A Phase 3, Randomized, Double-Blind Study of MK-7684A in Combination With Etoposide and Platinum Followed by MK-7684A vs Atezolizumab in Combination With Etoposide and Platinum Followed by Atezolizumab for the First-Line Treatment of Participants With Extensive-Stage Small Cell Lung Cancer (KEYVIBE-008)
Phase: PHASE3
Conditions: Small Cell Lung Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
 A Phase 3, Randomized, Double-Blind Study of MK-7684A 
in Combination with Etoposide and Platinum Followed by 
MK-7684A vs Atezolizumab in Combination with Etoposide 
and Platinum Followed by Atezolizumab for the First-Line 
Treatment of Participants with Extensive-Stage Small Cell 
Lung Cancer (KEYVIBE-008)
NCT05224141
22-Jan-2025

PRODUCT: MK-7684A
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PROTOCOL/AMENDMENT NO.: 008-05
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-Blind Study of MK-7684A in Combination 
with Etoposide and Platinum Followed by MK-7684A vs atezolizumab in Combination with 
Etoposide and Platinum Followed by atezolizumab for the First-Line Treatment of 
Participants with Extensive-Stage Small Cell Lung Cancer (KEYVIBE-008) 
Protocol Number: 008-05
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):
NCT
Not Applicable
EU CT
2023-503517-30
EudraCT
2021-005034-42
JAPIC-CT
Not Applicable
UTN/WHO
U1111-1287-4436
IND
157492
Approval Date: 22 January 2025
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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 05
22-JAN-2025
Based on a change in strategy, text was added to 
state that participants who have access to 
approved SOC should be considered for 
discontinuation from the study.
Amendment 04
05-NOV-2024
Based on recommendations of the eDMC to 
discontinue the experimental arm (MK-7684A) 
following an interim review which showed that 
overall survival met the prespecified futility 
criteria.
Amendment 03
06-MAY-2024
To update the protocol to align with Regulation 
(EU) 536/2014.
Amendment 02
05-JUL-2022
Response to agency requests.
Amendment 01
11-JAN-2022
Clarify that dose modifications and toxicity 
management for immune-related adverse events 
pertain to both MK-7684A and atezolizumab.
Original Protocol
05-NOV-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendment:
Based on a change in strategy, text was added to state that participants who have access to 
approved SOC should be considered for discontinuation from the study.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1, 
Protocol 
Summary
Added text to state that participants who have 
access to approved SOC (eg, immunotherapy, 
chemotherapy, targeted therapy) should be 
considered for discontinuation from the study.
Based on a change in strategy, text was added 
to state that participants who have access to 
approved SOC should be considered for 
discontinuation from the study.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 1, 
Protocol 
Summary
Added a brief summary of new data from MK-
7684A studies.
To provide context for the discontinuation of the 
vibostolimab/MK-7684A clinical program.
Section 1.1, 
Synopsis
Added atezolizumab row to the study 
interventions table for all participants.
As of Amendment 04, the experimental arm 
(Arm A: MK-7684A) was discontinued and all 
ongoing participants were offered an option to 
move to the comparator arm (Arm B: 
atezolizumab monotherapy) for the remainder of 
the study.
Section 4, Study 
Design
Section 6, Study 
Intervention
Section 7, 
Discontinuation 
of Study 
Intervention and 
Participant 
Withdrawal
Section 8, Study 
Assessments and 
Procedures
Section 9, 
Statistical 
Analysis Plan
Added text to state that:

Participants with access to approved SOC 
(eg, immunotherapy, chemotherapy, 
targeted therapy) should be considered for 
discontinuation from the study. Those 
benefiting from atezolizumab, but unable 
to access it as SOC outside the study, may 
continue on study and receive treatment 
with atezolizumab until discontinuation 
criteria are met. The final required study 
visit will be the Safety Follow-up Visit.

Participants who complete study treatment 
or otherwise meet EOT criteria will be 
discontinued from the study after the EOT 
visit and any required safety follow-up 
visit.
Refer to rationale for Section 1 (change in 
strategy).
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Section Number 
and Name
Description of Change
Brief Rationale

There will be no follow up for survival 
status. Participants currently in imaging 
follow-up or survival follow-up are 
considered to have completed the study 
and therefore should obtain imaging and 
further oncological care as per local SOC. 
Standard safety reporting should, however,
continue, as applicable.

