial
The overall trial begins when the first subject (or the subject's legally acceptable 
representative) provides documented informed consent. The overall trial ends when the last 
subject completes the last study-related contact, discontinues from the trial, or is lost to 
follow-up (i.e., the subject is unable to be contacted by the investigator).
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The incidence or severity of adverse drug reactions in this, or other, trials suggest a 
potential health hazard to subjects;
2. Plans emerge to modify or discontinue the development of the trial drug(s);
3. There is poor adherence to the protocol and/or regulatory requirements; and/or
4. The quality or quantity of data recording is inaccurate or incomplete.
Ample notification will be provided to the sites if the Sponsor decides not to continue to 
supply MK-7684, MK-7684A, or pembrolizumab.
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6.0 TRIAL FLOW CHART
Visit / Treatment Cycle
Screening
Treatment Period 
Cycle = 21 days
End of 
Treatment 
Post-Treatment Period 
Cycle 1
Cycles 2-4
Cycles 
≥5
Treatment 
dis-
continuation
Safety 
Follow-
Up
Disease 
Status 
Follow-
Up
Survival 
Follow-
Up
Visit Timing / Cycle Day
Up to 28 
days prior 
to 1st dose
1
2
3
5
8
15
1
21
31
51
81
151
Every 9 
weeks
1
30 days 
after the 
last 
dose2
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
+/-
1
+/-
2
+/-
3
+/-
1
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
Administrative Procedures
Informed Consent3
X
Informed Consent for Future 
Biomedical Research4
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Oncology Disease Status and 
Prior Oncology Treatment 
History
X
Concomitant Medication 
Review
X
X
X
X
X
X
X1
X1
X1
X
X
X
Clinical Procedures/Assessments
Full Physical Examination
X
X5
X5
X5
X
X
Height
X
Weight
X
X
X
X
X
X
Vital Signs6
X
X
X
X
X
X
X
X1
X1
X1
X1
X
X
X
Pulse Oximetry (SpO2; subjects 
in Japan ONLY)
X
X
X
X
X
X
X
X1
X1
X1
X1
X
X
X
ECOG Performance Status
X
X5
X5
X5
X
X
12-Lead Electrocardiogram7
X
X5
X5
MK-7684 Drug Administration
(Arm 1 and Arm 2)8
X
X
X
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Visit / Treatment Cycle
Screening
Treatment Period 
Cycle = 21 days
End of 
Treatment 
Post-Treatment Period 
Cycle 1
Cycles 2-4
Cycles 
≥5
Treatment 
dis-
continuation
Safety 
Follow-
Up
Disease 
Status 
Follow-
Up
Survival 
Follow-
Up
Visit Timing / Cycle Day
Up to 28 
days prior 
to 1st dose
1
2
3
5
8
15
1
21
31
51
81
151
Every 9 
weeks
1
30 days 
after the 
last 
dose2
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
+/-
1
+/-
2
+/-
3
+/-
1
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
Pembrolizumab Drug 
Administration (Arm 2)8,9
X
X
X
 
