Clinical trial NCT04725188
Conditions: Metastatic Non Small Cell Lung Cancer
Keywords: Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1) Programmed Cell Death Receptor Ligand 2 (PD-L2) PD-1 PDL1 PD-L1 PD-L2
Sponsor: Merck Sharp & Dohme LLC
Start date: 2021-04-20; Completion date: 2024-10-17
Enrollment: 255 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to compare pembrolizumab/vibostolimab coformulation (MK-7684A) plus docetaxel or pembrolizumab/vibostolimab coformulation to normal saline placebo plus docetaxel. Participants with metastatic non-small cell lung cancer (NSCLC) and progressive disease (PD) after platinum doublet chemotherapy and treatment with one prior anti- programmed cell death 1 (PD-1)/ programmed cell death ligand 1(PD-L1) monoclonal antibody (mAb). MK-7684A is a coformulation product of pembrolizumab/vibostolimab. The dual primary hypotheses of the study are pembrolizumab/vibostolimab coformulation plus docetaxel and pembrolizumab/vibostolimab coformulation is superior to normal saline placebo plus docetaxel with respect to progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).

Detailed description:
Participants may receive additional 17 cycles of pembrolizumab/vibostolimab (each cycle length = 21 days) for an additional 1 year of treatment as second course phase at investigator's discretion.

Arms: arm 1: Participants receive pembrolizumab/vibostolimab (coformulation of 200 mg pembrolizumab and 200 mg vibostolimab) via intravenous (IV) infusion once every 3 weeks (Q3W) for up to 35 cycles up to approximately 2 years plus docetaxel 75 mg/m\^2 via IV infusion Q3W. Each cycle will be 21 days. arm 2: Participants receive pembrolizumab/vibostolimab (coformulation of 200 mg pembrolizumab and 200 mg vibostolimab) via IV infusion Q3W for up to 35 cycles up to approximately 2 years. Each cycle will be 21 days. arm 3: Participants receive normal saline placebo via IV infusion Q3W for up to 35 cycles up to approximately 2 years plus docetaxel 75 mg/m\^2 IV infusion Q3W. Each cycle will be 21 days.
Interventions: intervention 1: Pembrolizumab/Vibostolimab coformulation intervention 2: Docetaxel intervention 3: Placebo
Intervention descriptions: intervention 1: Pembrolizumab 200 mg + vibostolimab 200 mg/20 mL vial IV infusion Q3W up to approximately 2 years. intervention 2: Docetaxel 75 mg\^m2 IV infusion Q3W until discontinuation due to progressive disease or unacceptable toxicity. Docetaxel will serve as part of an experimental treatment in Arm 1, and as an active comparator in Arm 3. intervention 3: Normal saline IV infusion Q3W up to approximately 2 years

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2, Multicenter, Randomized Study to Compare the 
Efficacy and Safety of MK-7684A or MK-7684A Plus 
Docetaxel Versus Docetaxel Monotherapy in the Treatment of 
Participants With Metastatic Non-small Cell Lung Cancer 
With Progressive Disease After Treatment With a Platinum 
Doublet Chemotherapy and Immunotherapy
NCT04725188
19 December 2022