Participants remaining on study at the time 
of Amendment 05 should continue to be 
monitored in the study through the AE 
reporting period (Section 8.4).
Section 6.1, 
Study 
Intervention(s) 
Administered
Table 4: Added atezolizumab row to the study 
interventions table for all participants.
Refer to rationale for Section 1.1 
(discontinuation of the experimental arm).
Throughout
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................23
1.3
Schedule of Activities...........................................................................................24
2
INTRODUCTION..........................................................................................................39
2.1
Study Rationale....................................................................................................39
2.2
Background ..........................................................................................................39
2.2.1
SCLC Epidemiology and Current Therapeutic Options..............................39
2.2.1.1
Approved Immunotherapy in ES-SCLC............................................40
2.2.1.2
Pembrolizumab ..................................................................................41
2.2.1.3
MK-7684A.........................................................................................42
2.2.2
Pharmaceutical and Therapeutic Background .............................................42
2.2.2.1
MK-7684A.........................................................................................42
2.2.2.1.1
Pembrolizumab ........................................................................42
2.2.2.1.2
MK-7684..................................................................................43
2.2.2.2
Atezolizumab .....................................................................................44
2.2.3
Information on Other Study-related Therapy ..............................................44
2.3
Benefit/Risk Assessment......................................................................................44
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................46
4
STUDY DESIGN............................................................................................................51
4.1
Overall Design......................................................................................................51
4.2
Scientific Rationale for Study Design.................................................................52
4.2.1
Rationale for Stratification Factors..............................................................52
4.2.2
Rationale for Endpoints ...............................................................................53
4.2.2.1
Efficacy Endpoints.............................................................................53
4.2.2.1.1
RECIST 1.1:.............................................................................53
4.2.2.2
Safety Endpoints................................................................................53
4.2.2.3
Patient-reported Outcomes.................................................................54
4.2.2.3.1
EORTC QLQ-C30 ...................................................................54
4.2.2.3.2
EORTC QLQ-LC13.................................................................54
4.2.2.3.3
EQ-5D-5L ................................................................................54
4.2.2.4
Planned Exploratory Biomarker Research.........................................55
4.2.2.5
Future Biomedical Research..............................................................56
4.2.3
Rationale for the Use of Comparator...........................................................57
4.2.3.1
Justification for Dose.........................................................................57
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4.2.4
Starting Dose for This Study........................................................................57
4.2.4.1
Rationale for MK-7684A Dosing ......................................................57
4.2.4.2
Rationale for Atezolizumab Dosing...................................................58
4.2.4.3
Rationale for Etoposide/Platinum Chemotherapy Dosing.................58
4.3
Beginning and End-of-Study Definition ............................................................59
4.3.1
Clinical Criteria for Early Study Termination .............................................59
5
STUDY POPULATION ................................................................................................60
5.1
Inclusion Criteria.................................................................................................60
5.2
Exclusion Criteria................................................................................................63
5.3
Lifestyle Considerations......................................................................................66
5.3.1
Meals and Dietary Restrictions....................................................................66
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................66
5.3.3
Activity Restrictions ....................................................................................66
5.4
Screen Failures.....................................................................................................66
5.5
Participant Replacement Strategy......................................................................66
6
STUDY INTERVENTION............................................................................................67
6.1
Study Intervention(s) Administered...................................................................67
6.2
Preparation/Handling/Storage/Accountability .................................................70
6.2.1
Dose Preparation..........................................................................................70
6.2.2
Handling, Storage, and Accountability........................................................70
6.3
Measures to Minimize Bias: Randomization and Blinding..............................71
6.3.1
Intervention Assignment..............................................................................71
6.3.2
Stratification.................................................................................................71
6.3.3
Blinding........................................................................................................71
6.4
Study Intervention Compliance..........................................................................72
6.5
Concomitant Therapy..........................................................................................72
6.5.1
Rescue Medications and Supportive Care ...................................................74
6.5.1.1
Blinded Study Intervention (MK-7684A and Atezolizumab) ...........74
6.5.1.2
Etoposide/Platinum Chemotherapeutic Agents .................................74
6.6
Dose Modification ................................................................................................74
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................75
6.6.2
Management of Adverse Events and Dose Modifications for 
Etoposide/Platinum Chemotherapeutic Agents ...........................................82
6.6.2.1
Dose Modifications for Overlapping Toxicities ................................85
6.6.2.2
Other Allowed Dose Interruptions With Chemotherapeutic 
Agents ................................................................................................86
6.7
Intervention After the End of the Study............................................................86
6.8
Clinical Supplies Disclosure................................................................................86
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6.9
Standard Policies..................................................................................................87
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................88
7.1
Discontinuation of Study Intervention...............................................................88
7.2
Participant Withdrawal From the Study...........................................................90
7.3
Lost to Follow-up .................................................................................................90
8
STUDY ASSESSMENTS AND PROCEDURES........................................................91
8.1
Administrative and General Procedures ...........................................................92
8.1.1
Informed Consent.........................................................................................92
8.1.2
General Informed Consent...........................................................................92
8.1.2.1
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................93
8.1.3
Inclusion/Exclusion Criteria ........................................................................93
8.1.4
Participant Identification Card.....................................................................93
8.1.5
Medical History ...........................................................................................93
8.1.5.1
Tobacco Use Assessment...................................................................94
8.1.6
Prior and Concomitant Medications Review...............................................94
8.1.6.1
Prior Medications...............................................................................94
8.1.6.2
Concomitant Medications..................................................................94
8.1.7
Assignment of Screening Number...............................................................94
8.1.8
Assignment of Treatment/Randomization Number.....................................94
8.1.9
Study Intervention Administration ..............................................................95
8.1.9.1
Timing of Dose Administration.........................................................95
8.1.9.1.1
MK-7684A Administration......................................................95
8.1.9.1.2
Platinum/Etoposide Chemotherapy Administration ................96
8.1.10
Discontinuation and Withdrawal .................................................................97
8.1.10.1
Withdrawal From Future Biomedical Research ................................98
8.1.11
Participant Blinding/Unblinding..................................................................98
8.1.12
Calibration of Equipment.............................................................................99
8.1.13
Tumor Tissue for Biomarker Status.............................................................99
8.2
Efficacy/Immunogenicity Assessments ............................................................100
8.2.1
Tumor Imaging and Assessment of Disease..............................................100
8.2.1.1
Initial Tumor Scans..........................................................................101
8.2.1.2
Tumor Scans During the Study........................................................101
8.2.1.3
End-of-treatment and Follow-up Tumor Scans ...............................102
8.2.1.4
RECIST 1.1 Assessment of Disease................................................103
8.2.2
Patient-reported Outcomes.........................................................................104
8.3
Safety Assessments.............................................................................................105
8.3.1
Physical Examinations...............................................................................105
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8.3.1.1
Full Physical Examination...............................................................105
8.3.1.2
Directed Physical Examination........................................................105
8.3.2
Vital Signs..................................................................................................105
8.3.3
Audiometry ................................................................................................106
8.3.4
Electrocardiograms ....................................................................................106
8.3.5
Clinical Safety Laboratory Assessments ...................................................106
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)........................................................................................107
8.3.6
Pregnancy Testing......................................................................................107
8.3.7
Performance Assessments..........................................................................107
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................107
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................108
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....110
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.110
8.4.4
Regulatory Reporting Requirements for SAE ...........................................111
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................111
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................111
8.4.7
Events of Clinical Interest..........................................................................112
8.5
Treatment of Overdose......................................................................................112
8.6
Pharmacokinetics...............................................................................................112
8.6.1
Blood Collection for PK ............................................................................113
8.6.2
Blood Collection for Anti-drug Antibodies...............................................113
8.7
Pharmacodynamics............................................................................................113
8.8
Biomarkers .........................................................................................................113
8.8.1
Planned Genetic Analysis Sample Collection............................................113
8.9
Future Biomedical Research Sample Collection.............................................114
8.10
Medical Resource Utilization and Health Economics.....................................114
8.11
Visit Requirements.............................................................................................114
8.11.1
Screening....................................................................................................114
8.11.2
Treatment Period/Vaccination Visit ..........................................................115
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................115
8.11.4
Posttreatment Visit.....................................................................................115
8.11.4.1
Safety Follow-up Visit.....................................................................115
8.11.4.2
Efficacy Follow-up Visits................................................................115
8.11.4.3
Survival Follow-up Contacts ...........................................................116
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8.11.5
Vital Status.................................................................................................116
9
STATISTICAL ANALYSIS PLAN ...........................................................................117
9.1
Statistical Analysis Plan Summary...................................................................117
9.2
Responsibility for Analyses/In-house Blinding ...............................................120
9.3
Hypotheses/Estimation ......................................................................................120
9.4
Analysis Endpoints.............................................................................................120
9.4.1
Efficacy Endpoints.....................................................................................120
9.4.2
Safety Endpoints........................................................................................121
9.4.3
Patient-reported Outcome Endpoints.........................................................121
9.5
Analysis Populations..........................................................................................122
9.5.1
Efficacy Analysis Populations...................................................................122
9.5.2
Safety Analysis Populations ......................................................................122
9.5.3
PRO Analysis Populations.........................................................................122
9.6
Statistical Methods.............................................................................................122
9.6.1
Statistical Methods for Efficacy Analyses.................................................122
9.6.1.1
Overall Survival...............................................................................123
9.6.1.2
Progression-Free Survival (PFS) .....................................................123
9.6.1.3
Objective Response Rate (ORR) .....................................................124
9.6.1.4
Duration of Response (DOR)...........................................................124
9.6.1.5
Analysis Strategy for Efficacy Variables.........................................125
9.6.2
Statistical Methods for Safety Analyses ....................................................126
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses....................128
9.6.4
Summaries of Baseline Characteristics and Demographics.......................129
9.7
Interim Analyses ................................................................................................129
9.7.1
Efficacy Interim Analyses..........................................................................130
9.7.2
Safety Interim Analyses.............................................................................130
9.8
Multiplicity .........................................................................................................131
9.8.1
Overall Survival.........................................................................................131
9.8.2
Progression-free Survival...........................................................................133
9.8.3
Safety Analyses..........................................................................................133
9.9
Sample Size and Power Calculations ...............................................................134
9.10
Subgroup Analyses.............................................................................................135
9.11
Compliance (Medication Adherence)...............................................................135
9.12
Extent of Exposure.............................................................................................135
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................136
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......136
10.1.1
Code of Conduct for Interventional Clinical Trials ...................................136
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10.1.2
Financial Disclosure...................................................................................139
10.1.3
Data Protection...........................................................................................140
10.1.3.1
Confidentiality of Data ....................................................................140
10.1.3.2
Confidentiality of Participant Records.............................................140
10.1.3.3
Confidentiality of IRB/IEC Information..........................................141
10.1.4
Committees Structure.................................................................................141
10.1.4.1
Executive Oversight Committee......................................................141
10.1.4.2
External Data Monitoring Committee .............................................141
10.1.5
Publication Policy......................................................................................141
10.1.6
Compliance with Study Registration and Results Posting Requirements .142
10.1.7
Compliance with Law, Audit, and Debarment ..........................................142
10.1.8
Data Quality Assurance .............................................................................143
10.1.9
Source Documents .....................................................................................144
10.1.10
Study and Site Closure...............................................................................144
10.2
Appendix 2: Clinical Laboratory Tests............................................................145
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................147
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................147
10.3.2
Definition of AE ........................................................................................147
10.3.3
Definition of SAE ......................................................................................148
10.3.4
Additional Events Reported in the Same Manner as SAE.........................149
10.3.5
Recording AE and SAE .............................................................................150
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................153
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................155
10.5
Appendix 5: Contraceptive Guidance..............................................................156
10.5.1
Definitions..................................................................................................156
10.5.2
Contraceptive Requirements......................................................................157
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................158
10.7
Appendix 7: Country-specific Requirements..................................................163
10.7.1
Argentina....................................................................................................163
10.7.2
China..........................................................................................................163
10.7.3
France.........................................................................................................164
10.7.4
Germany.....................................................................................................164
10.7.5
Ireland ........................................................................................................164
10.7.6
Italy ............................................................................................................164
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10.7.7
Japan ..........................................................................................................165
10.7.8
Portugal......................................................................................................165
10.7.9
Romania.....................................................................................................165
10.7.10
United Kingdom.........................................................................................166
10.8
Appendix 8: Abbreviations ...............................................................................167
11
REFERENCES.............................................................................................................174
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LIST OF TABLES
Table 1
Schedule of Assessments (Intervention Period) ..............................................24
Table 2
Schedule of Assessments (Posttreatment Follow-up)......................................37
Table 3
Adequate Organ Function Laboratory Values .................................................63
Table 4
Study Interventions..........................................................................................68
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with MK-7684A or Atezolizumab ..........76
Table 6
MK-7684A or Atezolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines.......................................................................................80
Table 7
Dose Modifications for Chemotherapeutic Agents..........................................83
Table 8
Recommended Chemotherapy Dose Modifications for Hematologic 
Toxicity............................................................................................................83
Table 9
Recommended Chemotherapy Dose Modifications for Nonhematologic 
Toxicity............................................................................................................84
Table 10
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................109
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS.....................124
Table 12
Censoring Rules for DOR..............................................................................125
Table 13
Analysis Strategy for Key Efficacy Endpoints..............................................126
Table 14
Analysis Strategy for Safety Parameters........................................................128
Table 15
Censoring Rules for Time-to-True Deterioration ..........................................129
Table 16
Summary of Interim and Final Analyses Strategy.........................................130
Table 17
Efficacy Boundaries and Properties for OS Analyses ...................................132
Table 18
Efficacy Boundaries and Properties for PFS Analysis ..................................133
Table 19
Protocol-required Clinical Laboratory Assessments .....................................145
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LIST OF FIGURES
Figure 1
MK-7684A-008 Study Schema........................................................................23
Figure 2
Intervention Blinding Schema for Initial Infusion...........................................96
Figure 3
Study Intervention Decision-Making Process ...............................................104
Figure 4
Multiplicity Diagram for Type I Error Control..............................................131
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1
PROTOCOL SUMMARY
Four Phase 3 studies met prespecified futility criteria for OS or RFS: MK-7684A-003 in 
metastatic NSCLC with PD-L1 TPS ≥50% 
 