 
X
X
X
Adverse Event Monitoring10
X
X
X
X
X
X
X
X1
X1
X1
X1
X
X
X10
Tumor Imaging and RECIST, 
version 1.1 Response 
Assessment11
X
X
X
X
New Anticancer Therapy 
Status
X
X
X
Survival Status12
X
Laboratory Procedures/Assessments – LOCAL
Hematology13
X14
X5
X
X
X
X5
X1
X1
X5
X
X
Chemistry Panel13
X14
X5
X
X
X
X5
X1
X1
X5
X
X
Prothrombin Time 
(PT)/International Normalized 
Ratio (INR) and Activated 
Partial Thromboplastin Time 
(aPTT)15
X14
Lactate Dehydrogenase (LDH) 
and Gamma Glutamyl 
Transferase (GGT)
X14
X5
X5
X5
Thyroid Function Testing (T4, 
T3, TSH)16
X5
X5,
16
X5,16
X
Immunoglobulins (IgA, IgG, 
IgM)
X5
X5
X5
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Visit / Treatment Cycle
Screening
Treatment Period 
Cycle = 21 days
End of 
Treatment 
Post-Treatment Period 
Cycle 1
Cycles 2-4
Cycles 
≥5
Treatment 
dis-
continuation
Safety 
Follow-
Up
Disease 
Status 
Follow-
Up
Survival 
Follow-
Up
Visit Timing / Cycle Day
Up to 28 
days prior 
to 1st dose
1
2
3
5
8
15
1
21
31
51
81
151
Every 9 
weeks
1
30 days 
after the 
last 
dose2
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
+/-
1
+/-
2
+/-
3
+/-
1
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
Pregnancy Test (urine or serum 
-human chorionic 
gonadotropin [β-hCG]) - if 
applicable17
X
X5
X
HIV/Hepatitis Screen (at the 
discretion of the investigator)18
X
X14
X5
X
X
X14
X5
X
X
X
X
X
X
X
Urinalysis
X14
Laboratory Procedures/Assessments – CENTRAL
Serum for Cytokine Testing23
X
X
X
X
X
X1
X1
X
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Visit / Treatment Cycle
Screening
Treatment Period 
Cycle = 21 days
End of 
Treatment 
Post-Treatment Period 
Cycle 1
Cycles 2-4
Cycles 
≥5
Treatment 
dis-
continuation
Safety 
Follow-
Up
Disease 
Status 
Follow-
Up
Survival 
Follow-
Up
Visit Timing / Cycle Day
Up to 28 
days prior 
to 1st dose
1
2
3
5
8
15
1
21
31
51
81
151
Every 9 
weeks
1
30 days 
after the 
last 
dose2
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
+/-
1
+/-
2
+/-
3
+/-
1
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
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Visit / Treatment Cycle
Screening
Treatment Period 
Cycle = 21 days
End of 
Treatment 
Post-Treatment Period 
Cycle 1
Cycles 2-4
Cycles 
≥5
Treatment 
dis-
continuation
Safety 
Follow-
Up
Disease 
Status 
Follow-
Up
Survival 
Follow-
Up
Visit Timing / Cycle Day
Up to 28 
days prior 
to 1st dose
1
2
3
5
8
15
1
21
31
51
81
151
Every 9 
weeks
1
30 days 
after the 
last 
dose2
Every 9 
weeks
Every 12 
weeks
Visit Window (Days)
-28 to -1
+/-
1
+/-
2
+/-
3
+/-
1
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
1.
As of Amendment 9 for subjects in Part B and Amendment 10 for subjects in Part A, all assessments on Days 2, 3, 5, 8, and 15 of Cycles 2 through 4 
are not required.
2.
If a subject initiates a new anticancer therapy within 30 days after the last dose of study treatment, the Post-Treatment Safety Follow-Up visit should 
occur before the first dose of the new therapy.
3.
Documented informed consent must be obtained prior to performing any protocol-specific procedures. Tests performed prior to the subject providing
consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified timeframe.
4.
Consent for future biomedical research (FBR) is optional, and may be provided at any time during the subject’s participation in the trial. Detailed 
instructions for the collection and management of FBR specimens are provided in the Procedure Manual.
5.
Procedure/sample collection may be performed up to 72 hours prior to dosing. Screening procedures/sample collections done within this timeframe do 
not need to be repeated for the Cycle 1, Day 1 assessment.
6.
Vital signs include body temperature, pulse, respiratory rate, and blood pressure. Vital signs should be measured at screening, and prior to dosing, and 
2 hours, 4 hours, and 6 hours after the start of the MK-7684 infusion on Day 1, and once daily on Day 2, Day 3, Day 8, and Day 15 of Cycles 1 through 
4. Beginning in Cycle 5, vital signs should be measured prior to dosing on Day 1 only. Vitals signs should also be measured at the End of Treatment 
visit and at the Post-Treatment Safety Follow-Up visit. As of Amendment 10, vital signs for subjects in Part A and Part B should be measured at 
screening, prior to dosing and 2 hours, 4 hours, and 6 hours after the start of the MK-7684 infusion (or MK-7684A infusion, as of Amendment 11) on 
Day 1, and once daily on Day 2, Day 3, Day 8, and Day 15 of Cycle 1. Beginning in Cycle 2, vital signs should be measured prior to dosing on Day 1 
only. Vitals signs should also be measured at the End of Treatment visit and at the Post-Treatment Safety Follow-Up visit.
7.
A 12-lead electrocardiogram (ECG) should be performed at screening and prior to dosing and within 30 minutes after the end of the MK-7684 or MK-
7684A infusion on Day 1 of Cycles 1 through 4.
8.
Subjects may receive up to 35 cycles of study treatment (MK-7684 in Arm 1, MK-7684 and pembrolizumab in Arm 2, 
 In Cycle 2, study treatment may be administered up to 5 days after the scheduled Day 1. Beginning in Cycle 3, study 
treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle.
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9.
In Arm 2, pembrolizumab will be administered first on Day 1 of each cycle, with administration of MK-7684 occurring approximately 30 minutes after 
completion of the pembrolizumab infusion. 
10. Adverse events and serious adverse events will be recorded from the time of treatment allocation. All adverse events and serious adverse events that 
occur after documented informed consent is provided but before treatment allocation must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy or 
a trial procedure. After treatment discontinuation, subjects will be monitored for adverse events and serious adverse events for 90 days, 30 days if the 
subject initiates new anticancer therapy less than 30 days after study treatment discontinuation, or the day new anticancer therapy is initiated if between 
30 days and 90 days after study treatment discontinuation. The investigator will make every attempt to follow all subjects with non-serious adverse 
events for outcome. All subjects with serious adverse events must be followed up for outcome.
11. Tumor imaging should be performed within 28 days prior to the first dose of study treatment. Tumor imaging and response assessment should be 
performed 9 weeks after the first dose of study treatment and every 9 weeks thereafter, until disease progression. The timing of imaging assessments 
should not be adjusted for delays in cycle starts. Subjects who discontinue treatment for reasons other than confirmed disease progression will have 
post-treatment follow-up for disease status until disease progression, initiating a new anticancer therapy, withdrawing consent for trial participation, or 
becoming lost to follow-up, whichever occurs first. The same imaging technique should be used on a subject throughout the trial. Scans used for tumor
measurements may be requested for potential central review.
12. Upon Sponsor request, participants may be contacted for survival status at any time during the course of the study. After confirmed disease 
progression, each subject will be contacted by telephone every 12 weeks for survival until withdrawal of consent to participate in the trial, becoming 
lost to follow-up, death, or the end of the trial, whichever occurs first.
13. Samples for hematology and chemistry panel should be collected at screening, and prior to dosing and 4 hours after the start of the MK-7684 infusion 
on Day 1 of Cycles 1 through 4. In Cycle 1, samples should also be collected once daily on Day 2, Day 8, and Day 15. In Cycles 2 through 4, samples 
will also be collected once daily on Day 8 and Day 15. Beginning in Cycle 5, samples for hematology and chemistry panel should be collected prior to 
dosing on Day 1 only. Samples should also be collected at the End of Treatment visit and at the Post-Treatment Safety Follow-Up visit. As of 
Amendment 10, samples for subjects in Part A and Part B should be collected at screening, and prior to dosing and 4 hours after the start of the 
MK-7684 infusion (or MK-7684A infusion, as of Amendment 11) on Day 1 of Cycles 1 through 4. In Cycle 1, samples should also be collected once 
daily on Day 2, Day 8, and Day 15. Beginning in Cycle 5, samples for hematology and chemistry panel should be collected prior to dosing on Day 1 
only. Samples should also be collected at the End of Treatment visit and at the Post-Treatment Safety Follow-Up visit.
14. Laboratory tests at screening are to be performed within 7 days prior to the first dose of study treatment.
15. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Furthermore, any subject receiving 
anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
16. Samples for thyroid function testing should be collected on Day 1 of Cycle 1, every other cycle thereafter, and at the Post-Treatment Safety Follow-Up 
visit.
17. For women of reproductive potential, a urine pregnancy test will be performed at screening, within 72 hours prior to the first dose of study treatment, 
and at treatment discontinuation. A urine pregnancy test may also be performed whenever an expected menstrual cycle is missed or when pregnancy is 
otherwise suspected, and as required locally. If a urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required.
18. HIV testing should include HIV Type 1 and Type 2 (e.g., HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed). Hepatitis 
testing should include HCV, RNA (qualitative), or Hepatitis C antibody, and HBsAg.
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Cross-over Flow Chart
Subjects who discontinue MK-7684 in the monotherapy arm due to radiographic disease progression may, at the investigator’s 
discretion and after consultation with the Sponsor, cross over to combination treatment (Arm 2). The list and schedule of procedures to 
be performed are provided in the following flow chart.
Visit / Treatment Cycle
Treatment Period1, 2
Cycle = 21 days
End of Treatment 
Post-Treatment Period
Cycle 1
Cycles ≥2
Safety Follow-Up
Disease Status
Follow-Up
Survival
Follow-Up
Visit Timing / Cycle Day
13
8
15
1
Every 9 
weeks
Treatment dis-
continuation
30 days after the 
last dose4
Every 9 weeks
Every 12 
weeks
Visit Window (Days)