PRODUCT: MK-7684A  
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PROTOCOL/AMENDMENT NO.: 002-02
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2, Multicenter, Randomized Study to Compare the Efficacy and 
Safety of MK-7684A or MK-7684A Plus Docetaxel Versus Docetaxel Monotherapy in the 
Treatment of Participants With Metastatic Non-small Cell Lung Cancer With Progressive 
Disease After Treatment With a Platinum Doublet Chemotherapy and Immunotherapy
Protocol Number: 002-02
Compound Number: MK-7684A
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
147424
EudraCT
2020-004034-38
EU CT
2022-500420-30-00
Approval Date: 19 December 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
19-DEC-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted in an entity name 
change and update to the address. Additional changes were made throughout to align 
with the EU CTR and for clarification of study procedures.
Amendment 01
28-FEB-2021
The Dose Modification and Toxicity Management Guidelines for irAEs and table were 
updated to align with the USPI as requested by the FDA. Also, per FDA’s request, 
added polysorbate 80 as an example of severe hypersensitivity to study treatment.
Original Protocol
19-OCT-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address. Additional changes were made throughout to align with the EU 
CTR and for clarification of study procedures.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
10.1.1 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.
Title Page
Added EU CT number.
Alignment with the EU CTR.
1.3.1 Initial Treatment Phase
Corrected the time window for assessment 
of ECOG performance status during the 
screening period before randomization of 
the participant.
Participants should have ECOG performance status of 
0 to 1 assessed within 7 days prior to randomization.
1.3.1 Initial Treatment Phase
Added predose PK samples at Safety 
Follow-up visit.
Pharmacokinetics samples should be collected for all 
participants during the Safety Follow-up visit (30 days 
post last dose).
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Section # and Name
Description of Change 
Brief Rationale 
4.4 Beginning and End of 
Study Definition
Added statements regarding when the 
study ends for purposes of analysis and 
reporting and the EEA local start of study 
definition.
Alignment with the EU CTR.
5 Study Population
Added text to clarify the collection, use, 
and confidentiality of demographic data 
provided by participants.
Alignment with the EU CTR.
5.4 Screen Failures
Deleted the requirement of consultation 
between the investigator and Sponsor and 
written documentation for rescreening 
after screen failure.
Participants may be rescreened after initially failing to 
meet the inclusion/exclusion criteria.
6.1 Study Intervention(s) 
Administered
Replaced “NIMP” with “NIMP/AxMP.”
In the “Use” column, “Experimental” was 
replaced with “Test Product.”
Alignment with the EU CTR.
6.5.1 Rescue Medications 
and Supportive Care
Clarified that participants in the docetaxel 
arm should receive premedication with 
corticosteroids for 3 days starting 1 day
before docetaxel administration.
Consistency with Section 8.1.8.1.
8.3.2 Vital Signs
Corrected the frequency of BP 
measurements by removing the 
requirement for 3 consecutive BP readings 
at each visit.
Only 1 BP measurement is needed for participants at 
each visit (unless additional BP measurements are 
medically indicated by the investigator or medically 
qualified designee [consistent with local 
requirements]).
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Section # and Name
Description of Change 
Brief Rationale 
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Added that investigators need to document 
if an SAE was associated with a 
medication error, misuse, or abuse.
Alignment with the EU CTR.
10.3 Appendix 3 Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
Added a new section with definitions of 
medication error, misuse, and abuse.
Alignment with the EU CTR.
Throughout Document
Minor administrative, formatting, 
grammatical, and typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of the 
intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.2.1
Initial Treatment Phase ................................................................................19
1.2.2
Second Course Treatment Phase..................................................................20
1.3
Schedule of Activities...........................................................................................21
1.3.1
Initial Treatment Phase ................................................................................21
1.3.2
Second Course Treatment Phase (Arms 1 and 2 Only) ...............................26
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................31
2.2.1.1
MK-7684 Background .......................................................................31
2.2.1.2
Pembrolizumab Background..............................................................32
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.2.1
MK-7684A Preclinical Studies..........................................................32
2.2.2.2
Pembrolizumab Preclinical and Clinical Studies...............................35
2.2.3
Ongoing Clinical Studies.............................................................................35
2.2.3.1
MK-7684 Ongoing Clinical Studies ..................................................35
2.2.3.2
Pembrolizumab Ongoing Clinical Studies.........................................36
2.3
Benefit/Risk Assessment......................................................................................37
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................37
4
STUDY DESIGN............................................................................................................39
4.1
Overall Design......................................................................................................39
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................41
4.2.1.1
Efficacy Endpoints.............................................................................41
4.2.1.2
Safety Endpoints................................................................................41
4.2.1.3
Pharmacokinetic Endpoints ...............................................................42
4.2.1.4
Planned Exploratory Biomarker Research.........................................42
4.2.1.5
Future Biomedical Research..............................................................43
4.2.2
Rationale for the Use of Comparator/Placebo .............................................44
4.3
Justification for Dose...........................................................................................44
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4.3.1
MK-7684A...................................................................................................44
4.3.2
Pembrolizumab ............................................................................................45
4.3.3
Maximum Dose/Exposure for This Study ...................................................45
4.4
Beginning and End of Study Definition .............................................................46
4.4.1
Clinical Criteria for Early Study Termination .............................................46
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................47
5.2
Exclusion Criteria................................................................................................52
5.3
Lifestyle Considerations......................................................................................54
5.3.1
Meals and Dietary Restrictions....................................................................54
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................54
5.3.3
Activity Restrictions ....................................................................................54
5.4
Screen Failures.....................................................................................................54
5.5
Participant Replacement Strategy......................................................................54
6
STUDY INTERVENTION............................................................................................55
6.1
Study Intervention(s) Administered...................................................................55
6.2
Preparation/Handling/Storage/Accountability .................................................58
6.2.1
Dose Preparation..........................................................................................58
6.2.2
Handling, Storage, and Accountability........................................................58
6.3
Measures to Minimize Bias: Randomization and Blinding..............................59
6.3.1
Intervention Assignment..............................................................................59
6.3.2
Stratification.................................................................................................59
6.3.3
Blinding........................................................................................................59
6.4
Study Intervention Compliance..........................................................................59
6.5
Concomitant Therapy..........................................................................................60
6.5.1
Rescue Medications and Supportive Care ...................................................61
6.6
Dose Modification (Escalation/Titration/Other)...............................................62
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................62
6.6.2
Initial Treatment or First Course..................................................................69
6.6.3
Second Course .............................................................................................70
6.7
Intervention After the End of the Study............................................................70
6.8
Clinical Supplies Disclosure................................................................................70
6.9
Standard Policies..................................................................................................71
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................71
7.1
Discontinuation of Study Intervention...............................................................71
7.2
Participant Withdrawal From the Study...........................................................72
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7.3
Lost to Follow-up .................................................................................................72
8
STUDY ASSESSMENTS AND PROCEDURES........................................................73
8.1
Administrative and General Procedures ...........................................................74
8.1.1
Informed Consent.........................................................................................74
8.1.1.1
General Informed Consent.................................................................74
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................74
8.1.2
Inclusion/Exclusion Criteria ........................................................................75
8.1.3
Participant Identification Card.....................................................................75
8.1.4
Medical History ...........................................................................................75
8.1.5
Prior and Concomitant Medications Review...............................................75
8.1.5.1
Prior Medications...............................................................................75
8.1.5.2
Concomitant Medications..................................................................75
8.1.6
Assignment of Screening Number...............................................................76
8.1.7
Assignment of Treatment/Randomization Number.....................................76
8.1.8
Study Intervention Administration ..............................................................76
8.1.8.1
Timing of Dose Administration.........................................................76
8.1.9
Discontinuation and Withdrawal .................................................................77
8.1.9.1
Withdrawal From Future Biomedical Research ................................77
8.1.10
Participant Blinding/Unblinding..................................................................77
8.1.11
Calibration of Equipment.............................................................................78
8.1.12
Tumor Tissue for Biomarker Status.............................................................78
8.2
Efficacy Assessments ...........................................................................................78
8.2.1
Tumor Imaging and Assessment of Disease................................................78
8.2.1.1
Initial Tumor Imaging........................................................................79
8.2.1.2
Tumor Imaging During the Study......................................................80
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................80
8.2.1.4
Second Course (Retreatment) Tumor Imaging..................................81
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................81
8.3
Safety Assessments...............................................................................................83
8.3.1
Physical Examinations.................................................................................84
8.3.1.1
Full Physical Examination.................................................................84
8.3.1.2
Directed Physical Examination..........................................................84
8.3.2
Vital Signs....................................................................................................84
8.3.3
Electrocardiograms ......................................................................................85
8.3.4
Clinical Safety Laboratory Assessments .....................................................85
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................85
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8.3.5
Pregnancy Testing........................................................................................85
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................86
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................86
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................87
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......89
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...89
8.4.4
Regulatory Reporting Requirements for SAE .............................................89
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................89
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................90
8.4.7
Events of Clinical Interest............................................................................90
8.5
Treatment of Overdose........................................................................................90
8.6
Pharmacokinetics.................................................................................................91
8.6.1
Blood Collection for Plasma MK-7684 and Pembrolizumab......................91
8.6.1.1
Blood Collection for PK ....................................................................91
8.6.1.2
Blood Collection for Antidrug Antibodies ........................................91
8.7
Pharmacodynamics..............................................................................................91
8.8
Biomarkers ...........................................................................................................91
8.8.1
Planned Genetic Analysis Sample Collection..............................................92
8.9
Future Biomedical Research Sample Collection...............................................92
8.10
Health Economics Medical Resource Utilization and Health Economics.......92
8.11
Visit Requirements...............................................................................................92
8.11.1
Screening......................................................................................................93
8.11.2
Initial Treatment Period ...............................................................................93
8.11.3
Second Course Treatment Phase..................................................................93
8.11.4
Discontinued Participants Continuing to be Monitored in the Study ..........93
8.11.5
Posttreatment Visit.......................................................................................94
8.11.5.1
Safety Follow-up Visit.......................................................................94
8.11.5.2
Efficacy Follow-up Visits..................................................................94
8.11.5.3
Survival Follow-up Contacts .............................................................94
8.11.6
Survival Status .............................................................................................95
9
STATISTICAL ANALYSIS PLAN .............................................................................95
9.1
Statistical Analysis Plan Summary.....................................................................95
9.2
Responsibility for Analyses/In-house Blinding .................................................96
9.3
Hypotheses/Estimation ........................................................................................97
9.4
Analysis Endpoints...............................................................................................97
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9.4.1
Efficacy Endpoints.......................................................................................97
9.4.2
Safety Endpoints..........................................................................................97
9.5
Analysis Populations............................................................................................98
9.5.1
Efficacy Analysis Populations.....................................................................98
9.5.2
Safety Analysis Populations ........................................................................98
9.6
Statistical Methods...............................................................................................98
9.6.1
Statistical Methods for Efficacy Analyses...................................................98
9.6.1.1
Progression-free Survival (PFS) ........................................................98
9.6.1.2
Objective Response Rate (ORR) .....................................................100
9.6.1.3
Overall Survival (OS) ......................................................................100
9.6.1.4
Duration of Response (DOR)...........................................................101
9.6.1.5
Analysis Strategy for Key Efficacy Variables.................................101
9.6.2
Statistical Methods for Safety Analyses ....................................................102
9.6.3
Demographic and Baseline Characteristics ...............................................104
9.7
Interim Analyses ................................................................................................104
9.8
Multiplicity .........................................................................................................105
9.9
Sample Size and Power Calculations ...............................................................105
9.10
Subgroup Analyses.............................................................................................106
9.11
Compliance (Medication Adherence)...............................................................106
9.12
Extent of Exposure.............................................................................................106
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................107
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......107
10.1.1
Code of Conduct for Clinical Trials...........................................................107
10.1.2
Financial Disclosure...................................................................................109
10.1.3
Data Protection...........................................................................................109
10.1.3.1
Confidentiality of Data ....................................................................110
10.1.3.2
Confidentiality of Participant Records.............................................110
10.1.3.3
Confidentiality of IRB/IEC Information..........................................110
10.1.4
Committees Structure.................................................................................111
10.1.4.1
Steering Committee .........................................................................111
10.1.4.2
Executive Oversight Committee......................................................111
10.1.4.3
External Data Monitoring Committee .............................................111
10.1.5
Publication Policy......................................................................................111
10.1.6
Compliance with Study Registration and Results Posting Requirements .112
10.1.7
Compliance with Law, Audit, and Debarment ..........................................112
10.1.8
Data Quality Assurance .............................................................................113
10.1.9
Source Documents .....................................................................................114
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10.1.10
Study and Site Closure...............................................................................114
10.2
Appendix 2: Clinical Laboratory Tests............................................................115
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................117
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................117
10.3.2
Definition of AE ........................................................................................117
10.3.3
Definition of SAE ......................................................................................118
10.3.4
Additional Events Reported in the Same Manner as SAE.........................120
10.3.5
Recording AE and SAE .............................................................................120
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................123
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................125
10.5
Appendix 5: Contraceptive Guidance..............................................................126
10.5.1
Definitions..................................................................................................126
10.5.2
Contraception Requirements......................................................................127
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................128
10.7
Appendix 7: Country-specific Requirements..................................................133
10.7.1
Argentina-specific Requirements...............................................................133
10.7.2
France-specific Requirements....................................................................133
10.7.3
Germany-specific Requirements................................................................134
10.8
Appendix 8: Eastern Cooperative Oncology Group Performance Status....135
10.9
Appendix 9: Abbreviations ...............................................................................136
11
REFERENCES.............................................................................................................141
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LIST OF TABLES
Table 1
Study Schedule of Activities – Initial Treatment Phase ............................21
Table 2
Study Schedule of Activities - Second Course Treatment Phase ..............26
Table 3
Adequate Organ Function Laboratory Values ...........................................51
Table 4
Study Interventions....................................................................................56
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................64
Table 6
MK-7684A Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................68
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................88
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS...............100
Table 9
Censoring Rules for DOR........................................................................101
Table 10
Analysis Strategy for Key Efficacy Variables.........................................102
Table 11
Analysis Strategy for Safety Parameters..................................................104
Table 12
Protocol-required Safety Laboratory Assessments..................................115
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LIST OF FIGURES
Figure 1
Initial Treatment Schema...........................................................................19
Figure 2
Second Course Schema..............................................................................20
Figure 3
Results of a Dose Titration Study of Anti-TIGIT 18G10-IgG2a in the 
MC38 Colon Carcinoma Mouse Model.....................................................33
Figure 4
Antitumor Efficacy of Anti-TIGIT 18G10-IgG2a as a Single Agent 
and in Combination With Anti-PD-1(muDX400) Therapy in the 
Murine Subcutaneous CT26 Colon Carcinoma Tumor-bearing Model ....34
Figure 5
Decision-Making Process When Progression Observed by Investigator ..83
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, Multicenter, Randomized Study to Compare the Efficacy and 
Safety of MK-7684A or MK-7684A Plus Docetaxel Versus Docetaxel Monotherapy in the 
Treatment of Participants With Metastatic Non-small Cell Lung Cancer With Progressive 
Disease After Treatment With a Platinum Doublet Chemotherapy and Immunotherapy
Short Title: MK-7684A or MK-7684A plus docetaxel versus docetaxel for metastatic 
NSCLC after platinum doublet chemotherapy and immunotherapy
Acronym: MK-7684A-002
Hypotheses, Objectives, and Endpoints:
Male/female participants with metastatic NSCLC with progressive disease after treatment 
with a platinum doublet chemotherapy and immunotherapy who are 18 years of age or older 
may be enrolled in this study.
Primary Objectives
Primary Endpoints
- Objective: To compare MK-7684A + 
docetaxel to normal saline placebo + 
docetaxel with respect to PFS per RECIST 
1.1 by BICR.
- Hypothesis (H1): MK-7684A + docetaxel is 
superior to normal saline placebo + docetaxel 
with respect to PFS per RECIST 1.1 by 
BICR.
- Objective: To compare MK-7684A to 
normal saline placebo + docetaxel with 
respect to PFS per RECIST 1.1 as assessed 
by BICR.
- Hypothesis (H2): MK-7684A is superior to 
normal saline placebo + docetaxel with 
respect to PFS per RECIST 1.1 by BICR.
- PFS: The time from randomization to the 
first documented disease progression or 
death due to any cause, whichever occurs 
first.
Secondary Objectives
Secondary Endpoints
- To evaluate ORR in participants treated 
with MK-7684A +docetaxel, MK-7684A, or 
normal saline placebo + docetaxel per 
RECIST 1.1 by BICR.
- Objective response: defined as a 
confirmed CR or PR.
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- To evaluate OS in participants treated with 
MK-7684A + docetaxel, MK-7684A, or 
normal saline placebo + docetaxel.
- OS: defined as the time from 
randomization to the date of death due to 
any cause.
- To evaluate DOR per RECIST 1.1 as 
assessed by BICR in participants treated with 
MK-7684A + docetaxel, MK-7684A, or 
normal saline placebo + docetaxel.
- DOR: for participants who demonstrate 
confirmed CR or PR, DOR is defined as 
the time from first documented evidence of 
CR or PR until disease progression or 
death due to any cause, whichever occurs 
first.
- To evaluate the safety and tolerability in 
participants treated with MK-7684A + 
docetaxel, MK-7684A, or normal saline 
placebo + docetaxel. 
- AEs.
- Discontinuations of study intervention 
due to an AE.
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Metastatic NSCLC
Population
Participants with metastatic NSCLC who have experienced PD 
after platinum doublet chemotherapy and immunotherapy
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo- and active-control
Study Blinding
Arm 1 and Arm 3: Double-blind with in-house blinding
Arm 2: Unblinded Open-label
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of 
Study
The Sponsor estimates that the study will require approximately 5
years from the time the first participant (or their legally 
acceptable representative) provides documented informed consent 
until the last participant’s last study-related contact.
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Number of Participants:
Approximately 240 participants will be randomized in the study, as described in Section 9.1.
Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administr-
ation
Regimen/ 
Treatment 
Period
Use
Arm 1
MK-7684A 200 mg/ 
200 mga
Q3W
IV
Up to 35 cycles
Test Product
Docetaxel 75 mg/m2
Q3W
IV
Until a 
discontinuation 
criterion is met 
or as per 
approved local 
label
Arm 2
MK-7684A 200 mg/ 
200 mg a
Q3W
IV
Up to 35 cycles
Test Product
Arm 3
Normal 
saline 
placebo
0 mg
Q3W
IV
Up to 35 cycles
Placebo
Docetaxel 75 mg/m2
Q3W
IV
Until a 
discontinuation 
criterion is met
or as per 
approved local 
label
Test Product
Abbreviations: IV = Intravenous; Q3W = Every 3 weeks.
a. MK-7684A = coformulated as 200 mg MK-7684 and 200 mg pembrolizumab. 
Total 
Number of 
Intervention 
Groups/ 
Arms
3
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Duration of 
Participation
Each participant will participate in the study for approximately 3 years
from the time the participant provides documented informed consent 
through the final contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until disease progression is radiographically 
documented, per RECIST 1.1 and verified by BICR, confirmed by the site 
when clinically appropriate, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, investigator’s 
decision to discontinue the participant, or administrative reasons requiring 
cessation of treatment, or until the participant has received 35 
administrations of MK-7684A (approximately 2 years). Participants 
randomized to study intervention with docetaxel may receive docetaxel 
until a discontinuation criterion is met or as per approved local label. 
Participants who stop study intervention after receiving 35 administrations 
of MK-7684A for reasons other than disease progression or intolerability, 
or participants who attain a complete response and stop study intervention 
may be eligible for up to 17 additional administrations of MK-7684A 
(approximately 1 year) upon experiencing disease progression
(Section 6.6.3).
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1
and verified by BICR, the start of a new anti-cancer treatment, withdrawal 
of consent, pregnancy, death, or loss to follow-up. All participants will be 
followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study.
Study Governance Committees:
Steering Committee
Yes
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
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Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
1.2.1
Initial Treatment Phase 
The Initial Treatment study design is depicted in Figure 1.
Figure 1
Initial Treatment Schema
Abbreviations: ALK=anaplastic lymphoma kinase; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth 
factor receptor; IV=intravenous; NSCLC=non–small cell lung cancer; PD=progressive disease; PD-1=programmed cell 
death 1; PD-L1=programmed cell death ligand 1; Q3W=every 3 weeks; Q12W=every 12 weeks; Rand=randomization; 
RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1; ROS1=reactive oxygen species; TPS=tumor proportion 
score.
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1.2.2
Second Course Treatment Phase
The Second Course study design is depicted in Figure 2.
Figure 2
Second Course Schema
Abbreviations: IV=intravenous; PD=progressive disease; Q3W=every 3 weeks; Q12W=every 12 weeks.
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1.3
Schedule of Activities
1.3.1
Initial Treatment Phase
Table 1
Study Schedule of Activities – Initial Treatment Phase
Posttreatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy
Follow-
up
Survival
Follow-
up
All procedures are to be 
performed before study 
intervention administration unless 
otherwise indicated. Refer to 
Section 8.11 for visit details.
Visit Timing/Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Administrative Procedures
Informed consent
X
Documented informed consent must 
be obtained before any protocol-
specific screening procedures are 
performed. Reconsent required to 
continue study intervention after 
PD.
Informed consent for FBR
X
This is optional for the participant.
Inclusion/exclusion criteria
X
Participant identification card
X
X
Update with randomization number 
at C1D1.
Demographic and medical 
history
X
Prior and concomitant 
medications review
X
X
X
X
X
X
X
X
X
Prior concomitant medications 
received within 30 days before the 
first dose of study intervention 
through 30 days after the last dose 
of study intervention (or 90 days if 
used to treat an SAE) will be 
recorded.
Treatment randomization
X
Dose within 3 days of 
randomization.
Clinical Procedures/Assessments
Complete physical examination
X
X
To be performed within 7 days 
before start of study intervention.
Directed physical examination
X
X
X
X
X
X
X
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Posttreatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy
Follow-
up
Survival
Follow-
up
All procedures are to be 
performed before study 
intervention administration unless 
otherwise indicated. Refer to 
Section 8.11 for visit details.
Visit Timing/Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Height
X
Vital signs and weight
X
X
X
X
X
X
X
X
X
Predose and as clinically indicated. 
12-lead ECG
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Performed within 7 days prior to 
randomization and before each 
treatment administration.
Study intervention 
administration
X
X
X
X
X
X
AE/SAE monitoring
X
X
X
X
X
X
X
X
X
X
Report AEs occurring within 30 
days after the last dose of study 
intervention.
Report SAEs occurring within 90 
days after the last dose of study 
intervention, or 30 days after the last 
dose of study intervention if a new 
anticancer therapy is initiated, 
whichever is earlier.
Subsequent antineoplastic 
therapy status
X
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of Survival Follow-up.
If a clinic visit is not feasible, 
follow-up information may be 
obtained via documented contact.
Survival status
X
Refer to Sections 8.11.5.3 & 8.11.6. 
Updated survival status may be 
requested by the Sponsor at any 
time during the course of the study.
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Posttreatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy
Follow-
up
Survival
Follow-
up
All procedures are to be 
performed before study 
intervention administration unless 
otherwise indicated. Refer to 
Section 8.11 for visit details.
Visit Timing/Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Imaging
Brain imaging
X
Required for all participants at 
screening. See Section 8.2.1.2 for 
other requirements. If MRI is 
contraindicated or cannot be 
performed, CT of the head with IV
contrast is acceptable.
Bone imaging
X
Required at screening for 
participants with bone metastases.
See Section 8.2.1.2 for other 
requirements.
Tumor imaging and response 
assessment (chest, abdomen, and
pelvis)
X
X
X
X
Schedule should be followed
regardless of treatment delays.
Perform imaging at Screening, 
then Q6W (42 days ±7 days) from 
randomization through 36 weeks
(±7 days), Q9W (±7 days) through 
54 weeks, and Q12W (±7 days)
thereafter until PD confirmed by 
BICR or initiation of a new 
anticancer regimen. 
If imaging was obtained within 
4 weeks prior to treatment DC, 
scan at DC is not mandatory. 
Follow-up visits may be scheduled 
to coincide with the imaging 
schedule.
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Posttreatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy
Follow-
up
Survival
Follow-
up
All procedures are to be 
performed before study 
intervention administration unless 
otherwise indicated. Refer to 
Section 8.11 for visit details.
Visit Timing/Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Laboratory Assessments
Pregnancy test for WOCBP
X
X
X
X
X
X
X
X
X
WOCBP require negative serum 
test within 72 hours or negative 
urine test within 24 hours prior to 
each dose of study intervention. 
Hepatitis B and C and HIV 
serology
X
Required at baseline if mandated 
by local health authority.
CBC with differential
X
X
X
X
X
X
X
X
Performed locally within 10 days 
before first dose. After C1, collect 
within 3 days before dosing.
Urinalysis should be performed 
every 4 cycles (C5, etc.).
Chemistry panel
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
PT/INR and aPTT/PTT
X
Screening samples collected within 
10 days prior to first dose of study 
intervention. Additional testing to 
be conducted as clinically indicated 
for participants taking anticoagulant 
therapy.
Thyroid function (T3, T4, and 
TSH)
X
X
X
X
X
X
Should be performed at Screening
and Day 1 of every other cycle 
starting from C2. Participants may 
be dosed in subsequent cycles after 
C1 while thyroid function tests are 
pending. Free T3 and free T4 are 
acceptable.
Tumor Tissue Collection
Newly obtained/archival tissue 
sample for PD-L1 analysis and 
other biomarkers
X
May use archival tissue sample 
obtained before screening as part of 
the participant’s SOC.
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Posttreatment
Notes
Study Period
Screening
Treatment Cycle = 21 Days
EOT
Safety 
Follow-up
Efficacy
Follow-
up
Survival
Follow-
up
All procedures are to be 
performed before study 
intervention administration unless 
otherwise indicated. Refer to 
Section 8.11 for visit details.
Visit Timing/Cycle Number
-28 to -1
1
2
3
4
5
6 to 35
At DC
30 Days 
post last 
dose
Every
12 weeks
Every
12 weeks
Cycle Day
1
1
1
1
1
1