MK-7684A-007 in metastatic NSCLC with PD-L1 TPS ≥1% 
 MK-7684A-008 in ES-SCLC (OS HR, 1.26; 95% CI, 1.00-1.59; presented at Society 
for Immunotherapy of Cancer 2024), and MK-7684A-010 in adjuvant melanoma (RFS HR, 
1.25; 95% CI, 0.87-1.80; presented at Society for Melanoma Research 2024) (data on file). 
Overall, the lack of efficacy observed with MK-7684A rendered the risk-benefit balance 
unfavorable, so treatment with this investigational therapy was stopped in all studies.
At implementation of Amendment 05, the below changes apply. The changes listed below 
supersede any protocol content/instructions from previous amendments.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy) should be considered for discontinuation from the study. Those benefiting from 
atezolizumab, but unable to access it as SOC outside the study, may continue on study 
and receive treatment with atezolizumab until discontinuation criteria are met. The final 
required study visit will be the Safety Follow-up Visit.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow up for survival status. Participants currently in imaging follow-up 
or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. Standard safety reporting 
should, however, continue, as applicable.
•
Participants remaining on study at the time of Amendment 05 should continue to be 
monitored in the study through the AE reporting period (Section 8.4).
Existing protocol content is retained for historical reference.
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-Blind Study of MK-7684A in Combination 
with Etoposide and Platinum Followed by MK-7684A vs atezolizumab in Combination with 
Etoposide and Platinum Followed by atezolizumab for the First-Line Treatment of 
Participants with Extensive-Stage Small Cell Lung Cancer (KEYVIBE-008) 
Short Title: Phase 3 Study of Chemotherapy with MK-7684A or atezolizumab in First-Line 
ES-SCLC 
Acronym: MK-7684A-008/KEYVIBE-008 
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
CCI
CCI
CCI
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In participants with extensive-stage small cell lung cancer who are in need of first-line 
treatment:
Primary Objective
Primary Endpoint
•
To compare overall survival for 
MK-7684A in combination with the 
background therapy of 
etoposide/platinum followed by 
MK-7684A to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab.
•
Hypothesis (H1): MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A is superior 
to atezolizumab in combination 
with the background therapy of 
etoposide/platinum followed by 
atezolizumab with respect to 
overall survival.
•
Overall survival: the time from 
randomization to death due to any cause
Secondary Objectives
Secondary Endpoints
•
To compare progression-free 
survival per RECIST 1.1 as 
assessed by blinded independent 
central review for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A to 
atezolizumab in combination with 
the background therapy of 
etoposide/platinum followed by 
atezolizumab.
•
Progression-free survival: the time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
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•
Hypothesis (H2): MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A is superior 
to atezolizumab in combination 
with the background therapy of 
etoposide/platinum followed by 
atezolizumab with respect to 
progression-free survival per 
RECIST 1.1 by blinded 
independent central review.
•
To evaluate the objective response 
rate per RECIST 1.1 as assessed by 
blinded independent central review 
for MK-7684A in combination with 
the background therapy of 
etoposide/platinum followed by 
MK-7684A compared to 
atezolizumab in combination with 
the background therapy of 
etoposide/platinum followed by 
atezolizumab.
•
Objective response: complete response or 
partial response
•
To evaluate duration of response 
per RECIST 1.1 as assessed by 
blinded independent central review 
for MK-7684A in combination with 
the background therapy of 
etoposide/platinum followed by 
MK-7684A compared to 
atezolizumab in combination with 
the background therapy of 
etoposide/platinum followed by 
atezolizumab.
•
Duration of response: for participants with 
confirmed complete response or partial 
response, duration of response is defined as 
time from first documented evidence of 
complete response or partial response until 
disease progression or death due to any 
cause, whichever occurs first
•
To evaluate the safety and 
tolerability of the investigational 
treatment combination based on 
proportion of adverse events.
•
Adverse events
•
Study intervention discontinuations due to 
adverse events
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•
To evaluate the mean change from 
baseline in global health 
status/quality of life, physical 
functioning, dyspnea, cough, and 
chest pain for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A compared 
to atezolizumab in combination 
with the background therapy of 
etoposide/platinum followed by 
atezolizumab.
•
Change from baseline in the following 
patient-reported outcomes scales/items:
-
Global health status/quality of life score 
(EORTC QLQ-C30 items 29 and 30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Dyspnea score (EORTC QLQ-C30 
item 8)
-
Cough (EORTC QLQ-LC13 item 31)
-
Chest pain (EORTC QLQ-LC13 item 40)
•
To evaluate the time-to-true 
deterioration in global health 
status/quality of life, physical 
functioning, dyspnea, cough, and 
chest pain for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A compared 
to atezolizumab in combination 
with the background therapy of 
etoposide/platinum followed by 
atezolizumab.
•
Time-to-true deterioration: defined as the 
time from baseline to the first onset of a 
≥10-point deterioration from baseline with 
confirmation by the subsequent visit of a 
≥10-point deterioration from baseline in the 
following scales/items:
-
Global health status/quality of life score 
(EORTC QLQ-C30 items 29 and 30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Dyspnea score (EORTC QLQ-C30 
item 8)
-
Cough (EORTC QLQ-LC13 item 31)
-
Chest pain (EORTC QLQ-LC13 item 40)
Overall Design:
Protocol Amendment 04 implementation: Based on recommendations of the eDMC 
following an interim efficacy and safety analysis showed that the primary endpoint of OS
met the prespecified futility criteria, the study was unblinded, and the experimental arm (Arm 
A: MK-7684A) was discontinued. All ongoing participants on MK-7684A treatment were
offered the option to move to the comparator arm (Arm B: atezolizumab monotherapy) for 
the remainder of the study. All participants still receiving study treatment will be informed of 
the analysis. The study will remain open for ongoing participantsto have continued access to 
atezolizumab if they qualify per protocol. The final analysis will be removed and there will 
be no further analyses for efficacy and ePRO endpoints. Participants currently in efficacy
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follow-up or in survival follow-up are considered to have completed the study and therefore 
should obtain imaging and further oncological care as per local standard of care. Participants
currently on study treatment will have tumor imaging assessed locally based on the site’s 
standard of care imaging schedule. Scans will not be submitted to the iCRO, and VOP 
request and central review of imaging will no longer be applicable. PK sampling, anti-drug 
antibody sampling, and blood for ctDNA analysis will no longer be collected on any 
participants. PROs will no longer be collected on any participants. Participants on study 
treatment will need to have safety follow-up after treatment is discontinued (participants will 
no longer be treated under the study). This safety follow-up will be considered their last visit.
Collection of AE and lab parameters for participants remaining in study will continue per 
SOA. These changes were communicated through the investigator letter dated 08-AUG-2024 
and Protocol Clarification Letter dated 13-AUG-2024.
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Small cell lung cancer
Population
Participants with extensive-stage small cell 
lung cancer
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Investigator
Participants or Subjects
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.
Number of Participants:
Approximately 450 participants will be randomized.
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Intervention Groups and Duration:
Protocol Amendment 04 implementation: All active participants in the experimental arm 
(Arm A: MK-7684A) stopped ongoing treatment with MK-7684A and were offered the 
option to move to the comparator arm (Arm B: atezolizumab monotherapy) for the remainder 
of the study.
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
A
(Protocol 
Amendment 
04: Arm A 
discontinued) MK-7684A
MK-7684 
200 mg + 
pembrolizumab 
200 mg/20 mL 
vial
200 MG/
200 MG
IV Infusion
Q3W (Day 1 of 
each cycle) until 
discontinuation 
criteria are met
Test 
Product
A
(Protocol 
Amendment 
04: Arm A 
discontinued) Saline placebo
Not applicable
Not applicable
IV Infusion
At Cycle 1 (and 
Q3W as needed 
beyond Cycle 1)
Placebo
A
Etoposide
100 mg (may 
vary according 
to supplier/ 
country)
100 mg/m2
IV Infusion
Q3W (Days 1, 2, 3 
of each cycle for up 
to 4 cycles)
Background 
Treatment
A
Cisplatin
50 mg (may 
vary according 
to supplier/ 
country)
75 mg/m2
IV Infusion
Q3W (Day 1 of 
each cycle for up to 
4 cycles)
Background 
Treatment
A
Carboplatin
600 mg (may 
vary according 
to supplier/ 
country)
AUC 
5 mg/mL/min
IV Infusion
Q3W (Day 1 of 
each cycle for up to 
4 cycles)
Background 
Treatment
B
Atezolizumab
1200 mg
1200 mg
IV Infusion
Q3W (Day 1 of 
each cycle) until 
discontinuation 
criteria are met
Comparator
B
Saline placebo
Not applicable
Not applicable
IV Infusion
At Cycle 1 (and 
Q3W as needed 
beyond Cycle 1)
Placebo
B
Etoposide
100 mg (may 
vary according 
to supplier/ 
country)
100 mg/m2
IV Infusion
Q3W (Days 1, 2, 3 
of each cycle for up 
to 4 cycles)
Background 
Treatment
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Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
B
Cisplatin
50 mg (may 
vary according 
to supplier/ 
country)
75 mg/m2
IV Infusion
Q3W (Day 1 of 
each cycle for up to 
4 cycles)
Background 
Treatment
B
Carboplatin
600 mg (may 
vary according 
to supplier/ 
country)
AUC 
5 mg/mL/min
IV Infusion
Q3W (Day 1 of 
each cycle for up to 
4 cycles)
Background 
Treatment
All 
participants
Atezolizumab
1200 mg
1200 mg
IV Infusion
Q3W (Day 1 of 
each cycle) until 
discontinuation 
criteria are met
Comparator
MK-7684A is a coformulation of vibostolimab (MK-7684) and pembrolizumab.
Other current or former name(s) or alias(es) for study intervention(s) are as follows:
atezolizumab (TECENTRIQ®); MK-7684A is a coformulation of MK-7684 (vibostolimab) 
and pembrolizumab (MK-3475, KEYTRUDA®).
Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
from the time that the participant provides 
documented informed consent through the 
final protocol-specified contact.
After a screening phase of 28 days, each 
participant will be assigned to receive study 
intervention until one of the conditions for 
discontinuation of study intervention is met.
After the end of treatment, each participant 
will be followed for the occurrence of 
adverse events and spontaneously reported 
pregnancy.
Participants who discontinue for reasons 
other than radiographic disease progression 
will have posttreatment follow-up imaging 
for disease status until any of the conditions 
for discontinuation of imaging are met.
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All participants will be followed for overall 
survival until death, withdrawal of consent, 
or the end of the study.
Protocol Amendment 04 implementation: 
There will be no collection of efficacy data
including tumor scans, vital status, and 
post-treatment anticancer therapy status.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1. Protocol Amendment 04 implementation: Following eDMC interim review of the data, the 
experimental arm (Arm A: MK-7684A) was discontinued and all ongoing participants were offered an option to move to the 
comparator arm (Arm B: atezolizumab monotherapy) for the remainder of the study.
Figure 1
MK-7684A-008 Study Schema
ECOG=Eastern Cooperative Oncology Group; ES-SCLC=extensive-stage small cell lung cancer; LDH=lactate dehydrogenase; PS=performance status; Q3W=every 3 weeks; 