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
Administrative Procedures
Informed Consent5
Concomitant Medication Review
X
X
X
X
Clinical Procedures/Assessments
Full Physical Examination
X6
X6
X
X
Weight
X
X
X
X
Vital Signs7
X
X
X
X
ECOG Performance Status
X6
X6
X
X
12-Lead Electrocardiogram8
X6
X6
MK-7684 Drug Administration9,10
X
X
Pembrolizumab Drug Administratio10,11
X
X
Adverse Event Monitoring12
X
X
X
X12
Tumor Imaging and RECIST, version 1.1 Response 
Assessment13
X
X
New Anticancer Therapy Status
X
X
X
Survival Status14
X
Laboratory Procedures/Assessments – LOCAL
Hematology15
X6
X
X
X6
X
X
Chemistry Panel15
X6
X
X
X6
X
X
Lactate Dehydrogenase (LDH) and Gamma Glutamyl 
Transferase (GGT)
X6
X6
Thyroid Function Testing (T4, T3, TSH)16
X6
X6,16
X
Immunoglobulins (IgA, IgG, IgM)
X6
X6
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Visit / Treatment Cycle
Treatment Period1, 2
Cycle = 21 days
End of Treatment 
Post-Treatment Period
Cycle 1
Cycles ≥2
Safety Follow-Up
Disease Status
Follow-Up
Survival
Follow-Up
Visit Timing / Cycle Day
13
8
15
1
Every 9 
weeks
Treatment dis-
continuation
30 days after the 
last dose4
Every 9 weeks
Every 12 
weeks
Visit Window (Days)
+/-
2
+/-
3
+/-
7
+/-
7
+/-
7
+/-
14
Pregnancy Test (urine or serum -human chorionic 
gonadotropin [β-hCG]) - if applicable17
X
X
X6
X
X6
X
1.
Any subject receiving anticoagulant therapy should continue to have coagulation factors (PT/INR and aPTT) monitored closely throughout the trial.
2.
Subjects will be requested to provide a post-treatment tumor biopsy sample between Day 8 and Day 15 of Cycle 2. Leftover tissue may also be saved for 
future biomedical research (FBR) if the subject provides documented informed consent for FBR.
3.
Cycle 1, Day 1 of combination treatment for subjects who cross over will not occur less than 21 days and no more than 42 days after the last dose of 
MK-7684 monotherapy the subject received in Arm 1. The Cycle 1, Day 1 visit in the combination treatment for cross-over subjects will replace the 
End of Treatment visit for the monotherapy arm. Any deviations from this timing must be approved by the Sponsor.
4.
If a subject initiates a new anticancer therapy within 30 days after the last dose of study treatment, the Post-Treatment Safety Follow-Up visit should 
occur before the first dose of the new therapy.
5.
If cross-over is being considered, the subject must be re-consented and the risks and benefits of continuing treatment after disease progression should be 
reviewed prior to performing any cross-over-related procedures.
6.
Procedure/sample collection may be performed up to 72 hours prior to dosing.
7.
Vital signs include body temperature, pulse, respiratory rate, and blood pressure. Vital signs should be measured prior to dosing, and 2 hours, 4 hours, 
and 6 hours after the start of the MK-7684 infusion on Day 1 of Cycle 1. Beginning in Cycle 2, vital signs should be measured prior to dosing on Day 1 
only. Vitals signs should also be measured at the End of Treatment visit and at the Post-Treatment Safety Follow-Up visit.
8.
A 12-lead electrocardiogram (ECG) should be performed prior to dosing and within 30 minutes after the end of the MK-7684 infusion on Day 1 of 
Cycles 1 through 4.
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9.
Subjects who cross over from the monotherapy arm will receive the dose of MK-7684 that has been determined to be safe in the combination arm (e.g., 
1 dose level below the dose being tested) at the time of treatment cross-over. The MK-7684 dose will not exceed the dose the subject received in the 
monotherapy arm.
10. Subjects may receive a total of up to 35 cycles of study treatment (number of cycles received in Arm 1 + number of cycles received in Arm 2).
Beginning in Cycle 2, study treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 of each cycle. 
11. Pembrolizumab will be administered first on Day 1 of each cycle, with administration of MK-7684 occurring approximately 30 minutes after 
completion of the pembrolizumab infusion. 
12. Adverse events and serious adverse events will be recorded from the time of treatment allocation. After treatment discontinuation, subjects will be 
monitored for adverse events and serious adverse events for 90 days, 30 days if the subject initiates new anticancer therapy less than 30 days after study 
treatment discontinuation, or the day new anticancer therapy is initiated if between 30 days and 90 days after study treatment discontinuation. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for outcome. All subjects with serious adverse events must 
be followed up for outcome.
13. Tumor imaging and response assessment should be performed 9 weeks after the first dose of combination treatment and every 9 weeks thereafter, until 
disease progression. The timing of imaging assessments should not be adjusted for delays in cycle starts. Subjects who discontinue treatment for reasons 
other than confirmed disease progression will have post-treatment follow-up for disease status until disease progression, initiating a new anticancer 
therapy, withdrawing consent for trial participation, or becoming lost to follow-up, whichever occurs first. The same imaging technique should be used 
on a subject throughout the trial. Scans used for tumor measurements may be requested for potential central review.
14. Upon Sponsor request, participants may be contacted for survival status at any time during the course of the study. After confirmed disease progression,
each subject will be contacted by telephone every 12 weeks for survival until withdrawal of consent to participate in the trial, becoming lost to follow-
up, death, or the end of the trial, whichever occurs first.
15. Samples for hematology and chemistry panel should be collected prior to dosing and 4 hours after the start of the MK-7684 infusion on Day 1, and once 
daily on Day 8 and Day 15 of Cycle 1. Beginning in Cycle 2, samples for hematology and chemistry panel should be collected prior to dosing on Day 1
only. Samples should also be collected at the End of Treatment visit and at the Post-Treatment Safety Follow-Up visit.
16. Samples for thyroid function testing should be collected on Day 1 of Cycle 1, every other cycle thereafter, and at the Post-Treatment Safety Follow-Up 
visit.
17. For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first dose of cross-over treatment, and at 
treatment discontinuation. A urine pregnancy test may also be performed whenever an expected menstrual cycle is missed or when pregnancy is 
otherwise suspected, and as required locally. If a urine pregnancy test cannot be confirmed as negative, a serum pregnancy test is required.
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee (consistent with local requirements) must obtain 
documented informed consent from each potential subject or each subject’s legally 
acceptable representative prior to participating in this clinical trial or Future Biomedical 
Research. If there are changes to the subject’s status during the trial (e.g., health or age of 
majority requirements), the investigator or qualified designee must ensure the appropriate 
documented informed consent is in place. 
General Informed Consent
Informed consent given by the subject or the subject's legally acceptable representative must 
be documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and/or agreement of the subject (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the subject (or 
his/her legally acceptable representative) before participation in the study.
The initial informed consent form (ICF), any subsequent revised ICF, and any written 
information provided to the subject must receive the IRB/IEC’s approval/favorable opinion 
in advance of use. The subject or his/her legally acceptable representative should be informed 
in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s or the subject’s legally acceptable 
representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the subject or the subject's 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. 
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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 future biomedical research
consent to the subject, or the subject’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to future biomedical research. A copy of the informed consent will be given to the subject
before performing any procedure related to future biomedical research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides documented informed consent. At the time of treatment allocation/randomization, 
site personnel will add the treatment/randomization number to the Subject Identification 
Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the previous 10 years 
that are considered clinically significant by the investigator. Details regarding the disease for 
which the subject has been enrolled in the trial will be recorded separately (see 
Section 7.1.1.5.1) and should not be listed in medical history.
Disease Details and Treatments
Oncology Disease Details
Prior and current details regarding the disease for which the subject has been enrolled in the 
trial will be obtained by the investigator or qualified designee
Prior Oncology Treatment History
The investigator or qualified designee will record all prior anticancer therapies including 
systemic treatments, radiation, radiosurgeries, and surgeries regardless of time prior to first 
dose of study treatment.
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Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before the first dose of study treatment. Treatment of the disease for which 
the subject has been enrolled in this trial will be recorded separately (see Section 7.1.1.5.2) 
and should not be listed in prior medications.
Concomitant Medications
The investigator or qualified designee will record medications, if any, taken by the subject 
during the trial and through to the Post-Treatment Safety Follow-Up visit. After the Safety 
Follow-Up visit, all medications related to reportable SAEs and ECIs should be recorded.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
Assignment of Treatment/Randomization Number
In Arms 1 and 2 of Part A and Part B, subjects will be allocated by non-random assignment. 
Allocation will alternate between the 2 arms when both arms are open for enrollment (see 
Section 5.3).
 