Scheduling Window (Days)
+3
±3
±3
±3
±3
±3
+14
±7
±14
Pharmacokinetics
Blood for Serum MK-7684 and
pembrolizumab  
X
X
X
X
X
PK and ADA samples should be 
drawn within 24 hours prior to study 
intervention administration. 
Additional postdose (end-of-
infusion) PK only samples will be 
drawn within 10 minutes after end 
of infusion at Cycles 1 and 8. Every 
effort should be taken to collect 
samples 30 days after end of study 
intervention.
Blood for ADA of MK-7684 and
pembrolizumaba
X
X
X
X
X
Biomarkers
Blood for genetic analysis
X
Collect before study intervention. 
Blood for serum biomarker
analyses
X
X
X
X
Collect at predose on Day 1 of C1, 
C2, and C3, and at EOT. 
Blood for RNA analysis
X
X
X
X
Collect at predose on Day 1 of C1, 
C2, C3, and at EOT.
Blood for ctDNA Analysis
X
X
X
X
X
X
X
X
X
Collect at Screening, predose on 
Day 1 of C1, C2, C3, C4, C5, C7, 
C9, C11, C13, C16, C19, and then 
on Day 1 of every 4 cycles. Collect 
also at EOT and Efficacy Follow-
up. During follow-up, if a clinic 
visit is not feasible, blood for 
ctDNA collection will not be 
collected.
Abbreviations: ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; CBC = complete blood count; CR = complete response; CT = computed tomography; 
CXDY= Cycle X Day Y; DC = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FBR = future biomedical research; hCG = human 
chorionic gonadotropin; HIV = human immunodeficiency virus; ICF = informed consent form; INR = international normalized ratio; IV = intravenous; MRI = magnetic resonance imaging; 
PD = progressive disease; PD-L1 = programmed cell death ligand 1; PK = pharmacokinetic(s); PT = prothrombin time; PTT = partial thromboplastin time; QXW = every X weeks; RNA = ribonucleic 
acid; SAE = serious adverse event; SOC = standard of care T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
Note: Country-specific requirements are noted in Appendix 7.
a.
PK/ADA of MK-7684 and pembrolizumab: Predose trough PK and anti-MK-7684 and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8, and every 4 cycles thereafter, 
and until discontinuation of study treatment (or until the participant starts new anticancer therapy). Note that 2 samples will need to be drawn at each PK and ADA collection time, 1 each for 
MK-7684 and pembrolizumab.
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1.3.2
Second Course Treatment Phase (Arms 1 and 2 Only)
Table 2
Study Schedule of Activities - Second Course Treatment Phase
Study Period:
Treatment Cycle = 21 Days
End of 
Treatment
Posttreatment
Notes
Visit Timing/ Cycle Number
1
2
3
4
5
6 to 
17
At DC
Safety 
Follow-up
Efficacy
Follow-Up
Survival 
Follow-
up
All procedures are to be 
performed before study 
intervention 
administration unless 
otherwise indicated. 
Refer to Section 8.11 for 
visit details.
30 days 
post last 
dose
Every 12
weeks 
post-DC
Every 12 
weeks
Scheduling Window (Days):
± 3
± 3
± 3
± 3
± 3
+ 14
± 7
± 14
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review
X
X
X
X
X
X
X
X
Concomitant medications 
received within 30 days before 
the first dose of study 
intervention in the Second 
Course through 30 days after 
the last dose of study 
intervention (or 90 days if 
used to treat an SAE) will be 
recorded.
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Complete Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
Predose and if clinically 
indicated. 
ECOG Performance Status
X
X
X
X
X
X
X
Performed within 7 days of 
beginning of Cycle 1 and 
before each treatment 
administration.
MK-7864A Administration
X
X
X
X
X
X
Poststudy Anticancer Therapy 
Status
X
X
X
X
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Study Period:
Treatment Cycle = 21 Days
End of 
Treatment
Posttreatment
Notes
Visit Timing/ Cycle Number
1
2
3
4
5
6 to 
17
At DC
Safety 
Follow-up
Efficacy
Follow-Up
Survival 
Follow-
up
All procedures are to be 
performed before study 
intervention 
administration unless 
otherwise indicated. 
Refer to Section 8.11 for 
visit details.
30 days 
post last 
dose
Every 12
weeks 
post-DC
Every 12 
weeks
Scheduling Window (Days):
± 3
± 3
± 3
± 3
± 3
+ 14
± 7
± 14
Survival Status
X
X
X
Refer to Sections 8.11.5.3 & 
8.11.6. Updated survival 
status may be requested by the 
Sponsor at any time during the 
course of the study.
Laboratory Procedures/Assessments:  Analyses performed by LOCAL laboratory
Pregnancy test for WOCBP
X
X
X
X
X
X
X
X
WOCBP require negative 
serum test within 72 hours or 
negative urine test within 24 
hours prior to each dose of 
study intervention.
PT/INR and aPTT/PTT
X
Required at C1. Additional 
testing as needed for 
participants on anticoagulation 
therapy.
CBC with Differential
X
X
X
X
X
X
X
X
Performed locally within 10 
days before first dose. After 
C1, collect within 3 days 
before dosing. Urinalysis 
should be performed every 4 
cycles (C1, C5, etc)
Chemistry Panel
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Thyroid function (T3, T4, and TSH)
X
X
X
X
X
Should be performed within 
10 days before C1, and every 
other cycle starting from C2. 
Participants may be dosed in 
subsequent cycles after C1 
while thyroid function tests 
are pending. Free T3 and free 
T4 are acceptable.
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Study Period:
Treatment Cycle = 21 Days
End of 
Treatment
Posttreatment
Notes
Visit Timing/ Cycle Number
1
2
3
4
5
6 to 
17
At DC
Safety 
Follow-up
Efficacy
Follow-Up
Survival 
Follow-
up
All procedures are to be 
performed before study 
intervention 
administration unless 
otherwise indicated. 
Refer to Section 8.11 for 
visit details.
30 days 
post last 
dose
Every 12
weeks 
post-DC
Every 12 
weeks
Scheduling Window (Days):
± 3
± 3
± 3
± 3
± 3
+ 14
± 7
± 14
Imaging
Tumor Imaging
(Chest, Abdomen and Pelvis)
X
X
X
X
X
X
Schedule should be followed 
regardless of treatment delays. 
Images are for investigator 
assessment of disease status 
only and should not be sent to 
the iCRO. If tumor image 
documenting PD was obtained 
>28 days before entry into 
Second Course, a new image 
must be obtained and 
reviewed by the site before 
treatment initiation. 
Perform imaging Q6W 
through 36 weeks, Q9W 
through EOT, and Q12W 
thereafter, until confirmed PD 
or initiation of a new 
anticancer regimen. The 
window for imaging is ±7 
days. If imaging was obtained 
within 4 weeks before DC, 
scan at DC is not mandatory. 
Follow-up visits may be 
scheduled to coincide with the 
imaging schedule.
aPTT = activated partial thromboplastin time; CXDY= Cycle X Day Y; CBC = complete blood count; CT = computed tomography; DC = Discontinuation Visit; ECOG = Eastern Cooperative Oncology 
Group; EOT = end of treatment; MRI = magnetic resonance imaging; PT/INR = prothrombin time/international normalized ratio; FT4 = free thyroxine; T3 = triiodothyronine; T4 = thyroxine; TSH = 
thyroid-stimulating hormone; WOCBP = women of childbearing potential.
Note: Country-specific requirements are noted in Appendix 7.
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2
INTRODUCTION
MK-7684A is a coformulation of MK-7684 and pembrolizumab. MK-7684 is a humanized, 
antagonist mAb that binds to the immune checkpoint receptor, TIGIT, and blocks the 
interaction between TIGIT and its ligands. Pembrolizumab is a potent humanized IgG4 mAb 
with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. The coformulation of MK-7684A is being developed as a cancer 
immunotherapeutic with the potential to be used to increase benefit to patients with 
metastatic NSCLC.
2.1
Study Rationale
The global incidence of lung cancer was 2.1 million cases in 2018, resulting in an estimated 
1.8 million deaths [International Agency for Research on Cancer 2018]. NSCLC represents 
approximately 85% of all lung cancers [National Cancer Institute 2020]. Of patients with 
NSCLC, tumor histology is approximately 46% adenocarcinoma, 16% squamous, and the 
remainder “not otherwise specified” [Sulpher, J. A., et al 2013], though histology varies 
somewhat by geographic region. At the time of diagnosis, approximately 80% of patients in 
the United States with lung cancer have locally advanced or metastatic disease that is not 
amenable to surgical resection, and the 5-year relative survival for patients with metastatic 
lung cancer is only approximately 6% [National Cancer Institute 2020].
The therapeutic landscape in metastatic NSCLC was dramatically changed with approvals of 
immunotherapy agents in both treatment naïve and previously treated cancer, irrespective of 
histology. In previously treated patients with advanced NSCLC, immune checkpoint 
inhibitors targeting the PD-1/PD-L1 pathway (pembrolizumab, nivolumab, and 
atezolizumab) have proven benefits for survival over the standard chemotherapy, docetaxel 
[Borghaei, H., et al 2015] [Brahmer, J., et al 2015] [Herbst, R. S., et al 2016] [Rittmeyer, A., 
et al 2017].
The results from the KEYNOTE-001 (a Phase 1 study evaluating efficacy and safety of 
pembrolizumab) and KEYNOTE-010 (a Phase 2/3 study of pembrolizumab versus docetaxel) 
showed that pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, 
and ORR in patients with NSCLC whose disease progressed after platinum-containing 
chemotherapy and whose tumor cells expressed PD-L1. Based on these 2 studies, 
pembrolizumab monotherapy is approved for the treatment of patients with metastatic 
NSCLC whose tumors express PD-L1 (TPS ≥1%), with PD during or after platinum-
containing chemotherapy. In addition, the NCCN Guidelines recommend immune checkpoint 
inhibitors as the preferred agent for subsequent therapy in patients with metastatic NSCLC 
based on improved survival rates, longer DOR, and fewer AEs compared with cytotoxic 
chemotherapy [National Comprehensive Cancer Network 2018].
Furthermore, the PROLUNG investigator-initiated, Phase 2 randomized study of 
pembrolizumab plus docetaxel versus docetaxel alone in IO-naïve advanced NSCLC patients 
who were previously treated with platinum-based chemotherapy revealed a statistically 
significant improvement in ORR and PFS in the pembrolizumab plus docetaxel arm 
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[Arrieta, O., et al 2020]. Pembrolizumab and docetaxel was well tolerated and improved 
ORR and PFS irrespective of PD-L1 or EGFR mutation status.
Although cancer immunotherapies have revolutionized treatment paradigms in first-line and 
second-line treatment of metastatic NSCLC, unfortunately, many patients do not benefit from 
or become resistant to IO monotherapy, or IO in combination with chemotherapy. For 
patients with disease recurrence or disease progression while on IO therapy, the prognosis is 
very poor, with a median OS of 9 months [Metro, G., et al 2019]. Tumor resistance to 
immunotherapy is an emerging issue impacting outcomes. Patients have either primary 
resistance to immune checkpoint inhibitors and do not respond to initial therapy or acquire 
resistance and relapse after response to treatment. Therefore, there is still a substantial unmet 
medical need for novel treatments that can potentiate the clinical benefit of IO therapies, 
extend the benefit to a broader population of patients, and further improve treatment response 
and survival in patients with metastatic NSCLC with prior exposure to IO therapies. 
Furthermore, pembrolizumab use in second-line NSCLC is declining due to first-line 
utilization. Docetaxel is an accepted second-line SOC treatment for patients with NSCLC, 
demonstrating an ORR of approximately 5% to 10%, median PFS of approximately 3 
months, and median OS of approximately 7.5 months. Outcomes remain poor, especially in 
those that have progressed after immunotherapy [Fossella, F. V., et al 2000] [Shepherd, F. 
A., et al 2000] [Hanna, N., et al 2004].
Enhancing the proven anti-PD-1 immune stimulatory mechanism through a novel mechanism 
of action is therefore an attractive scientific concept. One avenue for further investigation is 
the T-cell stimulatory/inhibitory network CD226-TIGIT/PVRIG/TACTILE TIGIT pathway. 
Antibody blockade of TIGIT, a T-cell inhibitory receptor within this network, has shown 
promising activity in preclinical cancer models, as well as in clinical studies. MK-7684 is a 
humanized IgG1 that blocks the inhibitory checkpoint receptor TIGIT expressed on T-cells 
and NK cells. Therefore, a strong rationale exists to develop anti-PD-1 and anti-TIGIT 
combination therapies. MK-7684 is being developed in combination with pembrolizumab in 
advanced solid tumors. Preliminary data for MK-7684-001, a Phase 1 study of MK-7684 as 
monotherapy or coformulated with pembrolizumab (known as MK-7684A) in advanced solid 
tumors demonstrates promising activity in PD-1 naïve and PD-1 refractory NSCLC (see 
Section 2.2.3.1).
In conclusion, there remains a great unmet need to develop newer, more efficacious, well 
tolerated therapies for the treatment of patients with metastatic NSCLC that have progressed 
on immunotherapy. The goal of this study is to enhance the approved anti-PD-1 immune 
stimulatory mechanism of pembrolizumab through combining it with a novel immune 
modulatory mechanism of action, blockade of TIGIT, along with the SOC chemotherapy for 
this population. This Phase 2 study is designed to assess the efficacy and safety of MK-
7684A alone or MK-7684A plus docetaxel versus docetaxel alone. This study will examine 
whether MK-7684A alone or in combination with docetaxel will result in greater PFS and OS 
than SOC docetaxel in this population of patients. The MK-7684A alone arm provides the 
opportunity to explore a potential chemotherapy-free regimen as well, which is of particular 
interest to both patients and physicians. Outcomes of this study could inform future Phase 3 
studies.
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2.2
Background
Refer to the MK-7684A IB and the pembrolizumab IB for detailed background information 
on MK-7684A and pembrolizumab, respectively.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (Tregs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian cancer, colorectal
cancer, and pancreatic cancer; hepatocellular carcinoma, malignant melanoma, and renal cell 
carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] 
[Hunder, N. N., et al 2008].
2.2.1.1
MK-7684 Background
MK-7684 is a humanized, antagonist mAb that binds to the immune checkpoint receptor, 
TIGIT, and blocks the interaction between TIGIT and its ligands. This human 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, NK cells, and NKT cells. Its structure reveals a single extracellular immunoglobulin 
domain, a transmembrane region, an immunoglobulin tail tyrosine-like phosphorylation 
motif, and an immunoreceptor tyrosine-based inhibitory motif. 
TIGIT forms part of a costimulatory 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 [Levin, S. D., et al 2011]. Whereas 
CD226 is widely expressed on most immune cells, TIGIT is highly expressed on memory T-
cells, Tregs, NK cells, and NKT cells [Dardalhon, V., et al 2005] [Stanietsky, N., et al 2013]. 
CD155/PVR (poliovirus receptor) and CD112/PVRL-2 (poliovirus receptor-related 2) are 2
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 [Carlsten, M., et al
2007] [Hirota, T., et al 2005] [Masson, D., et al 2001] [Soriani, A., et al 2009] [Stanietsky, 
N., et al 2009].
In addition, TIGIT is highly coexpressed with PD-1 on both CD4+ and CD8+ TILs including 
Tregs, in mouse and human tumors, and has been reported to be coexpressed with PD-1 and 
T-cell immunoglobulin and mucin domain containing-3 (Tim-3) on the TILs with the most 
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exhausted phenotype [Chauvin, J. M., et al 2015] [Johnston, R. J., et al 2014]. Furthermore, 
enhanced antitumor efficacy is observed in preclinical models when an anti-TIGIT antibody 
is used with an anti-PD-1 antibody. We hypothesize, therefore, that combining MK-7684 
with pembrolizumab will offer substantially augmented antitumor efficacy.
2.2.1.2
Pembrolizumab Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the IB.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
MK-7684A Preclinical Studies
Evaluation of TIGIT modulation as an approach to enhance tumor immunity was prompted 
by preclinical observations showing that antagonizing TIGIT has potent immunostimulatory 
effects. Results of studies performed showed in vivo antitumor activity of rat anti-mouse
TIGIT antibodies. In order to understand how antibody backbone differences may impact the 
antitumor efficacy of anti-TIGIT antibodies, parental rat anti-mouse TIGIT mAbs, or 
chimeric versions of these antibodies, were tested in multiple established (80-180mm3) 
syngeneic tumor models as single agents and in combination with an anti-mouse PD-1 mAb 
(muDX400). All anti-TIGIT mAbs tested resulted in a trend toward enhanced antitumor 
activity when combined with an anti-mouse PD-1 mAb (mDX400). The chimeric anti-TIGIT 
IgG2a mAbs (strong FcγR binding) showed the most robust single-agent activity as 
compared with anti-TIGIT IgG1 (D265A mutant; minimal FcγR binding) mAbs and the most 
combination benefit when combined with anti-mouse PD-1.
A representative dose titration study demonstrating significant single-agent efficacy of the 
anti-mouse TIGIT 18G10-mIgG2a antibody in the murine MC38 colon carcinoma tumor 
model is shown in Figure 3. Anti-mouse TIGIT (18G10-mIgG2a) displayed single-agent 
activity comparable to anti-mouse PD-1 (mDX400). The MC38 tumor model has been 
classified as very responsive to anti-PD-1 treatment, and MC38 model selection was based 
on baseline TIGIT protein surface expression on CD8+ and CD4+ TILs, baseline mRNA 
expression of CD155, and induction of TIGIT and CD155 expression in tumors after 
anti-PD-1 treatment.
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Figure 3
Results of a Dose Titration Study of Anti-TIGIT 18G10-IgG2a in the MC38 
Colon Carcinoma Mouse Model
C57BL/6 mice bearing MC38 mouse syngeneic tumors (mean tumor volume at start of treatment 98 mm3) were 
administered anti-mouse TIGIT antibodies at doses of 2 mg/kg, 10 mg/kg, or 20 mg/kg, anti-mouse PD 1 (mDX400)  at a  
dose of 5  mg/kg, or isotype controls every 4 days for 5 cycles (n=10/group). Tumor volume curves are presented for the 
average of 10 animals within each group. The anti-mouse TIGIT 18G10-IgG2a antibody resulted in 82%, 94%, and 96% 
tumor growth inhibition at the 2 mg/kg, 10 mg/kg, and 20 mg/kg doses, respectively. Anti-mouse PD-1 (mDX400) resulted 
in 17% tumor regression at the 5 mg/kg dose. Ig = immunoglobulin; mpk = mg/kg; PD 1 = programmed death 1; TIGIT = T-
cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif.
A representative study evaluating anti-TIGIT treatment as a single agent and in combination 
with anti-PD-1(muDX400) therapy in the murine subcutaneous CT26 tumor-bearing model is 
shown in Figure 4. The CT26 colon carcinoma model has been classified as partially 
responsive to anti-PD-1 treatment with only partial tumor growth inhibition observed. CT26 
model selection was based on baseline TIGIT protein surface expression on CD8+ and CD4+ 
TILs, baseline mRNA expression of CD155, and induction of TIGIT and CD155 expression 
in tumors after anti-PD-1 treatment. Combination treatment of 18G10-G2a with anti-PD-1 
(mDX400) showed significantly enhanced efficacy and survival as compared with
anti-TIGIT and anti-PD-1 monotherapy treatments. Animals with complete responses 
showed curative protection from tumor rechallenge, consistent with the development of 
immune memory (data not shown).
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Figure 4
Antitumor Efficacy of Anti-TIGIT 18G10-IgG2a as a Single Agent and in 
Combination With Anti-PD-1(muDX400) Therapy in the Murine Subcutaneous CT26 Colon 
Carcinoma Tumor-bearing Model
CT26 tumor-bearing BALB/cAnN mice (mean tumor volume at start of treatment ~100 mm3) were administered anti-TIGIT antibody 
(18G10-G2a) at a dose of 18 mg/kg and an anti-murine anti-PD-1 antibody (mDX400) at a dose of 10 mg/kg by intraperitoneal injection, 
every 4 days for 5 cycles. Tumor volume curves are presented for individual animals within each group (n=10/group). CR = complete 
response; Ig = immunoglobulin; PD 1 = programmed death 1; TIGIT = T-cell immunoglobulin and immunoreceptor tyrosine-based 
inhibitory motif.
These studies (and others) have demonstrated that anti-mouse TIGIT mAb treatment can 
augment antitumor T-cell responses and induce tumor rejection in several murine tumor 
models when used alone and in combination with an anti-mouse PD-1 mAb. In these studies, 
the combination of anti-mouse TIGIT and anti-mouse PD-1 led to an increased ratio of Teffs 
to Tregs in the tumor, but these effects were not observed in the draining lymph node. 
The results of studies using chimeric anti-mouse TIGIT mAbs on the IgG2a backbone 
revealed that administration of single-agent anti-mouse TIGIT mAbs are efficacious in 
treating multiple established subcutaneous murine tumors and that combining anti-mouse 
TIGIT 18G10-G2a with anti-mouse PD-1 leads to enhanced combination benefit over either 
single agent alone.
Findings in toxicology studies of MK-7684 monotherapy and pembrolizumab monotherapy 
in nonhuman primates were attributed to the proinflammatory pharmacology of each agent, 
but were not overlapping. Moreover, using an in vitro cytokine release assay, the 
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combination of MK-7684 and pembrolizumab did not enhance cytokine induction in human 
peripheral blood monocytes. Potential increase in immune-mediated adverse effects resulting 
from the combination of MK-7684 and pembrolizumab, however, cannot be ruled out. See 
MK-7684 and pembrolizumab IBs for more information.
2.2.2.2
Pembrolizumab Preclinical and Clinical Studies
Refer to the IB for preclinical and clinical study data for pembrolizumab.
2.2.3
Ongoing Clinical Studies
2.2.3.1
MK-7684 Ongoing Clinical Studies
Study MK-7684-001
MK-7684-001 is a safety, efficacy, and PK study examining MK-7684 as monotherapy and 
in combination with pembrolizumab or with pembrolizumab plus chemotherapy in adults 
with metastatic solid tumors for which there are no available therapies expected to convey 
clinical benefit. The study consists of a Part A dose escalation phase and a Part B expansion 
phase. 
Part A of this study is a dose escalation and confirmation phase to evaluate safety and 
estimate the RP2D for MK-7684 monotherapy or in combination with pembrolizumab, or 
pembrolizumab with chemotherapy.
As of 03-MAR-2020, Part A was completed. A total of 85 participants were treated with 
escalating doses of MK-7684 from 2.1 mg to 700 mg either as monotherapy (n=34), in 
combination with a fixed dose of 200 mg pembrolizumab (n=41), or in combination with 
pembrolizumab and chemotherapy (n=10). No DLTs were observed in the MK-7684 
monotherapy or MK-7684 plus pembrolizumab arms. Antitumor activity was observed in 
Part A, particularly in participants treated with MK-7684 in combination with 
pembrolizumab. In the monotherapy arm, the combined best overall response by RECIST 1.1 
was 2.9% without confirmation, with 1 of the 34 participants experiencing a PR. In the 
combination therapy arm, the combined best overall response without confirmation was 
17.1%, with 7 of the 41 participants experiencing a PR.
Part B of this study intends to assess the antitumor efficacy of MK-7684 at the RP2D of 
200 mg when used as monotherapy and in combination with pembrolizumab in distinct 
tumor indications, including PD-1 refractory NSCLC and PD-1 naïve NSCLC.
As of 03-MAR-2020, MK-7684 was given as monotherapy and in combination with 
pembrolizumab 200 mg with or without chemotherapy to 366 participants. It was well 
tolerated and had a manageable safety profile. In addition, in Part B, MK-7684 has showed
promising antitumor activity across multiple tumor types, particularly for MK-7684 plus
pembrolizumab.
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As of March 2020, preliminary safety and efficacy results were available for 41 participants 
with anti-PD-1/PD-L1-naïve NSCLC treated with MK-7684 + pembrolizumab[Niu, J., et al 
2020]. Of the 41 participants enrolled, 73% had received ≥1 prior lines of therapy. Median 
age was 62 years; 68% were male and 83% had an ECOG Performance Status of 1. Median 
follow-up was 11 months (range, 7-18). TRAEs occurred in 34 participants (83%); pruritus 
(34%), hypoalbuminemia (29%), and pyrexia (20%) were the most frequent (≥20%). In all 
participants (ITT population) investigator-assessed ORR by RECIST 1.1 was 29% (95% CI: 
16, 46). In participants with available PD-L1 testing (n=25), the ORR was 46% (95% CI: 19, 
75) in participants with tumors expressing PD-L1 TPS ≥1% (6/13 participants experienced a 
response), and ORR was 25% (95% CI: 5, 57) in participants with tumors expressing PDL-1 
TPS<1% (3/12 participants experienced a response). There was also a trend toward improved 
median PFS in participants with PD-L1 TPS ≥1% (8.4 months, 95% CI: 3.9, 10.2) compared 
with participants with tumors expressing PD-L1<1% (4.1 months, 95% CI: 1.9, NR) or the 
ITT population 5.4 months (95% CI: 2.1, 8.2). In this limited dataset, ORR and PFS are 
improved compared with historical pembrolizumab monotherapy efficacy in 2L NSCLC in 
KEYNOTE-010 (n=690): ORR by BICR was 18% and median PFS was4.0 months (95% CI: 
3.1,4.1). Overall, these data are promising and warrant further study of MK-7684 and 
pembrolizumab therapy in NSCLC naïve to PD-1 therapy. 
Part B also tested MK-7684 alone or in combination with pembrolizumab in NSCLC 
participants that had progressed on previous anti-PD-1 or PD-L1 therapy. In this cohort, 
median follow-up was 11 months (range, 5 to 16) for 79 participants with anti-PD-1/PD-L1–
refractory NSCLC (n = 41, MK-7684; n = 38 MK-7684 plus pembrolizumab). Median age 
was 65 years, 60% were male, and 78% received ≥2 lines of prior therapy. AEs were 
reported in ≥97% and TRAEs in ≥65% of participants in both arms. The most common 
TRAEs (≥10% in either arm) were pruritus, fatigue, rash, arthralgia, and decreased appetite. 
Ten participants reported Grade 3-4 TRAEs; the most common were lipase increased and 
hypertension. One participant in the MK-7684 plus pembrolizumab arm died due to 
treatment-related pneumonitis. ORR was 7% (95% CI: 2, 20) with MK-7684 monotherapy 
and 5% (95% CI: <1, 18) with MK-7684 plus pembrolizumab. Median DOR was 9 months 
(range, 9 to 9) with MK-7684 monotherapy and 13 months (range, 4+ to 13) with MK-7684 
plus pembrolizumab. The data show that MK-7684 was well tolerated as a monotherapy and 
in combination with pembrolizumab and that modest antitumor activity was observed in 
participants with advanced NSCLC refractory to anti-PD-1/PD-L1 therapy in both treatment 
arms, though a trend toward longer treatment duration was observed in the combination 
therapy arm.
Additional details regarding other ongoing studies of MK-7684 and specific benefits and 
risks for participants in the MK-7684 studies may be found in the IB.
2.2.3.2
Pembrolizumab Ongoing Clinical Studies
Numerous clinical studies involving pembrolizumab are currently ongoing in a number of 
advanced solid tumor indications, as well as in hematological malignancies.
In the NSCLC development program, pembrolizumab monotherapy for PD-L1 positive 
NSCLC was approved in the first-line setting based on KEYNOTE-024 and KEYNOTE-042 
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and approved in the second-line setting based on KEYNOTE-001 and KEYNOTE-010. 
KEYNOTE-189 and KEYNOTE-407 led to the approval of pembrolizumab in combination 
with chemotherapy for first-line treatment of metastatic NSCLC irrespective of PD-L1 status, 
while KEYNOTE-021 established the benefits of the combination. For further details, refer 
to the IB.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have been approved as 
first-line therapy for NSCLC. There is an unmet medical need for safe and efficacious for 
second-line therapy and beyond (2L+) in patients whose disease has progressed with first-
line treatment. The existing data suggest that blockade of TIGIT with MK-7684 offers a new 
immunological mechanism, which has been shown to enhance the activity of pembrolizumab 
in preclinical and early clinical observations. The combination of both MK-7684 and 
pembrolizumab as coformulated MK-7684A is believed to achieve increased therapeutic 
efficacy with minimal added toxicity over pembrolizumab monotherapy. We hypothesize 
that MK-7684A will enhance the efficacy of pembrolizumab therapy without significant 
added toxicity. Therefore, risk/benefit is expected to be favorable.
Inhibiting TIGIT in combination with PD-1 blockade is a promising therapeutic strategy, and 
the benefit/risk assessment for patients in this study is favorable, making MK-7684A alone or 
in combination with docetaxel a promising 2L+ therapeutic option in patients with metastatic 
NSCLC and no EGFR or ALK or ROS1 genomic tumor aberrations, regardless of PD-L1 
expression.
Additional details regarding specific benefits and risks for participants in this study may be 
found in the accompanying IBs and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Male/female participants with metastatic NSCLC with progressive disease after treatment 
with a platinum doublet chemotherapy and immunotherapy who are 18 years of age or older 
may be enrolled in this study.
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Objectives
Endpoints
Primary