ULN=upper limit of normal
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1.3
Schedule of Activities
Table 1
Schedule of Assessments (Intervention Period)
Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Administrative 
Procedures
Informed Consent
X
Documented informed consent 
must be obtained before any 
protocol-specific procedures.
If the investigator plans to treat 
beyond disease progression, 
additional consent is required.
Informed Consent 
for Future 
Biomedical 
Research
X
This is optional for the 
participant. Participants can still 
participate in the study if they 
decline to provide documented 
informed consent for FBR.
Inclusion/Exclusion 
Criteria
X
Verification documented by the 
investigator.
Participant 
Identification Card
X
X
Add the randomization number at 
the time of randomization.
Demographics and 
Medical History
X
SCLC History
X
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
Study intervention should begin 
within 3 days of randomization.
Posttreatment 
Anticancer Therapy 
Status
X
As of Amendment 04, 
posttreatment anticancer therapy 
status will no longer be collected 
for any participants.
Study Intervention 
Administration  
(atezolizumab)
X
X
X
X
X
Atezolizumab will be 
administered Q3W until any of 
the reasons for intervention 
discontinuation are met.
Cisplatin or 
Carboplatin 
Administration
X
X
X
X
Cisplatin or carboplatin will be 
administered Q3W starting with 
C1D1, for a maximum of 4 
cycles. Administration will occur 
after completion of the blinded 
study intervention infusions. 
Dose should be recalculated if 
there is a ≥10% weight change.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Etoposide 
Administration
X
X
X
X
X
X
X
X
Etoposide will be administered 
Q3W on Days 1, 2, and 3 for a 
maximum of 4 cycles. Days 1, 2, 
and 3 must be consecutive days 
without interruption. 
Administration on D1 will occur 
after completion of platinum 
infusion. Dose should be 
recalculated if there is a 
≥10% weight change.
Vital Status
After verified disease progression 
or start of new anticancer 
treatment. In addition, upon 
Sponsor request, participants 
may be contacted for vital status 
at any time during the course of 
the study.
As of Amendment 04, vital status 
will no longer be collected for 
any participants.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Tumor Scans
Scans should follow calendar 
days from randomization and 
should not be adjusted for dose 
delays or cycle starts. 
Unscheduled scans can be 
performed as clinically indicated. 
See Section 8.2 for full details. 
As of Amendment 04, 
participants currently on study 
treatment will have tumor 
imaging assessed locally based 
on site’s standard of care imaging 
schedule. VOP request and 
central review of imaging are no 
longer applicable.
CT/MRI of chest, 
abdomen, and pelvis
X
X
X
Use the same imaging modality 
for all evaluations. Perform at 
6 weeks (42 days ±7 days from 
randomization). Repeat Q6W 
(42 days ±7 days) for the first 
48 weeks and Q9W (63 days 
±7 days) thereafter. EOT scan is 
not needed if tumor scans were 
obtained within the last 4 weeks.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Bone Scan
X
X
All participants are required to 
have bone scans (bone or PET 
scans) to assess for bone lesions 
during Screening. On-study bone 
scans should be acquired as 
clinically indicated or to confirm 
a CR when bone metastases were 
present at Screening. EOT scan is
not needed if tumor scans were 
obtained within the last 4 weeks.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Brain Scan
X
X
X
All participants are required to 
have brain scans during 
Screening. For participants 
without brain metastases at 
Screening, on-study brain scans 
are required Q12W (84 days 
±7 days) through Week 48 and 
then Q24W (168 days ±7 days) 
through Week 96 or more often 
as clinically indicated. For 
participants with brain metastases 
present at Screening, on-study 
brain scans are to be acquired at 
all scheduled post-baseline 
imaging timepoints, or more 
often as clinically indicated, and 
to confirm a CR. EOT scan is not 
needed if tumor scans were 
obtained within the last 4 weeks.
Safety Procedures
Full Physical 
Examination
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
If ≥10% change in body weight 
occurs, weight-based therapy 
should be readjusted.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DBP, SBP, heart rate, RR, 
temperature, pulse oximetry
12-lead ECG
X
Additional ECG may be 
performed as clinically indicated.
Audiometry
X
To be performed if this is the 
local standard of care only when 
cisplatin is chosen as the 
platinum agent. May be 
performed more often as 
clinically indicated.
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
At Screening, perform ≤7 days 
before randomization. Should be 
completed prior to dose 
administration.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Pregnancy Test –
Urine or Serum 
hCG (WOCBP only; 
per local SOP)
Please refer to 
Appendix 7 for 
country-specific 
requirements.
X
X
X
X
X
X
X
Serum test is only required if 
urine test is positive or not 
evaluable.
WOCBP require negative test 
before randomization. If more 
than 24 hours have elapsed 
before first dose of study 
intervention, another pregnancy 
test is required before starting 
study intervention.
A negative pregnancy test is 
required before study 
intervention on Day 1 of each 
cycle of study intervention.
Pregnancy testing should also be 
conducted as outlined in 
Section 8.3.6.
FSH (as needed in 
WONCBP only)
X
Refer to Appendix 5 for 
additional information.
HBV, HCV, and 
HIV testing
X
Only perform if required by local 
health authority. Please refer to 
Appendix 7 for country-specific 
requirements.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Thyroid Function 
Tests (TSH, T3, free 
T4)
X
X
X
X
X
Screening samples must be 
collected ≤7 days before start of 
study intervention. 
Thyroid function tests will be 
performed at Screening and 
every other cycle thereafter 
(ie, C2D1, C4D1, C6D1, etc).
Coagulation Tests 
(PT/INR and aPTT 
or PTT
X
Screening samples must be 
collected ≤7 days before start of 
study intervention.
Hematology and chemistry tests 
performed at Screening must be 
repeated if more than 72 hours 
has elapsed before first dose of 
study intervention.
Hematology
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Screening samples must be 
collected ≤7 days before start of 
study intervention. To be 
repeated every 6 cycles 
beginning at Cycle 6.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record all AEs occurring within 
30 days after last dose of study 
intervention. Record all SAEs 
occurring up to 90 days after last 
dose of study intervention or 
30 days after last dose of study 
intervention if the participant 
initiates new anticancer therapy, 
whichever comes first. Any 
treatment-related SAEs must be 
reported regardless of time they 
occur.
PK/PD/Biomarkers
As of Amendment 04, PK 
sampling, antidrug antibody 
sampling, and blood for ctDNA 
analysis will no longer be 
collected for any participants.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
PK Sampling
X
X
X
X
X
Predose PK samples should be 
drawn within 24 hours before the 
start of infusion of study 
intervention at C1D1, C2D1, 
C4D1, and C8D1 and every 
4 cycles thereafter.
Postdose PK samples will be 
drawn within 10 minutes after 
end of infusion of blinded study 
intervention at C1D1 and C8D1. 
Samples will also be drawn at 
EOT.
Anti-drug Antibody 
Sampling
X
X
X
X
X
Predose anti-drug antibody 
samples should be drawn within 
24 hours before start of infusion 
at C1D1, C2D1, C4D1, and 
C8D1 and every 4 cycles 
thereafter. Samples will also be 
drawn at EOT.
Archival or Newly 
Obtained Tissue 
Collection
X
A pretreatment tumor sample 
must be submitted before or 
within 4 weeks after 
randomization, if such sample 
exists (see inclusion criteria 
[Section 5.1]) for additional 
detail.
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
Blood for Genetic 
Analysis
X
Collect predose from randomized 
participants only. 
See Section 8.8.1.
Blood for ctDNA 
Analysis
X
X
X
X
X
Collect predose on C1D1, C2D1, 
C3D1, and then predose on D1 of 
every 2 cycles until C17D1, 
followed by predose on D1 of 
every 3 cycles thereafter and at 
EOT.
Patient-Reported 
Outcomes
As of Amendment 04, PROs will 
no longer be collected for any 
participants.
EORTC QLQ-C30
X
X
X
X
X
X
Completed on Day 1 of every 
cycle for Cycles 1-9 while the 
participant is receiving study 
intervention, then every other 
cycle up to Cycle 17, and then 
every 4 cycles onwards until 
EOT. 
EORTC QLQ-LC13
X
X
X
X
X
X
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Study Period:
Screen-
ing
Treatment (3-Week Cycles)
End-of-
Treatment
Notes
Treatment Cycle:
1
2
3
4
5+
Discon
Protocol Amendment 04 
implementation: Participants who 
continue atezolizumab under the 
study, safety assessments and 
safety related data collection 
including safety follow-up and 
laboratory assessments, should 
continue as per current protocol.
Day (in Cycle)
1
2&3
8
1
2&3
8
1
2&3
8
1
2&3
8
1
EOT
(±3 days)
Scheduling 
Window (Days)
-28 to -1
±1
±3
±1
±3
±1
±3
±1
±3
EQ-5D-5L
X
X
X
X
X
X
PROs will also be obtained at the 
EOT Visit. If EOT Visit occurs 
30 days from the last dose of 
study intervention, at the time of 
the mandatory Safety Follow-up 
Visit, ePROs do not need to be 
repeated.
ePROs should be administered in 
the following order: EORTC 
QLQ-C30, EORTC QLQ-LC13 
and EQ-5D-5L.
AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; CR=complete response; CT=computed tomography; D=day; DBP=diastolic blood pressure; 
discon=discontinuation; ECG=electrocardiogram; EORTC=European Organization for the Research and Treatment of Cancer; EOT=end-of-treatment; FBR=future biomedical 
research; FSH=follicle-stimulating hormone; HBV=hepatitis B virus; hCG=human chorionic hormone; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
ICF=informed consent form; MRI=magnetic resonance imaging; PD=pharmacodynamic(s); PET=positron emission tomography; PK=pharmacokinetic(s); PRO=patient-reported 
outcome; PT=prothrombin time; PTT=partial thromboplastin time; Q3W=every 3 weeks; Q6W=every 6 weeks; Q9W=every 9 weeks; QLQ=quality of life questionnaire; 
RR=respiratory rate; SAE=serious adverse event; SBP=systolic blood pressure; SCLC=small cell lung cancer; SOP=standard operating procedure; TSH=thyroid-stimulating 
hormone; WOBCP=woman/women of childbearing potential.
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Table 2
Schedule of Assessments (Posttreatment Follow-up) 
Protocol Amendment 04 implementation: Efficacy Follow-up and Survival Follow-up are no longer applicable. All participants on 
efficacy follow-up or survival follow-up are considered to have completed all study activities. Safety Follow-up will be the last visit 
for participants currently on treatment.
Study Period:
Posttreatment Follow-up
Notes
Treatment Cycle:
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Day (in Cycle)
30 days from last 
dose (+7 days)
Per imaging 
schedule
Every 12 weeks 
(±7 days)
Administrative Procedures
Prior/Concomitant Medication 
Review
X
Posttreatment Anticancer 
Therapy Status
X
X
X
Vital Status
X
After verified disease progression or start of new anticancer 
treatment. In addition, upon Sponsor request, participants 
may be contacted for vital status at any time during the course 
of the study.
Tumor Scan
Scans should follow calendar days from randomization and 
should not be adjusted for dose delays or cycle starts. 
Unscheduled scans can be performed as clinically indicated. 
Scans must be submitted and reviewed by BICR. 
See Section 8.2 for full details. 
CT/MRI of chest, abdomen, 
and pelvis
X
Use the same imaging modality for all evaluations. 
Bone Scan
X
On-study bone scans should be acquired as clinically 
indicated or to confirm a CR when bone metastases were 
present at Screening.
Brain Scan
X
For participants without brain metastases at Screening, on-
study brain scans are required at Q12W (84 days ±7 days)
through Week 48 and then Q24W (168 days ±7 days) through 
Week 96 or more often as clinically indicated. For 
participants with brain metastases present at Screening, 
on-study brain scans are to be acquired at all scheduled 
post-baseline imaging timepoints, or more often as clinically 