 
 
 
 
 
 
 
All 
eligible subjects in Parts A and B will receive a treatment/randomization number. This 
unique number is termed a randomization number throughout the protocol for operational 
purposes. Allocation of subjects will be managed by the Sponsor through an IVRS/IWRS.
Once a treatment/randomization number is assigned to a subject, it can never be re-assigned 
to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
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Trial Compliance (Medication)
Interruptions from the protocol specified treatment(s) for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Clinical Procedures/Assessments
Full Physical Examination
The investigator or qualified designee will perform a full physical examination during the 
screening period. Clinically significant findings from the screening examination should be 
recorded as medical history.
A full physical examination should be repeated at the timepoints outlined in the Trial Flow 
Charts (Section 6). After the first dose of study treatment, new clinically significant abnormal 
findings should be recorded as AEs.
Height, Weight, and Vital Signs
Height will be measured at screening only.
Weight will be measured at the timepoints outlined in the Trial Flow Charts (Section 6).
The investigator or qualified designee will measure vital signs at the timepoints outlined in 
the Trial Flow Charts (Section 6). Vital signs should include body temperature, pulse, 
respiratory rate, and blood pressure.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess the ECOG performance status 
(Appendix 12.4) of the subject at the timepoints outlined in the Trial Flow Charts (Section 6).
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed by the investigator or qualified 
designee at the timepoints outlined in the Trial Flow Charts (Section 6).
Administration of Study Treatment
MK-7684 and pembrolizumab (or MK-7684A) will be administered by IV infusion on Day 1 
of each 21-day cycle. The Pharmacy Manual contains specific instructions for the preparation 
and administration of the infusion solutions.
Designated site personnel will be responsible for preparing and administering MK-7684 and 
pembrolizumab (or MK-7684A). They will also be required to record limited information 
during each infusion (e.g., infusion date/time, lot number and expiry date for product 
administered, total dose/volume administered). See Pharmacy Manual for further details.
In the combination treatment arm (Arm 2), pembrolizumab will be administered first on 
Day 1 of each cycle, with administration of MK-7684 occurring approximately 30 minutes 
after completion of the pembrolizumab infusion.
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Subjects may receive up to 35 cycles of study treatment with MK-7684 in Arm 1, MK-7684 
and pembrolizumab in Arm 2, and MK-7684A in Arm 4.
Subjects who discontinue MK-7684 in the monotherapy arm due to radiologic disease 
progression may, at the investigator’s discretion and after consultation with the Sponsor, 
cross over to combination treatment (Arm 2). The total duration of treatment (monotherapy 
and combination therapy) will not exceed 35 cycles.
Disease Assessments
Initial imaging (e.g., CT scan, MRI, PET-CT, etc.) should be performed within 28 days prior 
to the first dose of study treatment, and should be repeated 9 weeks after the first dose and 
every 9 weeks until confirmed disease progression, initiating a new anticancer therapy, 
withdrawing consent for trial participation, or becoming lost to follow-up, whichever occurs 
first.
 
 
 
 
The same imaging technique should be used at each timepoint and the schedule of disease 
assessment should not be adjusted for delays, if any, in cycle starts.
Scans used for tumor measurements may be requested for potential central review.
Response will be based on RECIST, version 1.1 as assessed by investigator review.
Immunotherapeutic agents, such as MK-7684 and pembrolizumab (or MK-7684A), may 
produce antitumor effects by potentiating an endogenous cancer-specific immune response. 
The response patterns seen with such an approach may extend beyond the usual time course 
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of responses seen with typical cytotoxic agents, and can manifest a clinical response after an 
initial increase in tumor burden or even the appearance of new lesions. 
Subjects who have initial evidence of radiologic progressive disease (PD) 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 PD. This clinical 
judgment decision should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data. Clinical stability is defined as the 
following:
(1) Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values;
(2) No decline in ECOG performance status;
(3) Absence of rapid progression of disease; and
(4) Absence of progressive tumor at critical anatomical sites (e.g., spinal cord compression).
Any subject deemed clinically unstable should be discontinued from trial treatment and is not 
required to have repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per RECIST, 
version 1.1, the local site investigator should consider 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:

Tumor burden remains ≥20% and there is at least a 5 mm absolute increase compared 
to the nadir;

Non-target disease resulting in initial PD is qualitatively worse;

New lesion resulting in initial PD is qualitatively worse;

Additional new lesion(s) are identified since the last evaluation; OR

Additional new non-target progression is identified since the last evaluation.
At the investigator’s discretion and after consultation with the Sponsor, subjects who 
discontinue MK-7684 in the monotherapy arm due to radiologic disease progression may 
cross over to the combination arm (Arm 2) as described in Section 5.8.1. Subjects will 
continue to undergo disease assessments on a routine basis as described in the Cross-Over 
Flow Chart (Section 6.1). For cross-over subjects, disease burden will continue to be assessed 
by RECIST, version 1.1 after initiation of combination treatment. From an imaging 
perspective, management of these subjects will be identical to management of new subjects 
entering the study. Subjects who have initial evidence of radiologic PD by RECIST after 
starting cross-over combination treatment, should, at the discretion of the investigator, 
continue on study treatment until repeat imaging is obtained ≥4 weeks later to confirm PD.
Progressive disease will be confirmed at repeat imaging if ANY of the following occur:

Tumor burden remains ≥20% and there is at least a 5 mm absolute increase compared 
to the nadir;
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
Non-target disease resulting in initial PD is qualitatively worse;

New lesion resulting in initial PD is qualitatively worse;

Additional new lesion(s) are identified since the last evaluation; OR

Additional new non-target progression is identified since the last evaluation.
Brain Imaging
 
 
In addition, repeat brain imaging is to be performed at all post-baseline imaging 
assessments in subjects with brain metastases at diagnosis who have undergone treatment and 
as clinically indicated in subjects without brain metastases at diagnosis.
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as outlined in the Trial Flow Charts (Section 6), and more frequently, if 
clinically indicated. Adverse events will be graded according to the CTCAE, version 4.0. 
Toxicities will be characterized in terms of seriousness, causality, toxicity grade, and action 
taken with regard to study treatment(s).
Since this is a dose escalation trial to establish the RPTDs of MK-7684 when used as 
monotherapy and in combination with pembrolizumab, each dose escalation decision will be 
based on the safety and tolerability experienced by subjects at each dose level. Safety and 
tolerability for the DLT evaluation period in each cohort will be reviewed by the Sponsor and 
Principal Investigators independently in each treatment arm prior to the start of the next 
cohort to determine the appropriateness of dose escalation. The frequency of these 
communications will depend on enrollment at each dose level, as well as any potential new 
information regarding a safety concern in this trial or other relevant trials.
As this is a Phase 1 trial, there is no plan for an external safety reviewer. Data from 
individual subjects will be closely followed on an ongoing basis by the applicable Principal 
Investigator and the Sponsor.
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Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedure 
Manual. The schedule of laboratory assessments is outlined in the Trial Flow Charts
(Section 6).
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis will be performed at the local 
laboratory. Parameters to be measured are outlined in Table 10.
Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Red blood cell (RBC) 
count
Total protein 
Blood
Prothrombin time (PT)/International 
normalized ratio (INR)5
Hemoglobin 
Albumin
Glucose
Activated partial thromboplastin 
time (aPTT)5
Hematocrit
Alanine aminotransferase 
(ALT)
Protein
Thyroid function testing 
(T4, T3, TSH)6
White blood cell (WBC) 
count (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
Immunoglobulins (IgA, IgG, IgM)
Absolute neutrophil 
count (ANC)
Alkaline phosphatase
Microscopic exam, if 
abnormal results are 
noted
Serum β-human chorionic 
gonadotropin (β-hCG)4
Platelet count
Total bilirubin
Urine pregnancy test4
Follicle stimulating hormone 
(FSH)7
Direct bilirubin, if total 
bilirubin is above the upper 
limit of normal
Human immunodeficiency virus 
(HIV; HIV Type 1 and Type 2)8
Bicarbonate / Carbon dioxide 
(CO2)1
Hepatitis (HCV, RNA [qualitative], 
or Hepatitis C antibody, and 
HBsAg)8
Calcium
Chloride
Phosphorus
Potassium
Sodium
Glucose
Creatinine
Blood urea nitrogen 
(BUN)/Urea2
Uric acid
Amylase
Lipase
Lactate dehydrogenase 
(LDH)3
Gamma glutamyl transferase 
(GGT)3
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Hematology
Chemistry
Urinalysis
Other
1. If bicarbonate/CO2 is not done as part of standard of care in your region then these tests do not need to be performed.
2. Blood urea nitrogen is preferred; if not available urea may be tested.
3. LDH and GGT need to be tested at screening and on Day 1 of each cycle only.
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. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
6. Total T4 is preferred; if not available free T4 may be tested Total T3 is preferred; if not available free T3 may be 
tested.
7. In women <45 years of age, a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
8. Testing is at the discretion of the investigator.
Laboratory tests will be performed at the timepoints outlined in the Trial Flow Charts
(Section 6). Results must be reviewed by the investigator or qualified designee and found to 
be acceptable prior to administration of each dose of trial treatment. Note: Dosing will not be 
delayed for immunoglobulin test results that are not available at the time of dosing.
Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of MK-7684 and pembrolizumab in these
indications, sample collections for analysis of ADAs and PK are currently planned as shown 
in the Trial Flow Charts (Section 6). Blood samples collected for ADA and PK may only be 
stored at this time. Further analysis may be performed if required. If ongoing ADA and/or 
PK sampling is deemed to be unnecessary by the Sponsor, it may be reduced or discontinued.
Blood Collection for MK-7684
Samples for PK/PD evaluations will be collected at the timepoints outlined in the Trial Flow 
Charts (Section 6). Collection, storage, and shipment instructions for blood samples will be 
provided in the Procedure Manual.
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Blood Collection for Pembrolizumab (Arms 2, 3, 4, and 5 only)
Samples for PK/PD evaluations will be collected at the timepoints outlined in the Trial Flow 
Charts (Section 6). Collection, storage, and shipment instructions for blood samples will be 
provided in the Procedure Manual.
Sample Collection for Exploratory Biomarkers
Samples for exploratory biomarkers will be collected at the timepoints outlined in the Trial 
Flow Charts (Section 6). Collection, storage, and shipment instructions will be provided in 
the Procedure Manual. Any leftover samples will be stored for FBR if the subject provides 
documented informed consent for FBR.
Tumor Tissue Collection
Subjects will be required to provide a pretreatment tumor sample (archival or newly 
obtained). 
 