Objective: To compare MK-7684A + 
docetaxel to normal saline placebo +
docetaxel with respect to PFS per 
RECIST 1.1 by BICR.

Hypothesis (H1): MK-7684A + docetaxel 
is superior to normal saline placebo + 
docetaxel with respect to PFS per 
RECIST 1.1 by BICR.

Objective: To compare MK-7684A to 
normal saline placebo + docetaxel with 
respect to PFS per RECIST 1.1 as 
assessed by BICR.

Hypothesis (H2): MK-7684A is superior 
to normal saline placebo + docetaxel with 
respect to PFS per RECIST 1.1 by BICR.

PFS: The time from randomization to 
the first documented disease 
progression or death due to any cause, 
whichever occurs first.
Secondary

To evaluate ORR in participants treated 
with MK-7684A +docetaxel, MK-7684A,
or normal saline placebo + docetaxel per 
RECIST 1.1 by BICR.

Objective response: defined as a 
confirmed CR or PR.

To evaluate OS in participants treated 
with MK-7684A + docetaxel, 
MK-7684A, or normal saline placebo + 
docetaxel.

OS: defined as the time from 
randomization to the date of death due 
to any cause.

To evaluate DOR per RECIST 1.1 as
assessed by BICR in participants treated 
with MK-7684A + docetaxel, 
MK-7684A, or normal saline placebo + 
docetaxel.

DOR: for participants who 
demonstrate confirmed CR or PR, 
DOR is defined as the time from first 
documented evidence of CR or PR 
until disease progression or death due 
to any cause, whichever occurs first.

To evaluate the safety and tolerability in 
participants treated with MK-7684A +
docetaxel, MK-7684A, or normal saline 
placebo + docetaxel.

AEs.

Discontinuations of study intervention 
due to an AE.
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Objectives
Endpoints
Tertiary/Exploratory

To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, monitoring, 
and/or the mechanism of action of MK-
7684 and pembrolizumab and other 
treatments.

Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
The study will be considered a success if the success criterion for any of the primary 
hypotheses is met.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2 randomized, placebo- and active-controlled, parallel-group, multisite, 
double-blind (Arm 1 and Arm 3 only), 3 arm study comparing MK-7684A + docetaxel or
MK-7684A to normal saline placebo + docetaxel. Participants with metastatic NSCLC and 
PD after platinum doublet chemotherapy and treatment with one prior anti-PD-1/PD-L1 mAb 
(either sequentially or in combination with chemotherapy) will be enrolled in the study. This 
study will be conducted in participants with measurable disease in whom EGFR-, ALK-, or 
ROS1-targeted therapy is not indicated.
Participants will provide tumor tissue obtained any time from initial diagnosis of NSCLC and 
before receiving immunotherapy (anti-PD-1/PD-L1) for determination of PD-L1 expression
and study stratification. Participants will be stratified by:

Prior anti-PD-1/PD-L1 mAb (immediate prior therapy versus not immediate prior 
therapy)

PD-L1 TPS (<50% versus ≥50%)

ECOG Performance Status (0 versus 1)
Initial Treatment
Overall, approximately 240 participants will be randomized 1:1:1 to:

MK-7684A + docetaxel (Arm 1) 

MK-7684A (Arm 2)
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
Normal saline placebo + docetaxel (Arm 3)
No treatment crossover is planned for the study. The study design is shown in Figure 1
(Initial Treatment Phase) and The Second Course study design is depicted in Figure 2
(Second Course).
Participants will be evaluated with radiographic imaging to assess response to study 
intervention every 6 weeks from randomization through 36 weeks, every 9 weeks through 
54 weeks, and subsequently every 12 weeks until confirmed PD or initiation of a new 
anticancer regimen. All imaging obtained during the initial treatment phase of the study will 
be submitted to the iCRO for BICR, which will assess the images using RECIST 1.1 for 
determination of PFS, OR, and DOR. Tumor imaging showing site-assessed PD should be 
submitted immediately for verification by BICR before study intervention discontinuation.
Once disease progression is verified centrally, subsequent imaging (if acquired) should not 
be submitted to the iCRO. 
Participants may be permitted to continue study intervention beyond PD confirmed by BICR 
per RECIST 1.1 if the treating investigator considers that the participant may experience 
clinical benefit with continued treatment and the participant is clinically stable and tolerating 
study intervention; however, this decision must be approved by the Sponsor. If the 
investigator recommends continuation of study intervention beyond disease progression, the 
participant or legally acceptable representative will be asked to provide a new documented 
informed consent.
Survival follow-up will continue after PD, discontinuation of study intervention, and the start 
of new anticancer treatment. In addition, on Sponsor request, participants may be contacted 
for survival status at any time during the study.
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the NCI CTCAE, version 5.0.
Treatment with MK-7684A/normal saline placebo will continue for up to 35 treatment 
cycles, or until a discontinuation criterion is met (see Section 7.1). Treatment may be 
discontinued for participants with a confirmed CR (see Section 6.6.2 for requirements).
Treatment with docetaxel may continue until a discontinuation criterion is met (see 
Section 7.1), or as per approved local label.
Second Course Treatment Phase
The Second Course retreatment option is only available for Arm 1 and Arm 2. Treatment 
assignment will be unblinded only for those participants who meet all criteria for the Second 
Course Phase. Participants in Arm 3 (normal saline placebo + docetaxel) are not eligible for 
the Second Course Phase.
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Participants who stop MK-7684A after receiving 35 treatment cycles or participants who stop 
MK-7684A after attaining a confirmed CR may be eligible for the Second Course. See 
Section 6.6.3 for details. 
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This Phase 2, randomized, placebo- and active-controlled, double-blind study with respect to 
Arm 1 and Arm 3, and open-label with respect to Arm 2, is being conducted to compare the 
efficacy and safety of MK-7684A plus docetaxel or MK-7684A to docetaxel monotherapy in 
metastatic NSCLC. The results will inform future Phase 3 studies.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria as assessed by BICR as the primary 
endpoint. Progression-free survival is an acceptable measure of clinical benefit for a late 
stage study that demonstrates superiority of a new antineoplastic therapy, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use 
of BICR and RECIST 1.1 to assess PFS is considered acceptable by regulatory authorities. 
Images will be submitted to an iCRO and read by an independent central review blinded to 
treatment assignment to minimize bias in the response assessments. In addition, the final 
determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment. Expedited verification 
of radiologic progression as determined by central review will be communicated to the site.
The secondary efficacy endpoint OS has been recognized as the gold standard for the 
demonstration of superiority of a new antineoplastic therapy in randomized clinical studies.
The secondary efficacy endpoints of OR and DOR based on RECIST 1.1 and assessed by 
BICR is accepted by regulatory authorities and the oncology community.
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.5 for additional 
detail.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
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causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version [5.0].
4.2.1.3
Pharmacokinetic Endpoints
Blood samples will be obtained to characterize PK parameters and immunogenicity of 
MK-7684 and pembrolizumab when coadministered.
4.2.1.4
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. Finally, MSI may be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
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Tumor and blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue
and in blood may be performed to define gene signatures that correlate to clinical response to 
treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a response 
in tumors that likely reflects an inflamed/immune phenotype. Specific immune-related gene 
sets (ie, those capturing interferon-gamma transcriptional pathways) may be evaluated and 
new signatures may be identified. Individual genes related to the immune system may also be 
evaluated (eg, IL-10). MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an IVD device has been developed 
for use with pembrolizumab in NSCLC. Preliminary data indicates that this association may 
also be true in additional cancer types (ie, triple negative breast cancer, head and neck, and 
gastric). Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include but are not limited to immunoassays and liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. This research may include genetic analyses (DNA), gene expression profiling (RNA), 
proteomics, metabolomics (serum, plasma), and/or the measurement of other analytes, 
depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
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FBR is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. The overarching goal is to use such information 
to develop safer, more effective drugs/vaccines, and/or to ensure that participants receive the 
correct dose of the correct drug/vaccine at the correct time. The details of FBR research are 
presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Docetaxel is approved as second-line therapy for locally advanced or metastatic NSCLC after 
platinum therapy failure and is the most frequently prescribed second-line agent.
The use of normal saline placebo in combination with docetaxel will ensure that the 
investigators and participants (in Arm 1 and Arm 3) remain blinded during the study. The use 
of normal saline placebo also ensures the objectivity of investigator-assessed progression for 
Arm 1 and Arm 3, as well as any decisions regarding treatment interruption/discontinuation.
In this study, the efficacy of MK-7684A with or without docetaxel will be compared with
demonstrate superiority over docetaxel monotherapy. In addition, the MK-7684A alone arm 
will also serve to determine the contribution of components for MK-7684A + docetaxel 
combination.
4.3
Justification for Dose
4.3.1
MK-7684A
Based on the totality of available data, including preliminary clinical PK, 
pharmacodynamics, safety, and efficacy from the dose escalation and confirmation portion of 
Study MK-7684-001, the selected dose of MK-7684 is 200 mg, to be administered as 
MK-7684A (a coformulation with 200 mg pembrolizumab) as a 30-minute IV infusion Q3W. 
PK data from study MK-7684-001 in 323 participants across tumor types, including dose 
groups of 200/210 mg Q3W and 700 mg Q3W indicate that observed PK parameters were 
generally similar across tumor types. Observed PK profiles of MK-7684 suggest that 
target-mediated clearance of MK-7684 is saturated at the 200/210 mg and 700 mg doses. The 
PK of MK-7684 is generally consistent with that of other humanized mAbs, which typically 
have low CL and a limited Vc [Keizer,R.J., et al 2010] [Dostalek,M., et al 2012] [Dirks, N. 
L. and Meibohm, B 2010]. As with other mAbs, body weight was found to be related to MK-
7684 CL and Vc parameters, but the relationship was weak for both parameters. As such, this 
supports that fixed dosing would provide better control of PK variability than body weight-
based dosing [Hendrikx, J. J. M. A., et al 2017] [Bai,S., et al 2012].
Available clinical safety data indicated that MK-7684 is tolerable 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 the dose escalation and confirmation portion of 
Study MK-7684-001, and the MTD was not reached.
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Clinical activity was observed at the 200/210-mg and the 700-mg dose levels of MK-7684 
both during the dose escalation and confirmation portion of Study MK-7684-001 in 
participants with advanced solid tumors of all types and during the dose expansion portion,
particularly in PD-1/PD-L1 inhibitor treatment-naïve participants with NSCLC, ovarian 
cancer, breast cancer, and cervical cancer treated with MK-7684 in combination with 
pembrolizumab.
The 200 mg and 700 mg doses were compared in a randomized dose-finding cohort of 
participants with anti-PD-1/PD-L1 treatment naïve cervical cancer in MK-7684-001 Part B. 
Exploratory analysis of exposure versus best change in tumor size (based on preliminary data 
from 63 participants) shows a flat relationship, suggesting that 200 mg is at the plateau of the 
exposure-efficacy relationship. The mean difference in target lesion percent change from 
baseline between the 200 mg and 700 mg groups for the first scan was -2.1% (95% CI: -21.2, 
16.9) with 2-sided p-value of 0.824, and for best overall scan was -8.1% (95% CI: -31.1, 15) 
with 2-sided p-value of 0.488. Therefore, tumor size reduction showed no significant 
difference between the 2 dose groups.
Overall, the totality of data, including lack of a clinically meaningful effect of body weight 
on PK, consistency of PK across indications and a flat dose-exposure-tumor size response 
relationship support that a fixed dose of 200 mg Q3W is an optimal dose for MK-7684 in 
combination with 200 mg pembrolizumab. 
For more information, see the MK-7684A IB.
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the pembrolizumab development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. This 
dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg Q2W.

Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W.
For more information please refer to the pembrolizumab IB.
4.3.3
Maximum Dose/Exposure for This Study
The maximum dose/exposure of MK-7684A allowed in this study is 200 mg MK-7684/ 
200 mg pembrolizumab for up to 2 years (35 treatment cycles) of initial treatment 
(Section 6.6.2) and an additional 1 year (17 cycles) for Second Course (Section 6.6.3).
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The maximum dose of docetaxel is 75 mg/m2 IV. Docetaxel may be continued until a 
discontinuation criterion is met (Section 7.1) or as per approved local label.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. 
The overall study ends when the last participant completes the last study-related contact, 
withdraws consent, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems or the number of discontinuations for administrative reasons is 
too high.
Early study termination will be the result of the criteria specified below:
1. Incidence or severity of emerging effects/clinical endpoints is such that the risk/benefit 
ratio for the study population as a whole is unacceptable.
2. Plans to modify or discontinue the development of the study medication.
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-7684A.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), our studies include 
people of varying age, race, ethnicity, and sex. The collection and use of these demographic 
data are to follow all local laws and guidelines in keeping with the needs for participant 
confidentiality while supporting the study of the disease, its related factors, and the IMP 
under investigation.
Participants with metastatic NSCLC and PD after platinum doublet chemotherapy and an 
anti-PD-1/PD-L1 mAb (either concomitantly or sequentially) will be enrolled into the study.
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible for the study only if all of the following criteria are met:
Type of Participant and Disease Characteristics
1. Has a histologically or cytologically confirmed diagnosis of metastatic NSCLC
(Stage IV: M1a, M1b, M1c, AJCC Staging Manual, version 8).
Note: Mixed tumors will be categorized by the predominant cell type; if small cell 
elements are present, the participant is ineligible.
2. Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as 
primary therapy (documentation of the absence of tumor-activating EGFR mutations [eg, 
DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements).
Note: If participant’s tumor is known to have a predominantly squamous histology, 
molecular testing for EGFR mutation and ALK and ROS1 translocations will not be 
required, as this is not part of current diagnostic guidelines.
3. Has PD on treatment with one prior anti-PD-1/PD-L1 mAb administered either as 
monotherapy or in combination with other checkpoint inhibitors or other therapies. Anti-
PD-1/PD-L1 treatment progression is defined by meeting ALL of the following criteria:

Treatment with at least 2 doses of an anti-PD-1/PD-L1 mAb.

PD after an anti-PD-1/PD-L1 mAb as defined by RECIST 1.1, based on the 
following: 
o
Imaging before anti-PD-1/PD-L1 treatment or image showing nadir during anti-
PD-1/PD-L1 treatment; AND
o
Imaging to determine that radiographic progression has occurred per RECIST 1.1 
within 12 weeks (84 days) from the last dose of an anti-PD-1/PD-L1 mAb.
Note: Retreatment with the same anti-PD-L1/PD-L1 mAb is acceptable in the overall 
course of treatment.
4. Has PD as determined by the investigator after platinum doublet chemotherapy for 
metastatic disease.
Note: A platinum-containing doublet is defined as a platinum-based cytotoxic systemic 
agent administered in the same cycle as another cytotoxic systemic chemotherapeutic 
agent.
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Note: Completion of treatment with a platinum-containing doublet as neo-adjuvant or 
adjuvant therapy or as part of definitive chemo-radiation treatment for early stage disease 
(Stage I-III) within 1 year of signing the ICF will satisfy the prior platinum doublet 
chemotherapy treatment requirement.
Note: Eligible participants will have PD after an anti-PD-1/PD-L1 therapy AND 
platinum doublet chemotherapy (sequentially or concomitantly). 
5. Has measurable disease based on RECIST 1.1, as determined by the local site
assessment.
Note: Measurable disease is defined as having at least 1 measurable lesion by CT or MRI 
per RECIST 1.1. Lesions that appear measurable, but are situated in a previously 
irradiated area can be considered measurable (eligible for selection as target lesions) if 
they have shown documented growth since the completion of radiation.
6. Has provided tumor tissue for PD-L1 biomarker analysis from an archival sample 
(defined as: from initial diagnosis of NSCLC and before receiving immunotherapy [anti-
PD-1/PD-L1], from the primary lesion or a metastatic lesion) or newly obtained (defined 
as: after completion of immunotherapy [anti-PD-1/PD-L1] and before receiving a 
randomization number) core or excisional biopsy of a tumor lesion not previously 
irradiated.
Note: The tissue sample must be received and evaluated by the central vendor before 
randomization for stratification in the study. FFPE tissue blocks are preferred to slides. 
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
Demographics
7. Is male or female, ≥18 years of age at the time of providing documented informed 
consent.
8. Has a life expectancy of at least 3 months.
9. Has an ECOG Performance Status of 0 to 1 assessed within 7 days prior to 
randomization.
Male Participants
10. Male participants randomized to docetaxel are eligible to participate if they agree to 
the following during the intervention period and for at least 180 days after the last dose of 
docetaxel:

Refrain from donating sperm.
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PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR

Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
o
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. 
o
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile-vaginal penetration.
o
Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies. If the contraception requirements in the local label for any of the 
study interventions is more stringent than the requirements above, the local 
label requirements are to be followed.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least 120 days 
after the last dose of study intervention. The investigator should evaluate the potential for 
contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the 
first dose of study intervention.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours for urine or within 72 hours for serum 
before the first dose of study intervention.
•
A WOCBP randomized to docetaxel is eligible to participate if she is using a 
contraceptive method that is highly effective with low user dependency or is abstinent 
from heterosexual intercourse as her preferred and usual lifestyle and agrees not to donate 
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or freeze/store eggs during the intervention period and for at least 180 days after the last 
dose of docetaxel.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Section 8.3.5.
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
•
Contraceptive use by females should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirement above, the local label requirements are to be followed.
Informed Consent
12. The participant (or legally acceptable representative if applicable) provides documented 
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
13. Has adequate organ function as defined in Table 3. Specimens must be collected within 
10 days before the start of study intervention.
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1500/µL
Platelets
≥100,000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb CrCl
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
aPTT/PTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic-pyruvic transaminase); 
aPTT = activated partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum glutamic
oxaloacetic transaminase); CrCl = creatinine clearance; GFR = glomerular filtration rate; INR = international 
normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion 
within last 2 weeks.
b
CrCl should be calculated per institutional standard.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has known active or untreated CNS metastases and/or carcinomatous meningitis. 
Participants with previously treated brain metastases may participate provided they are 
radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat 
imaging (note: repeat imaging should be performed during study screening), clinically 
stable, and without requirement of steroid treatment for at least 7 days before the first 
dose of study intervention.
2. Has a known history of an additional malignancy, except if the participant has undergone 
potentially curative therapy with no evidence of that disease recurrence for at least 
3 years since initiation of that therapy.
Note: The time requirement for no evidence of disease for at least 3 years does not apply 
to the NSCLC for which a participant is enrolled in the study. The time requirement also 
does not apply to participants who underwent successful definitive resection of basal cell 
carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in 
situ cervical cancer, or other in situ cancers.
Prior/Concomitant Therapy
3. Has received docetaxel as monotherapy or in combination with other therapies.
4. Has received previous treatment with another agent targeting the TIGIT receptor
pathway.
5. Has received prior systemic anticancer therapy including investigational agents within 
4 weeks before randomization.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline (except alopecia). Participants with Grade ≤2 neuropathy may be 
eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or 
hormone replacement may be eligible.
6. Has received radiotherapy within 2 weeks of start of study intervention. Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation 
(≤2 weeks of radiotherapy) to non-CNS disease.
7. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines is allowed.
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Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks before the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
Diagnostic Assessments
9. Has severe hypersensitivity (≥Grade 3) to docetaxel or MK-7684A and/or any of its 
excipients (eg, polysorbate 80). 
10. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study intervention.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
13. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is 
not exclusionary.
14. Has an active infection requiring systemic therapy.
15. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
16. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
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18. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
19. If the participant had major surgery, the participant must have recovered adequately from 
the procedure and/or any complications from the surgery before starting study 
intervention. 
20. Has had an allogenic tissue/solid organ transplant.
Country-specific requirements are noted in Appendix 7.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are necessary.
5.3.3
Activity Restrictions
No restrictions are necessary.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws consent from the 
study will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (MK-7684A) will be packaged to support enrollment. Normal saline
placebo will be sourced locally by the site. Clinical supplies will be affixed with a clinical 
label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 4.
Country-specific requirements are noted in Appendix 7.
When concurrently administered, MK-7684A/normal saline placebo should be given before
chemotherapy; chemotherapy should be given as per the local label.
All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
Arm 1
Experimental
MK-7684A
Biological/
Vaccine
Solution 
for 
Infusion
MK-7684 
200 mg + 
pembrolizumab 
200 mg/ 20 mL 
vial
200mg/ 
200mg
IV 
Infusion
Q3W up to 
35 cycles
Test 
Product
IMP
Central
Arm 1
Experimental
Docetaxel
Drug
Solution 
for 
Infusion
20 mg/mL
75 mg/m2
IV 
Infusion
Q3W until a 
discontinuati
on criterion 
is met or as 
per approved 
local label. 
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor 
or locally 
by the 
study site, 
subsidiary 
or 
designee
Arm 2
Experimental
MK-7684A
Biological/
Vaccine
Solution 
for 
Infusion
MK-7684
200 mg + 
pembrolizumab 
200 mg/ 20 mL 
vial
200mg/ 
200mg
IV 
Infusion
Q3W up to 
35 cycles
Test 
Product
IMP
Central
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Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or
NIMP/
AxMP
Sourcing
Arm 3
Active 
Comparator
Docetaxel
Drug
Solution 
for 
Infusion
20 mg/mL
75 mg/m2
IV 
Infusion
Q3W until a 
discontinuati
on criterion 
is met or as 
per approved 
local label.
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor 
or locally 
by the 
study site, 
subsidiary 
or 
designee
Arm 3
Placebo 
Comparator
Normal 
saline
placebo
Biological/
Vaccine
Solution 
for 
Infusion
0 mg
0 mg
IV 
Infusion
Q3W up to 
35 cycles
Placebo
IMP
Local
MK-7684A = Coformulated as 200 mg MK-7684 and 200 mg pembrolizumab.
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-7684A/normal saline placebo are provided 
in the Pharmacy Manual. 
Docetaxel will be prepared and administered as per the approved local product label. 
Docetaxel 75 mg/m2 will be administered as an IV infusion over 1 hour every Q3W. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 3 study 
intervention arms. Participants will be assigned randomly in a 1:1:1 ratio to MK-7684A + 
docetaxel (Arm 1), MK-7684A (Arm 2), or normal saline placebo + docetaxel (Arm 3), 
respectively.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. ECOG PS (0 vs 1)
2. Prior anti-PD-1/PD-L1 mAb (immediate prior therapy vs not immediate prior therapy)
3. PD-L1 TPS (<50% vs ≥50%)
6.3.3
Blinding
For MK-7684A + docetaxel (Arm 1) and normal saline placebo + docetaxel (Arm 3), a
double-blinding technique with in-house blinding will be used. MK-7684A/normal 
saline placebo will be prepared and dispensed in a blinded fashion by an unblinded 
pharmacist or qualified study site personnel so that the blind is maintained. The participant, 
the investigator, and Sponsor personnel or delegate(s) who are involved in the study 
intervention administration or clinical evaluation of the participants are unaware of the 
intervention assignments.
Arm 2 (MK-7684A), which does not contain docetaxel, will be open-label; therefore, the 
Sponsor, investigator, and participant will know the study intervention administered.
Access to the randomization schedule and unblinded results for presentation of summaries 
and analyses to the eDMC will be restricted to an unblinded statistician and, as needed an 
unblinded scientific programmer performing the analysis, who will have no other 
responsibilities associated with the study.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with MK-7684A and for other allowed dose interruptions of MK-7684A.
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When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Participants are prohibited from receiving the following therapies during the screening and 
treatment periods of this study:
•
Antineoplastic systemic chemotherapy or biological therapy.
•
Immunotherapy not specified in this protocol.
•
Chemotherapy not specified in this protocol.
•
Investigational agents other than MK-7684A.
•
Radiation therapy for disease control.
Note: Palliative radiotherapy is permitted for nontarget lesions if considered medically 
necessary by the treating physician and on discussion with the Sponsor.
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. Note: Killed vaccines are allowed.
•
Systemic glucocorticoids are permitted only for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology.
-
As needed for the prevention of emesis.
-
Premedication for IV contrast allergies.
-
Short-term oral or IV use in doses >10 mg/day prednisone equivalent for COPD 
exacerbations.
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-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent.
•
In addition, the following glucocorticoid use is allowed:
-
For topical use or ocular use.
-
Intraarticular joint use.
-
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease.
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention (all study interventions in combination arms) must be 
discontinued.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 30 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.1.
Note: If after the evaluation of the event, it is determined not to be related to MK-7684A, the 
investigator does not need to follow the treatment guidance. Refer to Table 5 in Section 6.6.1 
for guidelines regarding dose modification and supportive care.
Participants in the docetaxel arm should receive premedication with corticosteroids for 
3 days starting 1 day before docetaxel administration to reduce the risk of fluid retention and 
the severity of hypersensitivity reactions. Refer to the approved product label for docetaxel 
dose interruptions and dose reductions.
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6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
Holding Study Interventions:
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
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Restarting Study Interventions:
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics 
for opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 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 -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer antihyperglycemic 
in participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
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
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
· Ensure adequate evaluation to confirm etiology 
or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
PersistentGrade2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to MK-
7684A
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 infusion. 
Dose modification and toxicity management guidelines on MK-7684A associated infusion 
reaction are provided in Table 6.
Table 6
MK-7684A Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
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/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the participant should 
be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h (±30 
minutes) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for MK-7684A
MK-7684A may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks of the originally scheduled 
dose and within 6 weeks of the previously administered dose, unless otherwise discussed 
with the Sponsor. The reason for study intervention interruption is to be documented in the 
participant's study record.
Docetaxel
Refer to the approved product label for docetaxel.
6.6.2
Initial Treatment or First Course 
The initial treatment or first course of MK-7684A Q3W consists of 35 treatments
(approximately 2 years). Note: The number of treatments is calculated starting with the first 
dose.
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For participants who have attained a confirmed CR and have received at least 8 doses of 
MK-7684A, including at least 2 doses of MK-7684A beyond the initial CR confirmation 
date, treatment may be stopped.
These participants may be eligible for Second Course described in Section 6.6.3.
6.6.3
Second Course
All participants who have SD, PR, or CR may be eligible for up to an additional 17 cycles of 
MK-7684A if there is BICR verification of radiographic disease progression by RECIST 1.1 
after initial treatment or first course has been completed or stopped for confirmed CR, as 
specified in Section 6.6.2. This retreatment is the Second Course of this study. 
Participants may enter the Second Course if all of the following criteria are met: 
1. The participant received MK-7684A, determined on unblinding if applicable
2. No new anticancer treatment was administered after the last dose of study 
intervention
3. The participant meets all of the inclusion criteria and none of the exclusion criteria 
4. The study is ongoing
An objective response or disease progression that occurs during the Second Course will not 
be counted as an event for the primary analysis of either endpoint in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity for MK-7684A or 
normal saline placebo (Arm 1 and Arm 3) of this study. The emergency unblinding call 
center should only be used in cases of emergency (see Section 8.1.10). In the event that the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
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6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos to provide the following advice:“You have participated in 
a study conducted by the Sponsor. This letter is to advise you that you were among those 
who received a look-alike solution for infusion created by the Sponsor to resemble the drug
MK-7684A as much as possible. You did not receive the active drug MK-7684A as 
manufactured by MSD.”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.4 unless the participant has 
withdrawn from the study (see Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.

The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a confirmed positive serum pregnancy test.
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
Taking any prohibited medications noted in Section 6.5.

Radiographic disease progression outlined in Section 8.2.1.5 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond iCRO-verified disease progression).

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.

Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.1.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
Participant Withdrawal From the Study
If a participant fails to return for scheduled visits and/or if the study site is unable to contact 
the participant after multiple attempts (ie, is lost to follow-up), the procedures to be 
performed are outlined in Section 7.3.
If a participant decides not to continue receiving study intervention, the participant is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants who withdraw consent during the study.
If the participant or participant’s legally acceptable representative withdraws consent from 
the study, the participant must be withdrawn from the study.
Section 8.1.9 delineates the specific procedures performed at the time of withdrawal and 
withdrawal from future biomedical research. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in 
Section 8.4.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
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known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical decisions must be made by an investigator who is a qualified 
physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
will be provided in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the documented informed consent form should be given to the participant (or their 
legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant or the participant's legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit (30 days after the last dose of study 
intervention or 90 days if used to treat an SAE). Any new anticancer therapy started after the 
participant’s discontinuation from initial treatment will be recorded separately. Additional 
information collected on this treatment will include, but is not limited to, best response and 
date of progression. 
In addition, medications taken within 30 days of the first dose of Second Course treatment 
through the Second Course Safety Follow-up Visit (30 days after the last dose of study 
intervention or 90 days if used to treat an SAE) should be recorded.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the Screening/rescreening visit 
requirements are provided in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study interventions will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual.
Study intervention should begin within 3 days of randomization.
8.1.8.1
Timing of Dose Administration
All study treatment will be dosed on Day 1 of each 21-day cycle. After Cycle 1 Day 1, study 
medication may be administered up to 3 days before or after the scheduled Day 1 of each 
subsequent cycle for administrative reasons.
The Pharmacy Manual contains specific instructions for the preparation and administration of 
the infusion solutions.
Arm 2 will receive MK-7684A on Day 1 of each cycle.
In Arm 1 and Arm 3 MK-7684A/normal saline placebo will be administered first on Day 1 of 
each cycle, followed by docetaxel. Participants should receive premedication per the 
approved product label for docetaxel.
Docetaxel will be prepared and administered as per the approved local product label. 
Docetaxel 75 mg/m2 will be administered as an IV infusion over 1 hour every Q3W. All 
participants randomized to docetaxel should be premedicated with steroids for 3 days starting 
1 day before docetaxel administration to reduce the risk of fluid retention and the severity of
hypersensitivity reactions (or according to the approved product label).
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8.1.9
Discontinuation and Withdrawal
Section 7.2 provides a complete description of withdrawal of consent from the study.
Participants who withdraw consent from the study should be encouraged to complete all 
applicable activities scheduled for the final study visit at the time of withdrawal.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
intensity/toxicity grade of the AEs observed, the relation to study intervention, the reason 
thereof, etc, in the medical record. If it is not possible to record this assessment in the 
medical record before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
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Once an emergency unblinding or a nonemergency unblinding that is part of the study design 
has taken place, the investigator, site personnel, and Sponsor personnel may be unblinded so 
that the appropriate follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue for Biomarker Status
During the Screening period, a tissue sample for each participant is required and is to be:
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD-L1 
IHC 22C3 pharmDx (Investigational Use Only) diagnostic kit. The diagnostic test is identical 
to the US FDA-approved PD-L1 IHC 22C3 pharmDx kit except it is labeled IUO.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
In addition to survival, efficacy will be assessed based on scans to evaluate changes in tumor 
burden over time, until the participant is discontinued from the study or enters the survival 
follow-up. The process for scan collection and transmission to the iCRO can be found in the 
Site Imaging Manual. 
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Chest, abdomen, and pelvis scans are required for all participants. CT scans are preferred 
over other tumor imaging methods. For the abdomen and pelvis, contrast-enhanced MRI may 
be used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. The same type of scan should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the response assessment. Note: for the purposes of assessing tumor scans, the 
term “investigator” refers to the local investigator at the site and/or the radiological reviewer 
at the site or at an offsite facility.
If brain scans are performed, MRI is preferred; however, CT scans are acceptable if MRI is 
medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain X-rays acquired for 
correlation, should also be submitted to the iCRO.
Additional imaging (including via other modalities, such as PET-CT, X-ray) that are obtained 
at an unscheduled time point to determine disease progression, and scans obtained for other 
reasons that capture radiologic progression based on investigator assessment, should be 
submitted to the iCRO. Other types of scans (eg, ultrasound) should not be submitted to the 
iCRO and will not be included in response assessment.
Participant eligibility will be determined using local assessment (investigator assessment) 
based on RECIST 1.1. When the investigator identifies radiographic progression per RECIST 
1.1, the iCRO will perform expedited verification of radiologic disease progression and 
communicate the results to the study site and Sponsor via email. In clinically stable 
participants, imaging should continue until disease progression has been verified by BICR (if 
initial site-assessed disease progression was not verified by BICR, each subsequent scan 
must be submitted to iCRO with verification of disease progression request until disease 
progression has been verified by BICR). Once disease progression is verified centrally, 
subsequent imaging (if acquired) should not be submitted to the iCRO.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days before the date of 
randomization. Tumor imaging performed as part of routine clinical management is 
acceptable for use as Screening tumor imaging if it is of diagnostic quality and performed 
within 28 days before randomization. The screening images must be submitted to the iCRO 
for retrospective review.
Brain imaging is required for all participants at Screening. Bone imaging is required at 
Screening for participants with a history of bone metastases and/or for those participants with 
clinical indication, such as bone pain or elevated alkaline phosphatase.
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8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days) 
from the date of randomization. Subsequent tumor imaging should be performed every 6 
weeks (42 days ±7 days), or more frequently if clinically indicated. After 36 weeks (252 days 
±7 days), imaging should be performed every 9 weeks (63 days ±7 days) through Week 54 
(378 days ±7 days), and every 12 weeks (84 days ±7 days) thereafter. Imaging timing should 
follow calendar days and should not be adjusted for delays in cycle starts. Imaging should 
continue to be performed until disease progression is identified by the investigator and 
verified by BICR, the start of new anticancer treatment, withdrawal of consent, or death, 
whichever occurs first. All supplemental imaging must be submitted to the iCRO.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the BICR.
On-study brain or bone imaging should be performed if clinically indicated or to confirm CR 
(if other lesions indicate CR and brain or bone lesions existed at baseline).
Treatment beyond BICR-verified PD per RECIST 1.1 may be permitted at the discretion of 
the investigator after consulting with the Sponsor and after the participant provides a new 
documented informed consent (Figure 5). Participants who continue treatment beyond BICR-
verified PD must continue tumor imaging assessments as described in the SoA (Section 
1.3.1). Investigator assessments are to be documented on the eCRF, but scans are not to be 
submitted to the iCRO. Further progression and discontinuation of study intervention are to 
be determined by the investigator.
For participants who have unconfirmed disease progression (investigator assessment of 
disease progression, but BICR assessment of disease progression per RECIST 1.1 = “No”), 
treatment can continue at the investigator’s discretion for clinically stable participants (see 
Section 8.2.1.5). Imaging should continue to be performed as per imaging schedule and must 
be submitted to the iCRO along with a VOP request until central confirmation of progression 
is received.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging.
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For participants who complete all 35 cycles of initial treatment or discontinue study 
intervention without documented disease progression, every effort should be made to 
continue monitoring disease status by tumor imaging using the same imaging schedule used 
while on treatment calculated from the date of randomization (see Section 8.2.1.2) until the 
start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of 
consent, or the end of the study, whichever occurs first.
8.2.1.4
Second Course (Retreatment) Tumor Imaging
Before a participant may enter the Second Course Phase, BICR verification of radiographic 
disease progression must have occurred. Tumor imaging must be performed within 28 days 
prior to restarting treatment with MK-7684A. The disease progression imaging may also be 
used as the Second Course baseline imaging if it is within 28 days before restarting treatment 
and otherwise meets the baseline standards outlined in the Site Imaging Manual.
Response assessments and progressive disease in the Second Course are determined by site 
assessment only. No imaging from the Second Course Phase should be provided to the 
central vendor, except for the Second Course Phase baseline scan if this scan is also the final 
imaging for the Initial Treatment Phase.
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days)
after the restart of treatment. Subsequent tumor imaging should be performed every 6 weeks 
(42 days ±7 days) through Week 36 (252 days ±7 days), every 9 weeks (63 days ±7 days)
through the end of treatment, and every 12 weeks (84 days ±7 days) thereafter, or more 
frequently if clinically indicated. Imaging should continue to be performed until disease 
progression, the start of a new anticancer treatment, withdrawal of consent, death, or 
notification by the Sponsor, whichever occurs first. The schedule should be followed 
regardless of treatment delays.
For participants who discontinue Second Course study intervention, tumor imaging should be 
performed at the time of intervention discontinuation (±4 week window). If previous imaging 
was obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging.
For participants who complete all 17 cycles of Second Course treatment or discontinue 
Second Course treatment without documented disease progression, every effort should be 
made to continue monitoring their disease status by radiologic imaging every 12 weeks (84 
days ±7 days) until the start of a new anticancer treatment, disease progression, death, or the 
end of the study, whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
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5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden. 
Upon investigator-assessed disease progression, the indicative scan(s) are to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will email the assessment to the site and Sponsor.
If disease progression is not verified, the process continues as follows:

If participant is clinically stable, continue study intervention per protocol 
o
Resume imaging per protocol schedule (≥4 weeks to next scan)
o
Send scans to iCRO 
o
Continue local assessment 
o
Do not change investigator assessment of progression
o
If subsequent scan(s) indicate progression, submit scan(s) to iCRO to request 
verification

If the participant is not clinically stable, best medical practice is to be applied
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor is required.
If disease progression is verified, the process continues as follows:

Investigator judgment will determine action

If the participant is clinically stable and study intervention is to continue, 
communication with the Sponsor is required and a reconsent addendum must be 
signed 
Note: the reconsent addendum may be signed any time after investigator-assessed 
progression is identified, but must be signed before starting study intervention after 
verification of disease progression is provided by the iCRO 

Obtain scans locally per original protocol schedule

Do not send scans to iCRO
Figure 5 illustrates the decision process involving verification of disease progression for 
participants.
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For the purpose of this decision process, lack of clinical stability is defined as:

Unacceptable toxicity

Clinical signs or symptoms indicating clinically significant disease progression

Decline in performance status

Rapid disease progression or threat to vital organs or critical anatomical sites (eg,
CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention
Figure 5
Decision-Making Process When Progression Observed by Investigator
iCRO = imaging CRO; RECIST = Response Evaluation Criteria in Solid Tumors.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
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Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Height will also be measured and recorded at Screening. Clinically 
significant abnormal findings should be recorded as medical history. The time points for full 
physical exams are described in Section 1.3. After the first dose of study intervention, new 
clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated before study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
•
Temperature (oral, tympanic, rectal, axillary, skin, or temporal artery), pulse rate, 
respiratory rate, and blood pressure will be assessed.
•
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
•
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 1 blood pressure measurement (after the participant has been sitting for 5 minutes, 
1 blood pressure reading will be recorded). OR
•
Vital signs will be measured in a semisupine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse and respiratory rate.
•
Weight will also be measured and recorded.
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8.3.3
Electrocardiograms
A standard 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, and QT
intervals.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2 and 
schedule is provided in the SoA (Section 1.3).
8.3.5
Pregnancy Testing
Pregnancy testing requirements for study inclusion are described in Section 5.1.
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Pregnancy testing (urine or serum as required by local regulations) should be conducted prior 
to every cycle (Q3W), or more frequently if required by local regulations.
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
120 days after the last dose of MK-7684A and 180 days after the last dose of docetaxel, 
whichever occurs latest.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participant’s participation in the study.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status at Screening, before the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days following cessation 
of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 90 
days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
randomization through 120 days following cessation of MK-7684A or 180 days 
following cessation of docetaxel, or 30 days following cessation of study intervention if 
the participant initiates new anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified 
Follow-up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event 
unless the participant 
has received study 
intervention.
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus. 
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Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor. 
Events of clinical interest for this study include: 
-
An overdose of Sponsor's product, as defined in Section 8.5.
-
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For this study, an overdose of MK-7684A will be defined as any dose exceeding 3 times or 
300% the prescribed dose. No specific information is available on the treatment of overdose 
of MK-7684A.
There is no known antidote for docetaxel overdose. In the event of overdose, the specific 
intervention should be withheld, and the participant should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
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Refer to the local package insert for the definition and treatment of overdose with docetaxel.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma MK-7684 and Pembrolizumab
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual.
8.6.1.1
Blood Collection for PK
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the procedure manual. Pharmacokinetic samples should be drawn according to the PK 
collection schedule for all participants. Every effort should be taken to collect samples at 
30 days after end of study intervention.
8.6.1.2
Blood Collection for Antidrug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the procedure manual. Antidrug antibody samples should be drawn according to the ADA 
collection schedule for all participants (Section 1.3). Every effort should be taken to collect 
samples at 30 days after end of study intervention for ADA. Simultaneous PK sampling is 
required for interpretation of ADA analysis.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:
•
Blood (DNA) for genetic analysis
•
Blood for serum biomarker analyses
•
Blood for RNA analyses
•
Blood for ctDNA Analysis
•
Newly obtained/archival tissue specimen
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
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8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:
•
Leftover DNA for future research
•
Leftover RNA
•
Leftover serum from biomarker analyses
•
Leftover plasma or derivative for ctDNA
•
Leftover tumor
8.10
Health Economics Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment allocation/randomization through 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention, if the participant initiates new 
anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.11.1
Screening
Written consent must be obtained before performing any protocol-specific procedure. Results 
of a test performed before the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days before the first dose of study 
intervention except for the following:
•
Laboratory tests are to be performed within 10 days before the first dose of study 
intervention. An exception is hepatitis testing which may be performed up to 28 days 
before the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 7 days before the first dose of study 
intervention.
•
For WOCBP, a serum pregnancy test will be performed within 72 hours or a urine 
pregnancy test within 24 hours prior to the first dose of study intervention. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory). Additional pregnancy testing can 
be conducted if required by local regulations or clinically indicated.
•
Archival tumor sample collection is not required to be obtained within 28 days before the 
first dose of study intervention. Newly obtained tumor tissue may be obtained according 
to the Procedures Manual.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial Screening period are acceptable in lieu of a repeat 
Screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
Screening number.
8.11.2
Initial Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.3
Second Course Treatment Phase
See Section 6.6.3 for details concerning the Second Course.
8.11.4
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment due to disease recurrence or start of a new 
anticancer therapy will have Safety Follow-up and then proceed directly to Survival Follow-
up as described in Section 8.11.5.
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
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the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed.
8.11.5
Posttreatment Visit
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
Participants who are eligible for Second Course Treatment with MK-7684A may have up to 
2 safety follow-up visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Treatment.
8.11.5.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin the 
Efficacy Follow-up Phase and should be assessed every 12 weeks to monitor disease status. 
Imaging should be continued to be collected in the Efficacy Follow-up Phase (see 
Section 8.2.1.3). Every effort should be made to collect information regarding disease status 
until the start of new anticancer therapy, disease progression, death, or end of study. 
Information regarding poststudy anticancer treatment will be collected if new treatment is 
initiated. Participants who completed all efficacy assessments and/or will not have further 
efficacy assessments must enter the Survival Follow-up Phase.
Participants who are eligible to receive Second Course Treatment with MK-7684A according 
to the criteria in Section 6 will move from the Efficacy Follow-up Phase to the Second 
Course Treatment Phase when they experience disease progression. Details are provided in 
the SoA (Section 1.3.2) for Second Course Treatment with MK-7684A.
8.11.5.3
Survival Follow-up Contacts
Participant Survival Follow-up status will be assessed approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
The first Survival Follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up Phase, the first Survival Follow-up contact will be scheduled 
12 weeks after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is 
last).
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
For participants who completed assessments in the Efficacy Follow-up Phase, the first
Survival Follow-up contact will be scheduled 12 weeks after the last efficacy 
assessment follow-up visit has been performed.
8.11.6
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an eDMC 
review, interim and/or final analysis. Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status (excluding participants that have a 
previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to final database lock, will be documented in a supplemental SAP (sSAP) and 
referenced in the CSR for the study. Post hoc exploratory analyses will be clearly identified 
in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
A Phase 2,multicenter, randomized, placebo- and active-controlled, 
parallel-group, double-blind (Arm 1 and Arm 3 only), 3 arm study 
comparing MK-7684A + docetaxel or MK-7684A to docetaxel alone in 
participants with metastatic NSCLC with PD after platinum doublet 
chemotherapy and anti-PD-1/PD-L1 immunotherapy.
Treatment Assignment
Approximately 240 participants will be randomized in a 1:1:1 ratio to:

Arm 1 (MK-7684A + docetaxel)

Arm 2 (MK-7684A) 

Arm 3 normal saline placebo + docetaxel) 
The stratification factors are: Prior anti-PD-1/PD-L1 mAb (immediate 
prior therapy versus not the immediate prior therapy); PD-L1 TPS (<50% 
versus ≥50%); and ECOG Performance Status (0 versus 1)
Analysis Populations
Efficacy: ITT
Safety: APaT
Primary Endpoint
PFS per RECIST 1.1 by BICR
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Secondary Endpoints

OR per RECIST 1.1 by BICR

OS

DOR per RECIST 1.1 by BICR

Safety and tolerability
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis will be evaluated by comparing Arm 1 to Arm 3, 
and Arm 2 to Arm 3 with respect to PFS using a stratified log-rank test. 
The HR will be estimated using a stratified Cox regression model. Event 
rates over time will be estimated within each treatment group using the 
Kaplan-Meier method.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers 
differ with respect to the analyses that will be performed. There are no 
events of interest that warrant elevation to Tier 1 events in this study. 
Tier 2 parameters will be assessed via point estimates with 95% CIs 
provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters. The 95% CIs 
for between treatment differences in the percentage of participants with 
events will be provided using the Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
There are 2 primary hypotheses. Each hypothesis is tested at 0.05 (one-
sided) alpha level. If significant, the hypothesis will further be tested at a 
more stringent alpha level 0.025 (one-sided).
Sample Size and Power 
The planned sample size is ~80 for each of Arm 1, Arm 2, and Arm 3 
with a total of ~240 participants in the study. 
 
 
 
 
 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics Department of the Sponsor.
The study will be conducted as a partially blinded study (Arm 1 and Arm 3 are double 
blinded, Arm 2 is open-label), ie, participants, investigator, and Sponsor personnel will be 
aware of participants treatment assignment to Arm 2 vs Arm 1 or Arm 3 after each 
participant is enrolled and treatment is assigned.
The Sponsor will generate the randomized allocation schedule(s) for study intervention 
assignment for this protocol, and the randomization will be implemented in IRT.
An eDMC will conduct regular safety monitoring at intervals specified in the eDMC charter. 
Treatment-level safety analyses will be provided by the unblinded statistician to the eDMC.
The eDMC will review the results of safety analyses and make recommendations for protocol 
modifications to the study EOC. If the eDMC recommends modifications to the design of the 
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protocol, the EOC (and potentially other limited Sponsor personnel) may be unblinded to 
results at the treatment level to act on these recommendations. The extent to which 
individuals are unblinded with respect to results of analyses for eDMC monitoring will be 
documented by the unblinded statistician external to the Sponsor. Additional logistical details 
will be provided in the eDMC charter. 
Prior to final study unblinding, the unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol or statistical methods, identification of 
protocol deviations, or data validation efforts.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary

Progression-free Survival (PFS)
PFS is defined as the time from randomization to the first documented disease 
progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs 
first. 
Secondary

Objective Response (OR)
A confirmed CR or PR per RECIST 1.1 based on BICR.

Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.