indicated, and to confirm a CR.
Safety Procedures
Directed Physical Examination
X
Vital Signs
X
DBP, SBP, heart rate, RR, temperature, pulse oximetry
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Study Period:
Posttreatment Follow-up
Notes
Treatment Cycle:
Safety Follow-up
Efficacy Follow-up
Survival Follow-up
Day (in Cycle)
30 days from last 
dose (+7 days)
Per imaging 
schedule
Every 12 weeks 
(±7 days)
Audiometry
X
To be performed if this is the local standard of care only 
when cisplatin is chosen as the platinum agent. May be 
performed more often as clinically indicated.
ECOG Performance Status
X
Thyroid Function Tests 
(TSH, T3, free T4)
X
Hematology
X
Chemistry
X
AE/SAE review
X
Record all AEs occurring within 30 days after last dose of 
study intervention. Record all SAEs occurring up to 90 days 
after last dose of study intervention or 30 days after last dose 
of study intervention if the participant initiates new 
anticancer therapy, whichever comes first. Any 
treatment-related SAEs must be reported regardless of time 
they occur.
Patient-Reported Outcomes
As of Amendment 04, PROs will no longer be collected on 
any participants.
EORTC QLQ-C30
X
EORTC QLQ-LC13
X
EQ-5D-5L
X
AE=adverse event; BICR=blinded independent central review; CR=complete response; CT=computed tomography; DBP=diastolic blood pressure; ECOG=Eastern Cooperative 
Oncology Group; EORTC=European Organization for the Research and Treatment of Cancer; EQ-5D-5L=5-level EQ-5D version; LC13=Lung Cancer 13; MRI=magnetic 
resonance imaging; PRO=patient-reported outcome; PS=performance status; Q12W=every 12 weeks; Q24W=every 24 weeks; QLQ=quality of life questionnaire; RR=respiratory 
rate; SAE=serious adverse event; SBP=systolic blood pressure.
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2
INTRODUCTION
This clinical study, MK-7684A-008 (KEYVIBE-008), will evaluate the combination of 
MK-7684A with etoposide/platinum chemotherapy followed by MK-7684A compared to the 
combination of atezolizumab with etoposide/platinum chemotherapy followed by 
atezolizumab in the first-line treatment of ES-SCLC.
Protocol Amendment 04 implementation: Following eDMC interim review of the data, the 
experimental arm (Arm A: MK-7684A) was discontinued and all ongoing participants were 
offered the option to move to the comparator arm (Arm B: atezolizumab monotherapy) for 
the remainder of the study.
2.1
Study Rationale
SCLC remains a worldwide public health problem as a major cause of cancer mortality. 
Studies of chemo-immunotherapy combinations for the first-line treatment of patients with 
ES-SCLC show that the combination of chemotherapy and anti-PD-1/L1 receptor therapy 
provides a clinically meaningful benefit in this patient population compared with 
chemotherapy alone. However, these regimens demonstrate short PFS and only modestly 
improve OS, reflecting the necessity for novel therapeutics that ideally have synergy with 
anti-PD-1/PD-L1 in this patient population.
2.2
Background
2.2.1
SCLC Epidemiology and Current Therapeutic Options
SCLC is an aggressive neuroendocrine malignancy of the lung, which remains a worldwide 
public health problem as it is a major cause of cancer mortality. This malignancy accounts 
for approximately 13% to 17% of all lung cancer cases, with approximately 30,000 patients 
diagnosed annually in the US [American Cancer Society 2020] [National Cancer Institute 
2014] [Zhao, H., et al 2018]. Worldwide, approximately 275,000 patients are diagnosed with 
SCLC annually [Majem, M. 2017]. This malignancy is strongly linked to tobacco use, with 
only 2% to 3% of cases occurring in never-smokers [Varghese, A. M., et al 2014] [Thomas, 
A., et al 2020].
SCLC is characterized by a short doubling time, high growth fraction, and early development 
of widespread metastases [Gazdar, A. F., et al 2017]. The overwhelming majority of patients 
with SCLC present with ES-SCLC, with advanced, bulky nodal disease or with tumors that 
have spread beyond a single tolerable radiation field in the chest. Therefore, SCLC is not 
considered a surgical disease and chemotherapy is the foundation of treatment [Gaspar, L. E., 
et al 2012]. The fundamental approach of first-line treatment of SCLC had not changed in 
nearly 4 decades since the introduction of an etoposide/platinum doublet, which is 
administered to both patients with LS-SCLC (cancer confined to the chest in a single 
tolerable radiation field) and patients with ES-SCLC. Although first-line treatment for SCLC 
yields high tumor response rates, essentially all patients with ES-SCLC, and most with LS-
SCLC, develop chemoresistance and relapse within months of completing initial therapy. 
Once patients develop recurrent or progressive, advanced or metastatic disease, treatment 
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options are limited, which is in stark contrast to the progress that has been made in NSCLC. 
Correspondingly, there has been very little improvement in survival rates; the overall 5-year 
survival rate of SCLC patients from diagnosis is <7% [National Cancer Institute 2014] 
[Gazdar, A. F., et al 2017] [American Cancer Society 2020].
Multiple efforts at improving first-line outcomes for patients with SCLC have been largely 
unsuccessful. OS is not improved if participants receive maintenance therapy with additional 
cycles of the same regimen used for induction or a different agent (eg, maintenance oral 
etoposide or sunitinib after an etoposide-containing first-line regimen) [Spiro, S. G., et al 
1989] [Hanna, N. H., et al 2002] [Hanna, N., et al 2006], consolidation with different 
chemotherapeutic regimens after 4 cycles of etoposide/platinum [Beith, J. M., et al 1996] 
[Schiller, J. H., et al 2001], or the addition of ipilimumab in a phased fashion to etoposide 
and platinum [Reck, M., et al 2016]. Therefore, treatment beyond 6 cycles of 
etoposide/platinum chemotherapy is not recommended for ES-SCLC by the NCCN [National 
Comprehensive Cancer Network 2018], the ESMO Guidelines [Fruh, M., et al 2013], or 
ASCO [Rudin, C. M., et al 2015]. Overall, as minimal improvement has been made in the 
fundamental treatment of SCLC in the past few decades since the introduction of the 
etoposide/platinum doublet, there remains critical need for new therapeutic approaches in the 
first-line treatment of this disease.
2.2.1.1
Approved Immunotherapy in ES-SCLC
Recently, immunotherapy has begun to change outcomes in the first-line treatment of 
ES-SCLC, as shown by the IMpower133 and CASPIAN studies. In the global Phase 3 
IMpower133 study, participants were randomized to receive etoposide and carboplatin with 
either atezolizumab or placebo for four 21-day cycles, followed by maintenance 
atezolizumab or placebo as assigned until they had unacceptable toxic effects, disease 
progression, or no additional clinical benefit [Horn, L., et al 2018]. Prophylactic cranial 
irradiation (PCI) was allowed based on investigators’ choice during the maintenance setting, 
which was administered to 11% of participants in each arm. Study results showed a 
significant improvement in OS for the atezolizumab combination compared with 
chemotherapy alone (HR 0.70 [95% CI: 0.54, 0.91], p=0.007; median OS of 12.3 months 
compared with 10.3 months, respectively). A significant PFS benefit was shown for the 
atezolizumab combination (median PFS of 5.2 months compared with 4.3 months for 
chemotherapy only; HR 0.77 (95% CI: 0.62, 0.96); p=0.02). Importantly, ORR was not 
improved and DOR was only minimally longer with atezolizumab. The combination of 
atezolizumab with etoposide and carboplatin was approved for the first-line treatment of ES-
SCLC by the US FDA on 18-MAR-2019, as it represented the first therapeutic regimen to 
improve survival in patients with SCLC. Recently, more mature data with median follow-up 
of 22.9 months were presented, which showed an OS HR of 0.76 (95% CI: 0.60, 0.95), 
nominal p-value of 0.0154 [Reck, M., et al 2019]. 
The CASPIAN study is an open-label, global Phase 3 study that randomized participants with 
ES-SCLC in need of first-line treatment to durvalumab in combination with etoposide and 
cisplatin/carboplatin, durvalumab and tremelimumab in combination with etoposide and 
cisplatin/carboplatin, or etoposide and cisplatin/carboplatin alone [Paz-Ares, L., et al 2019]. 
Participants in the immunotherapy groups received up to 4 cycles of the etoposide/platinum 
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doublet plus durvalumab with or without tremelimumab followed by maintenance 
durvalumab, while patients in the chemotherapy only group could have received an 
additional 2 cycles of the platinum doublet. PCI was only allowed in the chemotherapy only 
group and at the investigator’s discretion, being administered to only 8% of the participants. 
At an interim analysis, durvalumab plus etoposide/platinum was associated with a significant 
improvement in overall survival compared with the etoposide/platinum group (HR: 0.73; 
95% CI: 0·59, 0·91; p=0.0047; median overall survival 13.0 months [95% CI: 11.5, 14.8] vs. 
10.3 months [95% CI: 9.3, 11.2]) [Paz-Ares, L., et al 2019]. Progression-free survival was 
not formally tested, though median PFS was 5.1 months for the durvalumab plus 
etoposide/platinum group and 5.4 months for the etoposide/platinum group (HR of 0.78 [95% 
CI: 0.65, 0.94]). A post hoc analysis showed that confirmed objective response was 68% 
compared with 58% in the durvalumab plus etoposide/platinum and etoposide/platinum 
groups, respectively (odds ratio: 1.56, 95% CI: 1.10, 2.22), with a similar median duration of 
response in both groups. Durvalumab in combination with etoposide and either carboplatin or 
cisplatin was approved for first-line treatment of ES-SCLC by the US FDA on 27-MAR-
2020. The results from IMpower133 and CASPIAN provide evidence that the combination of 
standard chemotherapy with immunotherapy is a clinically meaningful approach in the 
treatment of SCLC.
2.2.1.2
Pembrolizumab
Keytruda® (pembrolizumab) is indicated for the treatment of patients across several 
indications and has been evaluated for the treatment of ES-SCLC in both previously treated 
and treatment-naïve patient populations. 
KEYNOTE-158 and KEYNOTE-028 were multicohort studies to evaluate the efficacy and 
safety of pembrolizumab monotherapy in multiple tumor types, including advanced or 
metastatic SCLC. In these studies, pembrolizumab monotherapy provided a clinically 
meaningful benefit in participants with locally advanced or metastatic SCLC who had 
received 2 or more lines of prior therapy, with an 18.3% ORR per RECIST 1.1 by BICR. 
Based on Kaplan-Meier estimation, 65.5% of responders had response durations ≥24 months, 
and the median response was not yet reached (4.1-35.8+ months). 
Pembrolizumab has also shown benefit in the treatment of first-line ES-SCLC in 
KEYNOTE-604, an ongoing Phase 3, placebo-controlled, double-blind study of 
pembrolizumab in combination with etoposide/platinum chemotherapy compared with 
etoposide/platinum chemotherapy alone [Rudin, C. M., et al 2020]. The primary efficacy 
results from KEYNOTE-604 showed clinically meaningful and statistically significant 
improvement of the pembrolizumab combination over chemotherapy alone for the PFS 
endpoint at IA2 (primary analysis). The pembrolizumab combination reduced the risk of 
progression or death by 25% with an HR of 0.75 (95% CI: 0.61, 0.91, p=0.00225) [Rudin, C. 
M., et al 2020]. PFS rates for the pembrolizumab combination were higher than the 
chemotherapy control (6-months [34.1% and 23.8% respectively], 9-months [17.2% and 
8.0%, respectively]). At the final analysis, the pembrolizumab combination showed a 
numerical improvement over the control with regard to OS, with an HR of 0.80 (95% CI: 
0.64, 0.98) and p-value of 0.0164 (p-value boundary: 0.0128). The magnitude of benefit for 
OS and PFS in KEYNOTE-604, as well as OS and PFS rates at milestone landmarks, were 
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similar to those shown by contemporaneous studies, showing the treatment effect of 
pembrolizumab in the first-line setting [Horn, L., et al 2018] [Reck, M., et al 2019] [Paz-
Ares, L., et al 2019] [Leal, T. A., et al 2020].
2.2.1.3
MK-7684A
Initial data indicate that the addition of MK-7684 to pembrolizumab may broaden the 
response without significant additional toxicity. 
 