. If an archival sample is 
not available, new biopsy should be performed if possible. If biopsy cannot be performed 
without significant risk to the patient, the biopsy requirement may be omitted after Sponsor 
consultation. All subjects will be requested to provide a post-treatment tumor biopsy sample 
as outlined in the Trial Flow Charts (Section 6).
Collection, storage, and shipment instructions for tumor samples will be provided in the 
Procedure Manual. Archival samples are not required to be submitted within the screening 
period but must be obtained by the site at the earliest convenient time.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual.
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research
Leftover RNA
Leftover serum
Leftover main study tumor
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue treatment prior to completion of the treatment should be 
encouraged to continue to be followed for all remaining study visits.
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When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the End of Treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:
1. The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
2. The investigator or designee must make every effort to regain contact with the subject 
at each missed visit (e.g., phone calls and/or a certified letter to the subject’s last 
known mailing address or locally equivalent methods). These contact attempts should 
be documented in the subject’s medical record.
Note:  A subject is not considered lost to follow-up until the last scheduled visit for the 
individual subject.  The amount of missing data for the subject will be managed via the pre-
specified data handling and analysis guidelines.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening Period
During the screening period, potential subjects will be evaluated to determine whether or not 
they fulfill the entry requirements as detailed in Section 5.1.
Documented informed consent must be provided prior to performing any protocol-specific 
procedures. Results of tests performed as part of routine clinical management prior to the 
subject providing documented informed consent are acceptable in lieu of a screening test if 
performed within the specified timeframe.
Screening procedures, including tumor imaging, are to be completed within 28 days prior to 
the first dose of study treatment except for screening laboratory tests that are to be performed 
within 7 days prior to the first dose of study treatment.
Screening procedures may be repeated after consultation with the Sponsor.
Treatment Period Visits
Subjects who are eligible for trial participation will be allocated to a treatment arm and 
assigned to receive a dose of MK-7684 or MK-7684A by the Sponsor. Subjects in Arms 2, 3 
and 5 will receive 200 mg of pembrolizumab in addition to their assigned dose of MK-7684. 
 
 
Study visits will occur as outlined in the Trial Flow Charts (Section 6). Subjects may be seen 
more frequently, if clinically indicated. Tumor imaging and response assessment will occur 
every 9 weeks after the first dose of study treatment.
 
 
 
Study treatment in all arms will be given on Day 1 of each 3-week cycle, except etoposide 
which will be given on Days 1, 2, and 3 of each 3-week cycle. Study treatment with 
MK-7684 (Arms 1-5), pembrolizumab (Arms 2-5), and MK-7684A (Arm 4) may be 
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administered for up to 35 cycles.
 
Subjects who discontinue MK-7684 in the monotherapy arm due to disease progression may, 
at the investigator’s discretion and after consultation with the Sponsor, cross over to 
combination treatment (Arm 2). Subjects eligible for cross-over must have received at least 
2 cycles of MK-7684 monotherapy and must have radiographic imaging to document disease 
progression by RECIST, version 1.1 and to establish a new imaging baseline prior to 
cross-over. The total duration of treatment (monotherapy and combination therapy) will not 
exceed 35 cycles. Specific details regarding procedures to be performed are provided in the 
Cross-Over Flow Chart in Section 6.1.
Post-treatment Period
When subjects discontinue study treatment, the assessments at the End of Treatment visit 
should be completed.
Furthermore, subjects will be required to return to the clinic for post-treatment follow-up 
visits to monitor safety. The Post-Treatment Safety Follow-Up visit should occur 
approximately 30 days after the last dose of study treatment. If a subject initiates a new 
anticancer therapy within 30 days after the last dose of study treatment, the Post-Treatment
Safety Follow-Up visit should occur before the first dose of the new therapy.
After treatment discontinuation, subjects will be monitored for AEs and SAEs for 90 days. 
Subjects who initiate new anticancer therapy less than 30 days after study treatment 
discontinuation will be monitored for AEs/SAEs for 30 days. Subjects who initiate new 
anticancer therapy between 30 days and 90 days after study treatment discontinuation will be 
monitored for AEs/SAEs until the day new anticancer therapy is initiated.
Subjects who discontinue treatment for reasons other than confirmed disease progression will 
have post-treatment follow-up for disease status until disease progression, initiating a new 
anticancer therapy, withdrawing consent for trial participation, or becoming lost to follow-up, 
whichever occurs first.
After confirmed disease progression, each subject will be contacted by telephone every 
12 weeks for survival until withdrawal of consent to participate in the trial, becoming lost to
follow-up, death, or the end of the trial, whichever occurs first.
Survival Status
To ensure current and complete survival data is available, updated survival status may be 
requested by the Sponsor during the course of the study. 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 a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
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unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after documented informed consent is provided but before 
treatment allocation/randomization must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. From the time of treatment allocation/randomization through 90
days following cessation of treatment, all adverse events must be reported by the 
investigator. Subjects who initiate new anticancer therapy less than 30 days after study 
treatment discontinuation will be monitored for adverse events for 30 days. Subjects who 
initiate new anticancer therapy between 30 days and 90 days after study treatment 
discontinuation will be monitored for adverse events until the day new anticancer therapy is 
initiated. Adverse events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The investigator will make every attempt to follow all subjects 
with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For the purpose of this trial, an overdose of MK-7684 or MK-7684A will be defined as any 
dose exceeding the prescribed dose by ≥20%. An overdose of pembrolizumab will be defined 
as any dose ≥1000 mg (i.e., ≥5 times the indicated dose).
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No specific information is available on the treatment of overdose of MK-7684, MK-7684A,
or pembrolizumab. In the event of overdose, the subject should be observed closely for signs 
of toxicity. Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after documented informed consent is provided but 
before treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 30 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
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●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 11 for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
For the time period beginning when documented informed consent is provided until 
treatment allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
All serious adverse events will be recorded from the time of treatment allocation. Subjects 
will be monitored for serious adverse events 90 days after treatment discontinuation. Subjects 
who initiate anticancer therapy less than 30 days after study treatment discontinuation will be 
monitored for serious adverse events for 30 days. Subjects who initiate new anticancer 
therapy between 30 days and 90 days after study treatment discontinuation will be monitored 
for serious adverse events until the day new anticancer therapy is initiated.
Serious adverse events or follow up to a serious adverse event, including death due to any 
cause, whether or not related to the Sponsor’s product, must be reported within 24 hours to 
the Sponsor either by electronic media or paper. Electronic reporting procedures can be 
found in the EDC data entry guidelines. Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when documented informed consent is provided until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
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subject must be reported within 24 hours to the Sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
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).
3. a Grade 3 or higher infusion-related reaction.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a MSD product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and key 
secondary analyses of the trial. Exploratory and other non-confirmatory analyses will be
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
If, after the trial has begun, changes are made to primary and/or key 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 trial. Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full details are
in the Statistical Analysis Plan (SAP), Section 8.2 to Section 8.12.
Trial Design 
Overview
Phase 1/1b trial of MK-7684 monotherapy and MK-7684 in combination with 
pembrolizumab in subjects with advanced solid tumors. The trial applies an mTPI 
design for dose escalation and confirmation of preliminary RPTDs, followed by an 
expansion phase with 
 (NSCLC, 
 