Duration of Response (DOR)
For participants who demonstrate confirmed CR or PR, DOR is defined as the time 
from the first documented evidence of CR or PR until disease progression or death 
due to any cause, whichever occurs first.
9.4.2
Safety Endpoints
Key safety endpoints are AEs and study treatment discontinuations due to AEs. In addition, 
safety parameters commonly used for evaluating investigational systemic anticancer 
treatments, including, but not limited to all AEs, SAEs, fatal AEs, and laboratory changes, 
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will be evaluated by clinical review. AEs will be assessed as defined by CTCAE, 
Version 5.0. A description of safety measures is provided in Section 8.3.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of efficacy endpoints are based on the ITT population. All randomized 
participants will be included in this population. Participants will be analyzed in the treatment 
arms to which they are randomized. 
9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed in the treatment arm corresponding to the study 
treatment they actually received. For most participants, this will be the treatment group to 
which they are randomized. Participants who received incorrect study treatment for the entire 
treatment period will be included in the treatment arm corresponding to the study treatment 
actually received. 
At least one laboratory 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.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP. The stratification factors used for randomization (see Section 6.3.2) will be applied to 
all stratified analyses, in particular, the stratified log-rank test, stratified Cox model, and 
stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. In the 
event that there are small strata, for the purpose of analysis, strata will be combined to ensure 
sufficient number of participants, responses, and events in each stratum. Details regarding the 
pooling strategy will be prespecified in the sSAP prior to the database lock, and decisions 
regarding the pooling will be based on a blinded review of response and event counts by 
stratum.
The efficacy analyses for PFS, ORR, and DOR will include documented progression events 
and responses that occur prior to Second Course Treatment.
9.6.1.1
Progression-free Survival (PFS)
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
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used to assess the magnitude of the treatment difference (ie, HR) between the treatment arms. 
The HR and its 95% CI from the stratified Cox model with a single treatment covariate will 
be reported. The stratification factors used for randomization (see Section 6.3.2) will be 
applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is always considered a PD event.
For the primary analysis, any participant who experiences an event (PD or death) 
immediately after 2 or more missed disease assessments will be censored at the last disease 
assessment prior to the missed visits. In addition, any participant who initiates new 
anticancer therapy prior to documented progression will be censored at the last disease 
assessment prior to the initiation of new anticancer therapy. Participants who do not start new 
anticancer therapy and who do not experience an event will be censored at the last disease 
assessment. If a participant meets multiple criteria for censoring, the censoring criterion that 
occurs earliest will be applied. Sensitivity analyses will be performed for comparison of PFS 
based on investigator’s assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 
2 sensitivity analyses with different sets of censoring rules will be performed. The first 
sensitivity analysis follows the intention-to-treat principle. That is, PDs/deaths are counted as 
events regardless of missed study visits or initiation of new anticancer therapy. The second 
sensitivity analysis considers initiation of new anticancer treatment or discontinuation of 
treatment due to reasons other than complete response, whichever occurs later, to be a PD 
event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for the primary and sensitivity analyses are summarized in Table 8. 
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Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity Analysis 1
Sensitivity Analysis 2
PD or death documented 
after ≤ 1 missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death 
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
Death or progression 
immediately after ≥2 
consecutive missed 
disease assessments, or 
after new anticancer
therapy
Censored at last disease 
assessment prior to 
the earlier date of ≥ 2 
consecutive missed 
disease assessment and 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
No PD and no death; and 
new anticancer treatment 
is not initiated
Censored at last disease 
assessment 
Censored at last 
disease assessment 
Progressed at treatment 
discontinuation due to 
reasons other than 
complete response; 
otherwise censored at last 
disease assessment if still 
on study treatment or 
completed study 
treatment.
No PD and no death; 
new anticancer treatment 
is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last 
disease assessment
Progressed at date of new 
anticancer treatment
9.6.1.2
Objective Response Rate (ORR)
The stratified Miettinen and Nurminen method will be used for comparison of the ORR 
between 2 treatment groups (Arm 1 vs Arm 3; Arm 2 vs Arm 3). The difference in ORR and 
its 95% confidence interval from the stratified Miettinen and Nurminen method with strata 
weighting by sample size will be reported. The stratification factors used for randomization
(see Section 6.3.2) will be applied to the analysis. The point estimate of ORR will be 
provided by treatment group, together with 95% CI using exact binomial method proposed 
by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 1934].
9.6.1.3
Overall Survival (OS)
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR). The HR and its 95% confidence interval 
from the stratified Cox model with a single treatment covariate will be reported. The 
stratification factors used for randomization (see Section 6.3.2) will be applied to both the 
stratified log-rank test and the stratified Cox model. Participants without documented death 
at the time of analysis will be censored at the date the participant was last known to be alive.
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9.6.1.4
Duration of Response (DOR)
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a confirmed complete response or 
partial response will be included in this analysis. Censoring rules for DOR are summarized in 
Table 9.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer treatment, have not been determined to be lost to follow-up, 
and have had a disease assessment within ~5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.  
Table 9
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(nonevent)
No progression nor death, new anticancer
therapy initiated
Last adequate disease assessment before new 
anticancer therapy initiated
Censor
(nonevent)
Death or progression immediately after 
≥2 consecutive missed disease 
assessments or after new anticancer
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed adequate 
disease assessments and new anticancer
therapy, if any
Censor
(nonevent)
Death or progression after ≤1 missed 
disease assessments and before new 
anticancer therapy, if any
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.
9.6.1.5
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 10. The strategy to address multiplicity issues with regard to multiple endpoints is 
described in Section 9.8.
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Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
PFS per RECIST 1.1
by BICR
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling 
method 
ITT
Censored according to rules 
in Table 8
Secondary Analyses
ORR per RECIST 1.1 
by BICR
Testing and estimation:
stratified M&N method
ITT
Participants with missing 
data are considered 
nonresponders
OS
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at participant’s last
known alive date
DOR per RECIST 1.1 
as assessed by BICR
Summary statistics using 
Kaplan-Meier method
Responders 
in ITT 
population
Censored according to rules 
in Table 9
Abbreviations: BICR=blinded independent central review; DOR=duration of response; DCR=disease control rate; ITT=intent-to-treat; 
ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) are either prespecified as “Tier 1” endpoints or will be classified as 
belonging to “Tier 2” or “Tier 3” based on the number of events observed. 
Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
“Tier 1” safety endpoints that will be subject to inferential testing for statistical significance. 
There are no Tier 1 events for this protocol. Based on a review of historic docetaxel data and 
data from ongoing MK-7684A clinical studies, there are no AEs that warrant inferential 
testing between treatment groups.
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group show
the event; all other AEs and predefined limits of change will belong to Tier 3. The threshold 
of at least 10% of participants was chosen for Tier 2 events because the population enrolled 
in this study is in critical condition and usually experiences various AEs of similar types 
regardless of treatment; events reported less frequently than 10% of participants would 
obscure the assessment of the overall safety profile and add little to the interpretation of 
potentially meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% of 
participants in 1 of the treatment groups) and SAEs (≥5% of participants in 1 of the treatment 
groups) will be considered Tier 2 endpoints. Because many 95% CIs may be provided 
without adjustment for multiplicity, the CIs should be regarded as a helpful descriptive 
measure to be used in safety review, not as a formal method for assessing the statistical 
significance of the between-group differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory parameters, summary 
statistics for baseline, on treatment, and change from baseline values will be provided by 
treatment group in table format.
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Table 11
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific Grade 3-5 AE (incidence ≥X% of participants 
in one of the treatment groups)
X
X
Specific SAE (incidence ≥X% of participants in one of 
the treatment groups)
X
X
Specific AEs (incidence ≥X% of participants in one of 
the treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Drug-Related SAE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence >0% of participants 
in all of the treatment groups)
X
Change from Baseline Results (laboratory test result:
toxicity shift)
X
Abbreviations: AE = adverse event; CI = confidence interval; SAE = serious adverse event; SOC = system 
organ class.
9.6.3
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
There is no interim analysis planned in this study. The eDMC will conduct regular safety 
monitoring. The timing of the safety monitoring will be specified in the eDMC charter. 
eDMC monitoring for safety will be conducted at a minimum every 6 months until such time 
that the eDMC determines that monitoring at a different frequency is appropriate.
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9.8
Multiplicity
There are 2 primary hypotheses in the study: H1 is for MK-7684A + docetaxel vs. control 
docetaxel in PFS; H2 is for MK-7684A vs. control in PFS. Since MK-7684A + docetaxel and 
MK-7684A may be considered as 2 different therapies (one is combination with 
chemotherapy and the other is a chemotherapy-sparing therapy) being evaluated in a 
multiarm study with shared control, family-wise error rate (FWER) adjustment is not 
necessary [Freidlin, B., et al 2008] [Howard, D. R., et al 2018] [Collignon, O., et al 2020]. In 
this study, each hypothesis is tested at 0.05 (one-sided) alpha level. If a given hypothesis is 
significant at the alpha level 0.05 (one-sided), that hypothesis will further be tested at a more 
stringent alpha level 0.025 (one-sided).
9.9
Sample Size and Power Calculations
The study will randomize approximately 240 participants in a 1:1:1 ratio into Arm 1 
(MK-7684A + docetaxel), Arm 2 (MK-7684A), and Arm 3 (docetaxel). PFS is the primary 
endpoint for the study, with ORR, OS, and DOR as the secondary endpoints. If the PFS result 
is positive in either arm at the final analysis, follow-up of the study may be extended to 
collect more OS data for the entire study population.
For the PFS endpoint, based on a target number of
 
 
approximately 
 
The above sample size and power calculations for PFS assume the following:

PFS follows an 
 for the control 
group [Herbst, R. S., et al 2016]. 

Enrollment period of 
. 

.

A follow-up period of approximately 6 months for PFS, after the last participant 
enrolls.
The sample size and power calculations were performed using EAST® 6.4 software.
 
 
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for PFS (with a nominal 95% CI) will be estimated and 
plotted by treatment group within each category of the following subgroup variables:

Geographic region (East Asia, Non-East Asia)

ECOG Performance Status (0, 1)

PD-L1 TPS (<50%, ≥50%)

Prior anti-PD-1/PD-L1 mAb (immediate prior therapy vs not immediate 
prior therapy)

Histology (squamous, nonsquamous)

Age category (<65 years, ≥65 years)

Sex (female, male)

Race (white, nonwhite)

Smoking status (never, former/current smoker)

Brain metastasis at baseline (presence, absence)

Liver metastasis at baseline (presence, absence)
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 10% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for PFS and OS will be conducted using 
an unstratified Cox model, and the subgroup analysis for ORR will be conducted using the 
unstratified Miettinen and Nurminen method.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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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.
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.
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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.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee is comprised of:
•
Sponsor personnel,
•
Investigators participating in the study, and
•
Consulting therapeutic-area experts and clinical trialists.
The Steering Committee will provide guidance on the operational aspects of the study, 
evaluate recommendations from the DMC, and make recommendations to the EOC.
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC or Steering Committee regarding the 
study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants' documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
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Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 12 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 12
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVa
MCHa
%Reticulocytesa
WBC count with Differentialb
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)c
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum Glutamic
Oxaloacetic 
Transaminase (SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonatea
Chloridea
Phosphorousa
Creatinined
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
TSHe
Free thyroxine
(FT4)e
Lactate dehydrogenase 
(LDH)
Amylase
Lipase
Triiodothyronine 
(Total T3)e
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte esterase)
by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
•
PT/INR and aPTT/PTTf
•
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) NOTE: certain ex-US 
sites require testing for HIV and hepatitis B and C during screening. Consult with 
regional health authorities and institutional standards to confirm if such testing is 
applicable.
•
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only).
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP).
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Laboratory 
Assessments
Parameters
Abbreviations: FT4 = free thyroxine; HBsAg = hepatitis B surface antigen; hCG = human chorionic 
gonadotropin; HIV = human immunodeficiency virus; INR = international normalized ratio; MCH = mean 
corpuscular hemoglobin; MCV, mean corpuscular volume; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cells; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-
stimulating hormone; WBC = white blood cell; WOCBP = women of childbearing potential.
a.
Performed only if considered local standard of care.
b.
Absolute or % acceptable per institutional standard.
c.
Urea is acceptable if BUN is not available as per institutional standard.
d.
Glomerular filtration rate (GFR) (measured or calculated) or creatinine clearance can be used in place of 
creatinine.
e.
Participants may be dosed in subsequent cycles after C1D1 while thyroid function tests are pending. 
Free T3 and free T4 are acceptable.
f.
Performed as part of the screening assessment and as clinically indicated for participants taking 
anticoagulants.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol-specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
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
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
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b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if 
the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent 1 of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
•
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
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10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
·
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
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-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
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 AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge.
If no, this is a negative dechallenge.
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(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant 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 study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
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product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
The biology of how drugs/vaccines work
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
Other pathways with which drugs/vaccines may interact
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention 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 study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study 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 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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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 study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Argentina-specific Requirements 
HBV, HCV, and HIV testing at screening is mandatory.
Section 1.3 Schedule of Activities - Screening and treatment Phase
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
Section 1.3 Schedule of Activities - Post-treatment Phase
Monthly urine pregnancy testing is required during study intervention as well as at the end of 
study intervention.
Section 1.3 Schedule of Activities - Long-term Follow-up Phase
Monthly urine pregnancy testing is required during study intervention as well as at the end of 
study intervention.
Section 10.5 Appendix 5: Contraceptive Guidance and Pregnancy Testing
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
10.7.2
France-specific Requirements
Section 1.3 Schedule of Activities
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
Section 1.3 Schedule of Activities - Post-treatment Phase
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
Section 1.3 Schedule of Activities - Long-term Follow-up Phase
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
Section 10.5 Appendix 5: Contraceptive Guidance
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study treatment.
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10.7.3
Germany-specific Requirements
Throughout the Protocol
Legally Acceptable Representative
In order for a participant to be eligible to participate in Germany, they must be capable of 
documenting the informed consent; therefore, all references to a participant’s “legally 
acceptable representative” in the protocol are not applicable for participants in Germany.
Section 1.3 Schedule of Activities
Monthly urine pregnancy testing is required during study intervention as well as at the end of 
study intervention.
Section 1.3 Schedule of Activities - Post-treatment Phase
Monthly urine pregnancy testing is required during study intervention as well as at the end of 
study intervention.
Section 1.3 Schedule of Activities - Long-term Follow-up Phase
Monthly urine pregnancy testing is required during study intervention as well as at the end of 
study intervention.
Section 5.2 Exclusion Criteria
Exclusion Criterion: HIV testing is required for participants.
Exclusion Criterion: hepatitis B and C testing is required for participants.
Section 10.5 Appendix 5: Contraceptive Guidance and Pregnancy Testing
Monthly urine pregnancy testing after randomization is required during study intervention as 
well as at the end of study intervention.
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10.8
Appendix 8: Eastern Cooperative Oncology Group Performance Status
Grade
Performance Status
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 
[ECOG-ACRIN Cancer Research Group 2016]
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
1L
first-line
2L
second-line
ACCP
American College of Chest Physicians
ADA
antidrug antibodies
ADL
activities of daily living  
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
antiretroviral therapy
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
AxMP
auxiliary medicinal product
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
BICR
blinded independent central review
BID
twice daily
BMI
body mass index
BP
blood pressure
CAC
Clinical Adjudication Committee
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CF
compact flash
CG
Cockcroft-Gault
CHS
cough hypersensitivity syndrome
CI
confidence interval
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CL
clearance
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSD
Cough Severity Diary
C-SSRS
Columbia-Suicide Severity Rating Scale 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CXDY
Cycle X, Day Y
DC
discontinuation
DCR
disease control rate
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Abbreviation
Expanded Term
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eDMC
External Data Monitoring Committee
EEA
European Economic Area
EGFR
epidermal growth factor receptor
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EOT
end of treatment
EU CTR
European Union Clinical Trial Regulation
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FSH
follicle-stimulating hormone 
FSR
First Site Ready
FVC
forced vital capacity
FWER
family-wise error rate
GCP
Good Clinical Practice 
G-CSF
granulocyte colony-stimulating factor
GERD
gastroesophageal reflux disease
GI
gastrointestinal
GM-CSF
granulocyte macrophage colony-stimulating factor
Gy
gray
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCG
human chorionic gonadotropin
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
imaging CRO
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG
immunoglobulin G
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Abbreviation
Expanded Term
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
IO
immuno-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
ITP
idiopathic thrombocytopenic purpura
ITT
intention-to-treat
IUD
intrauterine device
IUO
Investigational Use Only
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWRS
integrated web response system
LAM
lactational amenorrhoea method
LCQ
Leicester Cough Questionnaire
mAb
monoclonal antibody
MAD
maximum administered dose
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCS
not clinically significant
NEAB
noneosinophilic bronchitis
NK
natural killer
NKT
natural killer T
NSCLC
non–small cell lung cancer
NDA
New Drug Application 
NIMP
noninvestigational medicinal product
NOAEL
no observed adverse effect level 
NSAID
nonsteroidal anti-inflammatory drug
OR
objective response
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over-the-counter
PBPK
physiologically based pharmacokinetics
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
086RM4
088Y05


PRODUCT:  MK-7684A  
139
PROTOCOL/AMENDMENT NO.:  002-02  
MK-7684A-002-02 FINAL PROTOCOL
19-DEC-2022
Abbreviation
Expanded Term
PGIC
Patient Global Impression Change
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PopPK
population pharmacokinetics
PP
per protocol
PQC
product quality complaint
PR
partial response
PS
performance status
PT
prothrombin time
PTT
partial thromboplastin time
QXW
every X weeks
QOL
quality of life
QP2
department of quantitative pharmacology and pharmacometrics
RBC
red blood cells
RCC
refractory chronic cough
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
ROS
reactive oxygen species
RP2D
recommended Phase 2 dose
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
siDMC
Standing Internal Data Monitoring Committee
SIM
Site Imaging Manual
SJS
Stevens-Johnson Syndrome
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOC
standard of care
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine 
T4
thyroxine
Teffs
effector T-cells
TEA
treatment eligibility assessment
TEN
toxic epidermal necrolysis
TIGIT
T-cell immunoreceptor
TIL(s)
tumor-infiltrating lymphocyte(s)
TMDD
target-mediated drug disposition
TPS
tumor proportion score
TRAE(s)
treatment-related adverse event(s)
Tregs
regulatory T-cells
TSH
thyroid-stimulating hormone
UACS
upper airway cough syndrome
UCC
unexplained chronic cough
UDS
urine drug screen
Vc
volume of the central compartment
Vd
volume of distribution
VAS
Visual Analog Scale
VS
vital sign
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment
086RM4
088Y05


PRODUCT:  MK-7684A  
140
PROTOCOL/AMENDMENT NO.:  002-02  
MK-7684A-002-02 FINAL PROTOCOL
19-DEC-2022
Abbreviation
Expanded Term
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
086RM4
088Y05


PRODUCT:  MK-7684A  
141
PROTOCOL/AMENDMENT NO.:  002-02  
MK-7684A-002-02 FINAL PROTOCOL
19-DEC-2022
11
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19-DEC-2022
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[05HV55]
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19-DEC-2022
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