 
 
 
 
 
 
 
 
CD155, an immune checkpoint molecule that inhibits T-cells by binding to TIGIT has 
recently been found to be highly expressed in various SCLC cell lines and tumor tissues [Yu, 
H., et al 2018] [Dora, D., et al 2020]. In addition, high CD155 expression is associated with 
poor prognosis and advanced tumor stage in SCLC [Yu, H., et al 2018] [Xu, Y., et al 2019]. 
Therefore, targeting TIGIT pathway represents a therapeutic strategy of interest in SCLC.
2.2.2
Pharmaceutical and Therapeutic Background
2.2.2.1
MK-7684A
MK-7684A is a fixed-dose coformulation of pembrolizumab (200 mg) and MK-7684 
(200 mg). Combined TIGIT and PD-1 inhibition may result in synergistic tumor killing or an 
expansion of cancer indications responsive to anti-PD-1 containing therapy.
2.2.2.1.1
Pembrolizumab
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with its ligands PD-L1 and PD-L2. The PD-1 
receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.
Clinical safety, tolerability, and support for the selected dosing regimen may be found with 
other detailed background information in the IB/approved labeling.
CCI
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2.2.2.1.2
MK-7684
MK-7684 is a humanized, antagonistic IgG1 mAb that binds to the immune checkpoint 
receptor, TIGIT, and blocks the interaction between TIGIT and its ligands. TIGIT is one of 
multiple immune checkpoint molecules that maintain immune homeostasis and prevent 
uncontrolled immune activation. TIGIT competes with the activating receptor CD226 for its 
ligands, CD155/PVR/Necl5/Tage4 and CD112/PVRL-2, which are expressed on 
antigen-presenting cells. Binding of TIGIT to its ligands negatively modulates T-cell activity. 
The mechanism of TIGIT-mediated T-cell inhibition is not completely understood. Some 
reports showed that TIGIT knockdown increases T-cell proliferation and effector cytokine 
production [Zhang, T., et al 2014] and that anti-TIGIT antibodies characterized as agonists 
can decrease T-cell activation [Lozano, E., et al 2012]. Some reports have also showed that 
TIGIT may inhibit T-cell activation by opposing the CD226-mediated positive signal through 
ligand competition or heterodimerization with CD226 [Levin, S. D., et al 2011] [Johnston, R. 
J., et al 2014]. Importantly, it has been shown both in vitro and in vivo, that CD226 
knockdown or blockade (with an antagonist antibody) eliminates the positive impact of 
TIGIT antagonism [Levin, S. D., et al 2011] [Johnston, R. J., et al 2014].
In a variety of mouse and human tumor models, TIGIT is highly expressed on CD4+ and 
CD8+ TIL and its expression has been correlated with CD8+ T-cell infiltration [Johnston, R. 
J., et al 2014] [Chauvin, J. M., et al 2015]. Coordinated TIGIT and PD-1 blockade results in 
increased proliferation, cytokine production, and degranulation of CD8+ human TIL from 
melanoma [Chauvin, J. M., et al 2015].
 
 
 
 
 
 
 
 
Clinical safety, tolerability, and support for the selected dosing regimen may be found with 
other detailed background information in the combined MK-7684/MK-7684A IB.
CCI
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2.2.2.2
Atezolizumab
Atezolizumab (Tecentriq®) is a monoclonal IgG1κ antibody that binds to PD-L1 and blocks 
its interactions with both PD-1 and B7.1 receptors. Tecentriq is indicated in combination 
with carboplatin and etoposide for the first-line treatment of adult patients with ES-SCLC. 
Tecentriq is also indicated as monotherapy or in combination with other therapeutics in 
NSCLC, alveolar soft part sarcoma, HCC, and melanoma.
Clinical safety, tolerability, and support for the selected dosing regimen may be found with 
other detailed background information in the approved labeling.
2.2.3
Information on Other Study-related Therapy
Standard first-line treatment for the vast majority of patients with SCLC, regardless of stage, 
involves combination chemotherapy with etoposide plus cisplatin or carboplatin, a 
combination that has been used clinically for over 40 years [Sierocki, J. S., et al 1979].
A meta-analysis evaluated individual participant data from 4 randomized studies and found 
that median OS, median PFS, and response rates were similar in the cisplatin and carboplatin 
arms. While hematologic toxicities were higher in participants treated with carboplatin, 
nonhematologic toxicities were increased in participants treated with cisplatin [Rossi, A., et 
al 2012]. Based on these data, 4 cycles of etoposide with either cisplatin or carboplatin can be 
considered an appropriate first-line regimen to treat SCLC. This is also reflected in clinical 
utilization data and the NCCN [National Comprehensive Cancer Network 2018] and ESMO 
[Fruh, M., et al 2013] recommendations. Taken together, these data provide the basis for the 
chemotherapy induction regimen selected for this study.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
As described in Section 2.2.1, anti-PD-1/L1 therapy improves the survival of patients 
receiving first-line therapy for ES-SCLC. Still, these improvements have been short in 
duration; as a result, there is an unmet need for improving the survival of patients with 
newly diagnosed ES-SCLC.
 
 
 
 
 
 
 
 
 