 
 
Final RPTDs for MK-7684 when used as 
monotherapy and in combination with pembrolizumab will be determined using PK 
and PD endpoints, as well as all available safety data.
Analysis 
Populations
Safety (Primary): All-Subjects-as-Treated (ASaT)
PK (Secondary): Per-Protocol (PP)
Efficacy (Secondary & Exploratory): Full Analysis Set (FAS)
Primary 
Endpoint(s)
Safety: all available safety data from subjects in Part A and Part B, including DLT 
rates and the cumulative incidence of late toxicities (i.e., toxicities that occur after 
the 21-day DLT observation period)
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Key Secondary 
Endpoints
PK parameters
of MK-7684 monotherapy,
MK-7684
in combination with 
pembrolizumab,
 
 
 
 
 
 
ORR in subjects treated with MK-7684 monotherapy, MK-7684 in combination with 
pembrolizumab,
 
 
 
Statistical 
Methods for Key 
Efficacy/
Pharmacokinetic 
Analyses
Efficacy analyses are documented in the sSAP.
PK concentrations of study treatments will be summarized by planned visit and time 
for each dose separately; PK parameters of MK-7684 will be summarized by dose.
Treatment
Assignment
In all subjects in Part A 
 
and
in all subjects in Part B
 
 
 
subjects will be allocated by non-random assignment to receive 
MK-7684 monotherapy (Arm 1) or MK-7684 in combination with pembrolizumab 
(Arm 2) centrally through an IVRS/IWRS. Allocation will alternate between the 
2 arms when both arms are open for enrollment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The trial is open-label.
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Statistical 
Methods for Key 
Safety Analyses
Summary statistics (counts, percentages, means, standard deviations, etc.) will be 
provided for the safety endpoints as appropriate. The 2-dimensional pool-adjacent-
violators algorithm [1] that forces the DLT rate estimates to be non-decreasing with 
dose levels and to be no higher in the MK-7684 monotherapy arm (Arm 1) than in 
the combination therapy arm (Arm 2) will be used to estimate the DLT rates across 
doses. The estimates of the DLT rates among subjects treated at the preliminary 
RPTDs of MK-7684 when used as monotherapy and when used in combination with 
pembrolizumab and the 80% Bayesian credible intervals with prior distribution Beta
(1, 1) for the estimates will be provided.
Interim Analyses
Multiplicity
No multiplicity adjustment is planned for this Phase 1/1b trial.
Sample Size and 
Power 
The overall sample size for this trial depends on the observed DLT profiles of 
MK-7684 monotherapy (Arm 1), MK-7684 in combination with pembrolizumab
(Arm 2), 
 
 
 A maximum sample 
size of 492 subjects will be used for trial planning purposes.
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, i.e., subjects, investigators, and Sponsor personnel will be aware of 
subject treatment assignment after each subject is enrolled and treatment is assigned.
Trial Objectives
Objectives of the trial are outlined in Section 3.0.
Analysis Endpoints
Efficacy/Pharmacokinetic Endpoints
Overall response rate is a secondary endpoint of the trial. Overall response rate is defined as 
the proportion of subjects in the analysis population who experience CR or PR at any time 
during the trial using RECIST, version 1.1 as assessed by investigator review. For subjects 
with ES-SCLC treated in Arm 5, 6-month PFS rate is also a secondary endpoint. PFS is 
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defined as the time from the first dose of study treatment to the first documented disease 
progression per RECIST 1.1 as assessed by investigator review or death due to any cause, 
whichever occurs first. The 6-month PFS rate is defined as the percentage of subjects who 
achieve a 6-month PFS as estimated by the Kaplan-Meier method. 
 
Pharmacokinetic endpoints include serum concentrations of MK-7684 (Arms 1 through 5)
and pembrolizumab (Arms 2 through 5), as well as any derived PK parameters.
Safety Endpoints
The primary safety endpoint is the rate of DLTs. The toxicities and grades experienced by 
subjects who have received study treatment, including AEs and SAEs will be summarized.
Of particular interest are infusion-related reactions and immune-related AEs. Other safety 
measures evaluated in all parts of the trial include laboratory safety assessments, ECGs, vital 
signs, and physical examinations.
A description of safety measures is provided in Section 7.0.
Analysis Populations
Safety Analysis Population
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this trial. The ASaT population consists of all subjects who received at least one dose of 
study treatment. In case of treatment administration errors, subjects will be analyzed 
according to the treatment they actually received. For DLT evaluation, ASaT subjects that 
were observed for safety for 21 days after the first dose of assigned treatment or experienced 
a DLT prior to 21 days after the first dose of assigned treatment will be used. Data from 
subjects who experienced disease progression in the monotherapy arm and crossed over into 
the combination arm will be presented separately; data from these subjects will not be 
included in the DLT evaluation.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Pharmacokinetic Analysis and Target Engagement Populations
The Per-Protocol (PP) population will be used for the analysis of the PK and target 
engagement data in this trial. The PP population consists of the subset of subjects who 
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complied with the protocol sufficiently to ensure that the data they generated will be likely to 
exhibit the effects of treatment, according to the underlying scientific model. Compliance 
covers such considerations as exposure to treatment, availability of measurements, and 
absence of major protocol violations. Major protocol violators will be identified, to the extent 
possible, by individuals responsible for data collection/compliance, and its analysis and 
interpretation. Any subjects or data values excluded from analysis will be identified in the 
CSR, along with the reasons for exclusion. At the end of the trial, all subjects who were 
compliant with the trial procedures and have available data from at least one treatment may
be included in the PP analysis dataset. Data from subjects who experienced disease 
progression in the monotherapy arm and crossed over into the combination arm will be 
presented separately.
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will be used for the analysis of secondary and
exploratory efficacy data in this trial. The FAS population consists of all subjects with a 
baseline scan with measurable disease by investigator assessment who were administered a 
dose of study treatment regardless of dose level. Data from subjects who experienced disease 
progression in the monotherapy arm and crossed over into the combination arm will be 
presented separately.
Statistical Methods
Statistical Methods for Efficacy Analyses
For the secondary endpoint of ORR, the point estimate and 95% CI will be evaluated 
separately in subjects treated with MK-7684 monotherapy and subjects treated with 
MK-7684 in combination with pembrolizumab
 
 
 
 
 
 
 
 
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
Adverse events will be summarized by counts and frequencies for each dose level. 
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
Dose-limiting toxicities will be listed, and further summarized by dose level. The 
pool-adjacent-violators algorithm [1] that forces the DLT rate estimates to be non-decreasing 
with dose levels and pools adjacent violators for weighted estimates by sample size, will be 
used to estimate the DLT rates across doses in Arm 1 and Arm 2. The estimates of the DLT 
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rates among subjects treated at the preliminary RPTDs and the 80% Bayesian credible 
intervals based on a prior distribution of Beta (1,1) for the estimates will be provided.
 
 
 
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.
Population Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic and PD modeling analyses will be done on an ongoing basis throughout the 
trial and at the end of the trial. These analyses will be used to explore the relationships 
among PK, target engagement, exploratory biomarkers, and tumor response measurements.
 
Interim Analyses
Multiplicity
There will be no multiplicity control in this trial.
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Sample Size and Power Calculations
During Part A (dose escalation and confirmation), approximately 102 subjects (38 subjects 
each in Arm 1 and Arm 2, 
 are expected to be 
enrolled. The actual sample size will depend on the safety profiles of MK-7684 in each 
treatment arm, but is expected to be in line with a typical Phase 1 first-in-human oncology 
trial.
In Part B (expansion phase), approximately 338 to 390 subjects (94 to 120 subjects with 
NSCLC, 
 
 
 
are expected to be enrolled. Data 
from subjects treated at the preliminary RPTDs in Part A will be included in the analysis of
Part B if they meet the specifications described in Inclusion Criterion 1 (Section 5.1.2).
A maximum sample size of 492 subjects will be used for trial planning purposes.
Subgroup Analyses and Effect of Baseline Factors
Subgroup analyses of the secondary efficacy endpoint (ORR) will be conducted by treatment 
arm, dose level, and tumor type.
 
 
 
 
 
 
 
 
 
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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.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 12. Chemotherapy
will be sourced locally by the site.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
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Table 12
Product Descriptions
Treatment 
Group(s)
Product Name and 
Potency
Dose(s)
Route of 
Administration 
and Frequency
Source
Arms 1, 2, 3, and 
5
MK-7684
50 mg/mL,
2.0-mL vial, solution 
for infusion
Escalating doses 
based on 
pre-specified 
dose-limiting 
toxicity (DLT) 
criteria / 
RPTD(s)
Intravenous 
infusion on 
Day 1 of each 
21-day cycle
Centrally by 
the Sponsor
Arms 2, 3, and 5
Pembrolizumab 
(MK-3475)
25 mg/mL,
4.0-mL vial, solution 
for infusion
200 mg
Intravenous 
infusion on 
Day 1 of each 
21-day cycle
Centrally by 
the Sponsor
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Sites will receive open-label kits of MK-7684, MK-3475/pembrolizumab, 
as 
outlined in the Procedure Manual. Each kit of MK-7684 will contain 1 vial. Each kit of 
MK-3475/pembrolizumab will contain 2 vials.
.
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Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
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Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By providing documented informed
consent, the subject agrees to this process.  If trial documents will be photocopied during the 
process of verifying worksheet/case report form information, the subject will be identified by 
unique code only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
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Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in Section 12.1 -
Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
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documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
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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 subject 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 subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
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.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
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products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in 
patients with advanced colorectal carcinoma.
PLoS One. 2017 Dec 
28;12(12):e0189848.
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[70]
Fuchs SC, Doi T, Jang RWJ, Muro K, Satoh T, Machado M, et al. KEYNOTE-
059 cohort 1: efficacy and safety of pembrolizumab (pembro) monotherapy in 
patients with previously treated advanced gastric cancer [abstract]. Presented at: 
2017 American Society of Clinical Oncology (ASCO) Annual Meeting; 2017 
Jun 2-6; Chicago, IL. J Clin Oncol. 2017;35(15 suppl). Abstract no. 4003.
[71]
KEYTRUDA (pembrolizumab) Investigator's Brochure, Edition Number 17, 26-
JUL-2019.
[72]
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. 
American Society of Clinical Oncology/College Of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and 
progesterone receptors in breast cancer. J Clin Oncol. 2010 Jun 1;28(16):2784-
95.
[73]
Ji Y, Li Y, Li B, Bekele N. Dose-finding in phase I clinical trials based on 
toxicity probability intervals. Clin Trials 2007;4:235-44.
[74]
Ji Y, Wang S-J. Modified toxicity probability interval design: a safer and more 
reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol 
2013;31:1-12.
[75]
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 
2006 update of recommendations for the use of white blood cell growth factors: 
An evidence-based clinical practice guideline. J Clin Oncol 2006;24(19):3187-
205.
[76]
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
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12.0 APPENDICES
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.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.6 – Future Biomedical 
Research Sample Collection7.1.3.6 – Future Biomedical Research Sample Collection will 
be used to study various causes for how subjects may respond to a drug/vaccine.  Future 
biomedical research specimen(s) will be stored to provide a resource for future trials 
conducted by the Sponsor focused on the study of biomarkers responsible for how a 
drug/vaccine enters and is removed by the body, how a drug/vaccine works, other 
pathways a drug/vaccine may interact with, or other aspects of disease. The specimen(s) 
may be used for future assay development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the MSD Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
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mailbox (clinical.specimen.management@MSD.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair.
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Cockcroft-Gault Formula
Calculated Creatinine Clearance = Sex × ((140 - Age) / (Serum Creatinine))
× (Weight / 72), where male = 1 and female = 0.85
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Abbreviations
Abbreviation/Term
Definition
ADA
Anti-drug antibody
AE
Adverse event
ALK
Anaplastic lymphoma kinase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the curve 
BCG
Bacillus Calmette-Guérin
β-hCG
β-human chorionic gonadotropin
BRCA1/2
Breast cancer susceptibility gene 1/2
BUN
Blood urea nitrogen
CA 125
Cancer antigen 125
CD3ζ
CD3 zeta
CE
Conformité Européene
CEA
Carcinoembryonic antigen
CFR
Code of Federal Regulations
CI
Coordinating investigator
Cmax
Maximum concentration
CNS
Central nervous system
CO2
Carbon dioxide
CPS
Combined positive score
CR
Complete response
CRC
Colorectal cancer
CrCl
Creatinine clearance
CRF
Case report form
CRU
Clinical research unit
CSF
Colony-stimulating factor
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
Ctrough
Trough concentration in blood
DCR
Disease control rate
DL
Dose level
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response
ECG
Electrocardiogram
ECI
Event of clinical interest
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Abbreviation/Term
Definition
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
EGFR
Epidermal growth factor receptor
ER
Estrogen receptor
ERC
Ethics Review Committee
ES-SCLC
Extensive-stage small cell lung cancer
FAS
Full analysis set
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GEP
Gene expression profile
GFR
Glomerular filtration rate
GGT
Gamma glutamyl transferase
GI
Gastrointestinal 
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HER2
Human epidermal growth factor receptor 2
HIV
Human immunodeficiency virus
HPV
Human papillomavirus
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFNγ
Interferon gamma
Ig
Immunoglobulin
IgV
Immunoglobulin variable
IHC
Immunohistochemistry 
IL
Interleukin
ILD
Interstitial lung disease
IM
Intramuscular
INR
International normalized ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITIM
Immunoreceptor tyrosine-based inhibition motif
ITT
Immunoglobulin tail tyrosine
IUD
Intrauterine device
IV
Intravenous
IVD
In vitro diagnostic
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
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Abbreviation/Term
Definition
Km
Michaelis-Menten constant
LDH
Lactate dehydrogenase
LS-SCLC
Limited-stage small cell lung cancer
mAb
Monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
MCP-1
Monocyte chemoattractant protein 1
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MSI
Microsatellite instability
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
NCI
National Cancer Institute
NK cell
Natural killer cell
NKT cell
Natural killer T cell
NOAEL
No observed adverse effect level
NSAID
Non-steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Overall response rate
OS
Overall survival
OTC
Over-the-counter
PBMC
Peripheral blood mononuclear cell
PCI
Prophylactic cranial irradiation
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s) or Progressive disease
PD-1
Programmed death 1
PD-L1
Programmed cell death ligand 1
PD-L2
Programmed cell death ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PI
Probability interval
PIN
Personal identification number
PK
Pharmacokinetic(s)
PKCθ
Protein kinase C-theta
PARP
Poly(ADP-ribose) polymerase
PP
Per-protocol
PR
Partial response or Progesterone receptor
PT
Prothrombin time
PTT
Partial thromboplastin time
PVR
Poliovirus receptor
PVRL
Poliovirus receptor-related 2
RA
Receptor availability
RBC
Red blood cell
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
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Abbreviation/Term
Definition
RNA
Ribonucleic acid
RPTD
Recommended Phase 2 dose
SAC
Scientific Advisory Committee
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCLC
Small cell lung cancer
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SNP
Single nucleotide polymorphism
SOC
Standard of care
SOP
Standard Operating Procedure
sSAP
Supplementary Statistical Analysis Plan
t1/2
Half-life
TCR
T-cell receptor
Teff
Effector T cell
TIGIT
T-cell immunoglobulin and immunoreceptor tyrosine-based 
inhibitory motif 
TIL
Tumor infiltrating lymphocyte
Tim-3
T-cell immunoglobulin and mucin domain containing-3
Tmax
Time to maximum concentration
TNBC
Triple-negative breast cancer
TNF
Tumor necrosis factor alpha
TPI
Toxicity probability interval
TPS
Tumor Proportion Score
Treg
Regulatory T cell
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor
WBC
White blood cell
ZAP70
Zeta-chain-associated protein kinase
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MASCC 2016 Guidelines
Rolia F, Molassiotis A, Herrstedt J, et al. 2016 MASCC and ESMO guideline update for the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea 
and vomiting in advanced cancer patients. Ann Oncol (2016) 27 (suppl_5): v119-v133, 2016.
http://www.mascc.org/antiemetic-guidelines
Investigators may use local equivalent or more current guidelines, if available.
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Country-specific Requirements
Japan-specific Requirements
Japan has country-specific requirements for the protocol which are summarized below.
Section 5.2.1.4 – Definition of Dose-limiting Toxicity
In addition to all DLTs listed, the following will be considered a DLT for subjects in Japan:

Thrombocytopenia if associated with bleeding that requires a platelet transfusion.
Section 5.2.3.1 – Dose Modification and Toxicity Management for Adverse Events 
Associated with Pembrolizumab and MK-7684/MK-7684A
In addition to the MK-7684 dose modification and treatment discontinuation guidelines listed 
in Table 6, the investigator will use the guidelines in Table 13 for events of pneumonitis 
and/or interstitial lung disease deemed related to MK-7684 for subjects in Japan:
Table 13
Japan-specific MK-7684 Dose Modification and Treatment Discontinuation 
Guidelines for Treatment-related Adverse Events
Toxicity
Interrupt 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting 
Treatment
Criteria for 
Discontinuation after 
Consultation with 
Sponsor
Pneumonitis and/or Interstitial Lung Disease1, 2:
Grade 2
Yes
MK-7684 can be resumed after AE has improved to Grade 1 or less 
and corticosteroid has been tapered. MK-7684 should be 
permanently discontinued if AE does not resolve within 12 weeks 
of last dose or corticosteroids cannot be reduced to ≤10 mg 
prednisone or equivalent per day within 12 weeks.
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
N/A
N/A
N/A
1. Administer corticosteroids (initial dose of 1-2 mg/kg prednisone or equivalent) followed by taper.
2. Monitor participants for signs and symptoms of pneumonitis/interstitial lung disease.
Evaluate participants with suspected pneumonitis/interstitial lung disease with radiographic imaging and initiate 
corticosteroid treatment. Add prophylactic antibiotics for opportunistic infections.
Arm 4 (treatment with co-formulated MK-7684A product) is not open to sites in Japan.
In Table 6, dose interruption/discontinuation and toxicity management guidelines listed for 
pneumonitis will also apply to interstitial lung disease associated with pembrolizumab.
Section 5.5.2 – Prohibited Concomitant Medications
In addition to all prohibited concomitant medications listed, the following is a prohibited 
concomitant medication for subjects in Japan except for subjects with ES-SCLC enrolled as 
part of Amendment 12:

Prophylactic use of granulocyte colony-stimulating factor (G-CSF) during the DLT 
observation period is not permitted.
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Section 5.7.4 - Use in Nursing Women
In addition to the information given in Section 5.7.4, the following sentence is added for 
subjects in Japan:

Subjects who have discontinued breastfeeding but wish to restart are also ineligible.
Section 6.4 - Trial Flow Chart for Subjects with ES-SCLC Enrolled as Part of 
Amendment 12
•
To assist with early diagnosis of pneumonitis/interstitial lung disease (ILD) in study 
participants, the following items, such as SpO2, CRP, KL-6, and SP-D, will be measured 
in this study. These items should be measured as follows:

SpO2 at the time of vital sign assessment.

CRP, KL-6, and SP-D at screening1, prior to dosing on Day 1 of every cycle, at the 
End of Treatment visit and at the Post-Treatment Safety Follow-Up visit (30 days 
after the last dose).
1Should be measured at the time
of clinical laboratory tests
(such as 
hematology/chemistry).
If pneumonitis/ILD occurs, regardless of causality with study treatment, an independent ILD 
evaluation committee will conduct adjudication of cases of the pneumonitis/ILD. For this 
purpose, relevant data, such as chest imaging (from baseline to the recovery of 
pneumonitis/ILD) will be submitted to MSD K.K.
Section 7.1.2 –Clinical Procedures/Assessments
For subjects in Japan only, pulse oximetry will be performed using local standard procedures 
by the investigator or qualified designee at the timepoints outlined in the Trial Flow Chart 
(Section 6.0).
Clinical Study Conduct System
The clinical study conduct system in Japanese is included in the accompanying documents. 
The contents are as follows:
1. Sponsor
1.1 Name and Address of Sponsor
1.2 Sponsor’s Representative
1.3 Medical Expert
1.4 Field Monitor (CRA) Representative
2. Contract Research Organization
2.1 External Monitoring Agency
2.2 Patient Registration Center
2.3 Emergency Unblinding Call Center
2.4 MSD Emergency Center
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3. Central Testing Facilities
4. Investigators
5. Japan Enrollment Policy
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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