 
CCI
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In participants with extensive-stage small cell lung cancer who are in need of first-line 
treatment:
Primary Objective
Primary Endpoint
•
To compare overall survival for 
MK-7684A in combination with 
the background therapy of 
etoposide/platinum followed by 
MK-7684A to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab.
•
Hypothesis (H1): MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A is 
superior to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab with 
respect to overall survival.
•
Overall survival: the time from randomization 
to death due to any cause
Secondary Objectives
Secondary Endpoints
•
To compare progression-free 
survival per RECIST 1.1 as 
assessed by blinded independent 
central review for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A to 
atezolizumab in combination with 
the background therapy of 
etoposide/platinum followed by 
atezolizumab.
•
Progression-free survival: the time from 
randomization to the first documented disease 
progression or death due to any cause, 
whichever occurs first
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•
Hypothesis (H2): MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A is 
superior to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab with 
respect to progression-free 
survival per RECIST 1.1 by 
blinded independent central 
review.
•
To evaluate the objective 
response rate per RECIST 1.1 as 
assessed by blinded independent 
central review for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A 
compared to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab.
•
Objective response: complete response or 
partial response
•
To evaluate duration of response 
per RECIST 1.1 as assessed by 
blinded independent central 
review for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A 
compared to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab.
•
Duration of response: for participants with 
confirmed complete response or partial 
response, duration of response is defined as 
time from first documented evidence of 
complete response or partial response until 
disease progression or death due to any cause, 
whichever occurs first
•
To evaluate the safety and 
tolerability of the investigational 
treatment combination based on 
proportion of adverse events.
•
Adverse events
•
Study intervention discontinuations due to 
adverse events
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•
To evaluate the mean change 
from baseline in global health 
status/quality of life, physical 
functioning, dyspnea, cough, and 
chest pain for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A 
compared to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab.
•
Change from baseline in the following 
patient-reported outcomes scales/items:
-
Global health status/quality of life score 
(EORTC QLQ-C30 items 29 and 30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Dyspnea score (EORTC QLQ-C30 item 8)
-
Cough (EORTC QLQ-LC13 item 31)
-
Chest pain (EORTC QLQ-LC13 item 40)
•
To evaluate the time-to-true 
deterioration in global health 
status/quality of life, physical 
functioning, dyspnea, cough, and 
chest pain for MK-7684A in 
combination with the background 
therapy of etoposide/platinum 
followed by MK-7684A 
compared to atezolizumab in 
combination with the background 
therapy of etoposide/platinum 
followed by atezolizumab.
•
Time-to-true deterioration: defined as the time 
from baseline to the first onset of a ≥10-point 
deterioration from baseline with confirmation 
by the subsequent visit of a ≥10-point 
deterioration from baseline in the following 
scales/items:
-
Global health status/quality of life score 
(EORTC QLQ-C30 items 29 and 30)
-
Physical functioning score (EORTC 
QLQ-C30 items 1-5)
-
Dyspnea score (EORTC QLQ-C30 item 8)
-
Cough (EORTC QLQ-LC13 item 31)
-
Chest pain (EORTC QLQ-LC13 item 40)
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Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
•
To evaluate effect of PD-L1 
expression on outcomes including 
overall survival, as well as 
progression-free survival and 
objective response rate per 
RECIST as assessed by blinded 
independent central review
•
Overall survival by PD-L1 expression (tumor 
proportion score <1% versus ≥1%, combined 
positive score <1 versus ≥1).
•
Progression-free survival by PD-L1 expression 
(tumor proportion score <1% versus ≥1%, 
combined positive score <1 versus ≥1).
•
Objective response rate by PD-L1 expression 
(tumor proportion score <1% versus ≥1%, 
combined positive score <1 versus ≥1).
•
Duration of response by PD-L1 expression 
(tumor proportion score <1% versus ≥1%, 
combined positive score <1 versus ≥1).
•
To evaluate change from baseline 
in visual analog scale using the 
EQ-5D-5L questionnaire for 
MK-7684A in combination with 
the background therapy of 
etoposide/platinum followed by 
MK-7684A compared to 
atezolizumab in combination with 
the background therapy of 
etoposide/platinum followed by 
atezolizumab
•
Change from baseline in EQ-5D-5L visual 
analog scale
•
To identify molecular (genomic, 
metabolic, and/or proteomic) 
biomarkers that may be indicative 
of clinical response/resistance, 
safety, pharmacodynamic 
activity, and/or the mechanism of 
action of MK-7684A in 
combination with 
etoposide/platinum or 
atezolizumab in combination with 
etoposide/platinum
•
Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue
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•
To evaluate objective response 
rate, duration of response, and 
progression-free survival based 
on RECIST 1.1 as assessed by the 
investigator
•
Objective response rate
•
Duration of response
•
Progression-free survival
•
To evaluate the pharmacokinetic 
profile of MK-7684 and 
pembrolizumab when 
administered as a coformulation 
of MK-7684A
•
Pharmacokinetic parameters (Cmax, Ctrough) for 
MK-7684
•
Pharmacokinetic parameters (Cmax, Ctrough) for 
pembrolizumab
•
To evaluate immunogenicity of 
MK-7684 and pembrolizumab 
when administered as a 
coformulation of MK-7684A
•
Anti-drug antibody incidence for MK-7684
•
Anti-drug antibody incidence for 
pembrolizumab
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4
STUDY DESIGN
At implementation of Amendment 05, the below changes apply. The changes listed below 
supersede any protocol content/instructions from previous amendments.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy) should be considered for discontinuation from the study. Those benefiting from 
atezolizumab, but unable to access it as SOC outside the study, may continue on study 
and receive treatment with atezolizumab until discontinuation criteria are met. The final 
required study visit will be the Safety Follow-up Visit.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow up for survival status. Participants currently in imaging follow-up 
or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. Standard safety reporting 
should, however, continue, as applicable.
•
Participants remaining on study at the time of Amendment 05 should continue to be 
monitored in the study through the AE reporting period (Section 8.4).
Existing protocol content is retained for historical reference.
4.1
Overall Design
Protocol Amendment 04 implementation: Based on recommendations of the eDMC
following an interim review showed that the primary endpoint of OS met the prespecified 
futility criteria, study was unblinded, and the experimental arm (Arm A: MK-7684A) was
discontinued. All ongoing participants on treatment were offered an option to move to the 
comparator arm (Arm B: atezolizumab monotherapy) for the remainder of the study.
This is a Phase 3, randomized, double-blind, active-controlled, multisite study of MK-7684A 
combined with etoposide/platinum chemotherapy followed by MK-7684A compared to 
atezolizumab combined with etoposide/platinum chemotherapy followed by atezolizumab in 
the first-line treatment of ES-SCLC.
Following a screening period of up to 28 days, approximately 450 eligible participants will 
be randomized 1:1 into 2 intervention groups:
Group A – Participants will receive 4 cycles of etoposide/platinum chemotherapy in 
combination with MK-7684A followed by MK-7684A until any of the conditions for 
discontinuation are met (Section 7.1).
Group B – Participants will receive 4 cycles of etoposide/platinum chemotherapy in 
combination with atezolizumab followed by atezolizumab until any of the conditions for 
discontinuation are met (Section 7.1).
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Crossover will not be allowed between the intervention groups. A double-blinding technique 
will be used for atezolizumab and MK-7684A assignment. The chemotherapy agents will be 
open-label. The choice of platinum (cisplatin or carboplatin) in both arms is selected by the 
investigators before randomization.
Treatment randomization will be stratified according to ECOG performance status (0 or 1), 
LDH (≤ULN or >ULN), presence of liver metastases (yes or no), and presence of brain 
metastases (yes or no).
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
Tumor response will be evaluated per RECIST 1.1 and participants will have posttreatment 
follow-up imaging for disease status until any of the conditions for discontinuation of 
imaging are met (Section 8.2.1.3). All participants will be followed for overall survival until 
death, withdrawal of consent, or the end of the study.
Protocol Amendment 04 Implementation: There will be no collection of efficacy data 
including tumor scans, vital status and post-treatment anticancer therapy status. Participants 
currently on treatment will have tumor imaging assessed locally based on site’s standard of 
care imaging schedule. Disease progression will no longer be centrally verified.
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the NCI CTCAE v5.0 (Section 10.3.4). Each participant will be 
monitored for AEs and SAEs (refer to Section 8.4.1 for details). If study intervention is 
discontinued for toxicity, neither pembrolizumab nor MK-7684 will be offered as a single 
agent.
Protocol Amendment 04 implementation: In participants who continue atezolizumab under 
the study, safety assessments and safety related data collection including safety follow-up 
should continue as per current protocol, including laboratory assessments.
Please refer to Appendix 7 for country-specific requirements.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Stratification Factors
Treatment randomization will be stratified according to ECOG performance status (0 or 1), 
LDH (≤ULN or >ULN), presence of liver metastases (yes or no), and presence of brain 
metastases (yes or no) to ensure a balanced allocation of participants in populations with 
different prognoses. Elevated LDH values, higher ECOG PS, and liver and brain metastases 
are each associated with higher tumor burden and decreased survival in SCLC [Zhang, X., et 
al 2016] [Deng, T., et al 2018] [Foster, N. R., et al 2009] [Liu, S. V., et al 2020] [Steindl, A., 
et al 2019].
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4.2.2
Rationale for Endpoints
4.2.2.1
Efficacy Endpoints
Primary Efficacy Endpoints
OS is the primary endpoint for the study. OS has been recognized as the gold standard for the 
demonstration of superiority of a new antineoplastic therapy in randomized clinical studies.
Secondary Efficacy Endpoints
This study will use PFS, ORR, and DOR per RECIST 1.1 criteria as assessed by BICR as 
secondary efficacy endpoints. 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.
A PFS event can reflect tumor growth and be assessed before the determination of a survival 
benefit. Its determination is not confounded by subsequent therapy. Treatment effect 
measured by PFS can be a surrogate endpoint to represent direct clinical benefit based on the 
specific disease, context of use, magnitude of the effect, the disease setting, location of 
metastatic sites, available therapy, the risk-benefit relationship, and the clinical consequences 
of delaying or preventing progression in key disease sites (eg, delay of new lesions in the 
brain or spine) or delaying administration of more toxic therapies.
ORR is an appropriate endpoint to evaluate the antitumor activity of investigational 
combinations. Treatment effect measured by ORR can represent direct clinical benefit based 
on the specific disease, context of use, magnitude of the effect, the number of CRs, the 
durability of response, the disease setting, the location of the tumors, available therapy, and 
the risk-benefit relationship.
DOR per RECIST 1.1, as assessed by BICR, will serve as an additional measure of efficacy 
and is a commonly accepted endpoint by both regulatory authorities and the oncology 
community.
4.2.2.1.1
RECIST 1.1:
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures. 
Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in 
total and 2 per organ, this protocol has implemented an adjustment to RECIST 1.1 to allow a 
maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is 
needed to adequately represent the tumor burden. Refer to Section 8.2.1.4 for additional 
detail.
4.2.2.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational-systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
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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.
4.2.2.3
Patient-reported Outcomes 
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. As part of the 
analyses for this study, HRQoL and disease-related symptoms will be investigated among all 
participants via the following assessment tools: EORTC QLQ-C30, EORTC QLQ-LC13, and 
EuroQol EQ-5D-5L questionnaires. Health utilities will be evaluated using the EQ-5D-5L 
PRO instrument. These measures are not pure efficacy or safety endpoints because they are 
affected by both disease progression and treatment tolerability.
4.2.2.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL instrument, which contains 30 items and 
measures 5 functional dimensions (physical, role, emotional, cognitive and social), 3 
symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health 
and QoL scale [Aaronson, N. K., et al 1993]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. TTD and mean change from baseline 
in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary 
objectives.
4.2.2.3.2
EORTC QLQ-LC13
The EORTC QLQ-LC13, a supplemental lung cancer-specific module, comprises multi-item 
and single-item measures of lung cancer-associated symptoms (ie, coughing, hemoptysis, 
dyspnea, and pain) and side effects from chemotherapy and radiation (ie, hair loss, 
neuropathy, sore mouth, and dysphagia). It is scored on a 4-point scale (1 = not at all, 2 = a 
little, 3 = quite a bit, 4 = very much) and has been translated into 64 languages and validated.
4.2.2.3.3
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each 
dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). 
The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the 
participant rates his or her general state of health at the time of the assessment. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
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4.2.2.4
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/pharmacodynamic 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 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 called a ‘hyper-mutated’ 
state) may generate neoantigen 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 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.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or 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 
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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 and/or tumor
Tumor and/or 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.
4.2.2.5
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 and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for 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.
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4.2.3
Rationale for the Use of Comparator
Atezolizumab was the first anti-PD-1/L1 approved for ES-SCLC and has been considered the 
current standard of care for the first-line treatment of ES-SCLC since its approval in 2019. In 
an analysis of 347 patients diagnosed with ES-SCLC between 01-OCT-2018 (after the 
Impower133 study publication) and 31-DEC-2019, 267 patients (76.9%) were treated with 
atezolizumab in combination with carboplatin and etoposide [Nadler, E., et al 2021]. As 
such, atezolizumab will be used as the active comparator for this study.
4.2.3.1
Justification for Dose
4.2.4
Starting Dose for This Study
4.2.4.1
Rationale for MK-7684A Dosing
MK-7684A is a single-use drug product vial containing a fixed-dose combination of 200 mg 
MK-7684 and 200 mg pembrolizumab in a 20.0 mL fill volume. MK-7684A is to be 
administered Q3W. The single coformulation vial could provide simplified preparation and 
reduced infusion times compared to separate formulations administered sequentially. 
Study PN001 is evaluating the safety and PK biocomparability of this coformulated product 
to that of the sequential administration of MK-7684 and pembrolizumab.
Based on the totality of available data, including preliminary clinical PK, 
pharmacodynamics, safety, and efficacy from Study MK-7684-001, the selected dose of 
MK-7684 is 200 mg Q3W.
 
 
 
 
 
 
 
 
 
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.
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, 
 
CCI
CCI
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Overall, the totality of data,
 
 support that a fixed-dose of 200 mg Q3W is the RP2D for MK-7684 in 
combination with 200 mg pembrolizumab. For more information, see the 
MK-7684/MK-7684A IB.
Based on the totality of data generated in the Keytruda development program, 200 mg Q3W 
is an appropriate dose of pembrolizumab for adults across all indications. As outlined below, 
this dose is justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications showing 
flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W 
representing an approximate 5- to 7.5-fold exposure range

Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the distributions 
of exposures, supporting suitability of 200 mg Q3W

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.2.4.2
Rationale for Atezolizumab Dosing
Atezolizumab administration is approved for the treatment of ES-SCLC with doses of 
840 mg Q2W, 1200 mg Q3W, or 1680 mg Q4W. This study will use fixed-dose 1200 mg 
atezolizumab Q3W to correspond to the dosage used in the Impower133 Study and with the 
MK-7684A Q3W administration in this study.
4.2.4.3
Rationale for Etoposide/Platinum Chemotherapy Dosing
Platinum doublet chemotherapies used in this study are well-established regimen for SCLC. 
The regimen was first evaluated in SCLC because this combination produced synergistic 
CCI
CCI
CCI
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activity in preclinical studies. Etoposide 100 mg/m2 IV Q3W on Days 1, 2, and 3 in 
combination with either cisplatin 75 mg/m2 IV Q3W on Day 1 or carboplatin AUC of 5 
mg/mL/min IV Q3W on Day 1 are recommended by the NCCN Guidelines [National 
Comprehensive Cancer Network 2018].
4.3
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 test 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.
The Sponsor estimates that the maximum duration of the study from first participant entered 
through long-term follow-up will be approximately 5 years (~2 years after study intervention 
has been completed) to attain the final assessment of the study (eg, to evaluate safety and/or 
long-term efficacy) for all evaluable participants. Refer to the Synopsis, Section 1.1, for the 
duration of participation of participants.
Protocol Amendment 04 implementation: The study will end when all participants 
discontinue from treatment and complete safety follow up.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
4.3.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped 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.
Based on recommendations of the eDMC to discontinue the experimental arm (MK-7684A) 
following an interim review showed that the primary endpoint of OS met the prespecified 
futility criteria. The study will end when all participants discontinue from treatment and 
complete safety follow up.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant is eligible for inclusion in the study if the participant meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. The participant must have a histologically or cytologically confirmed diagnosis of
ES-SCLC in need of first-line therapy.
2. Has ES-SCLC defined as Stage IV (T any, N any, M1a/b/c) by the American Joint 
Committee on Cancer, Eighth Edition or T3-T4 due to multiple lung nodules that are too 
extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable 
radiation plan.
Demographics
3. Is an individual of any sex/gender, at least 18 years at the time of providing the informed 
consent.
Male Participants
4. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for each study intervention after the last dose of the intervention is as 
follows:
-
Etoposide, cisplatin, or carboplatin: 95 days
-
Blinded study intervention (MK-7684A or atezolizumab): no contraception measures
•
Refrain from donating sperm
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
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OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause Appendix 5) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
-
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
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent 
basis), as described in Appendix 5 during the intervention period and for at least the time 
needed to eliminate each study intervention after the last dose of study intervention and 
agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The length of time required to continue 
contraception for each study intervention after the last dose of the intervention is as 
follows:
-
Etoposide, cisplatin, or carboplatin: 180 days
-
Blinded study intervention (MK-7684A or atezolizumab): 5 months
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.
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-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.6.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Informed Consent
6. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
7. Has measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been shown in such lesions. At least 1 lesion that meets the 
criteria for being measurable, as defined by RECIST 1.1, must be appropriate for 
selection as a target lesion.
8. Note: for the purposes of this study, metastatic lesions situated in the brain are not 
considered measurable and should be considered non-target lesions.
9. Submits a pretreatment archival tumor tissue sample or newly obtained core, incisional, 
or excisional biopsy of a tumor lesion not previously irradiated where such sample exists. 
Biopsy/tissue is preferred, but cytology sample by fine needle aspiration is allowed. The 
sample may be submitted after enrollment but must be submitted within 4 weeks after 
randomization. Details pertaining to tumor tissue submission can be found in the 
Laboratory Manual.
10. Has an ECOG performance status of 0 to 1 assessed within 7 days before 
allocation/randomization. 
11. Has adequate organ function as defined in the following table (Table 3). Specimens must 
be collected within 7 days before the start of study intervention.
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥8.0 g/dL or ≥5.0 mmol/a
Renal
Measured or calculatedb creatinine clearance
≥60 mL/min for participant receiving cisplatin
≥50 mL/min for participants receiving carboplatin
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of 
normal.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
b
Creatinine clearance (CrCl) should be calculated using the Cockcroft-Gault formula.
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.
12. Has a predicted life expectancy of >3 months.
Please refer to Appendix 7 for country-specific requirements.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Is considered a poor medical risk due to a serious, uncontrolled medical disorder or 
nonmalignant systemic disease. Examples include, but are not limited to, uncontrolled 
major seizure disorder, unstable spinal cord compression, or severe or life-threatening 
superior vena cava syndrome.
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Prior/Concomitant Therapy
2. Has received prior treatment (systemic therapy including investigational agents, 
curative-intent radiotherapy, or curative-intent surgical resection) for SCLC.
Note: Palliative radiation therapy is allowed until 7 days before the first dose of study 
intervention, provided that the radiated lesion is clinically stable and the participant is not 
receiving steroids for at least 7 days before the first dose of study intervention. The 
radiated lesion must not be an intrathoracic lesion.
Note: Specific treatment options allowed in the presence of brain metastases are not 
exclusionary (See exclusion criterion number 8 for details).
3. Is expected to require any other form of antineoplastic therapy for SCLC while on study. 
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after Sponsor consultation.
4. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines are allowed.
Prior/Concurrent Clinical Study Experience
5. Has received an investigational agent or has used an investigational device within 
4 weeks prior to study intervention administration.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
6. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study medication.
7. Known additional malignancy that is progressing or has required active treatment within 
the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin,, low-risk, non-muscle-invasive bladder cancer or carcinoma in situ, excluding 
carcinoma in situ of the bladder, that have undergone potentially curative therapy are not 
excluded.
8. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
brain metastases may participate only if they satisfy all of the following: 
•
Completed treatment (eg, whole brain radiation treatment, stereotactic radiosurgery, or 
equivalent) at least 14 days before the first dose of study intervention
•
Have no evidence of new or enlarging brain metastases confirmed by posttreatment 
repeat brain imaging (preferably using the same modality) performed at least 4 weeks 
after treatment and within the screening period, and
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•
Are neurologically stable without the need for steroids at least 7 days before the first dose 
of study intervention as per local site assessment.
Note: Participants with untreated brain metastases will be allowed if they are 
asymptomatic, the investigator determines there is no immediate CNS-specific treatment 
required, there is no significant surrounding edema, and the brain metastases are of 5 mm 
or less in size and 3 or fewer.
9. Has a history of severe hypersensitivity reaction (≥Grade 3) to any study intervention 
and/or any of its excipients (refer to the IB and/or approved product label(s) for a list of 
excipients).
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 history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
12. Has a known history of, or active, neurologic paraneoplastic syndrome.
13. Has an active infection requiring systemic therapy.
14. History of HIV infection. HIV testing is not required unless mandated by local health 
authority. 
15. Hepatitis B (defined as HBsAg reactive) or Hepatitis C virus (defined as detectable HCV 
RNA [qualitative]) infection.
Note: Testing for Hepatitis B or C is not required unless mandated by local health 
authority.
16. History or current evidence of any condition, therapy, laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
17. Known psychiatric or substance abuse disorder that would interfere with the participant’s 
ability to cooperate with the requirements of the study.
Other Exclusions
18. Has had an allogenic tissue/solid organ transplant.
19. Has had major surgery within 3 weeks before receiving the first dose of study 
intervention or has not recovered adequately from toxicity and/or complications from an 
intervention prior to receiving the first dose of study intervention.
20. Has symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoraco- or paracentesis) 
is eligible.
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Please refer to Appendix 7 for country-specific requirements.
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 required.
Study-site personnel are encouraged to assist participants with activities aimed at 
discontinuing smoking. All participants who smoke should be strongly advised to cease 
smoking.
5.3.3
Activity Restrictions
No restrictions are required.
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 one time for eligibility. 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 are met. Participants who are rescreened will retain their original screening number.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
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6
STUDY INTERVENTION
At implementation of Amendment 05, the below changes apply. The changes listed below 
supersede any protocol content/instructions from previous amendments.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy) should be considered for discontinuation from the study. Those benefiting from 
atezolizumab, but unable to access it as SOC outside the study, may continue on study 
and receive treatment with atezolizumab until discontinuation criteria are met. The final 
required study visit will be the Safety Follow-up Visit.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow up for survival status. Participants currently in imaging follow-up 
or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. Standard safety reporting 
should, however, continue, as applicable.
•
Participants remaining on study at the time of Amendment 05 should continue to be 
monitored in the study through the AE reporting period (Section 8.4).
Existing protocol content is retained for historical reference.
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 (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 4.
Country-specific requirements are noted in Appendix 7.
Reasonable efforts are to be made to arrange central sourcing for atezolizumab. However, in 
the extenuating circumstances where central sourcing is logistically difficult, local sourcing 
is acceptable after headquarter approval. The blinding for study interventions that are locally 
sourced must be maintained; blinding procedures are described in the Pharmacy Manual.
Protocol Amendment 04 implementation: All active participants in the experimental arm 
(Arm A: MK-7684A) stopped ongoing treatment with MK-7684A and were offered the 
option to move to the comparator arm (Arm B: atezolizumab monotherapy) for the remainder 
of the study.
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Table 4
Study Interventions
Arm Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administ
ration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
A
(Protocol 
Amendmen
t 04: Arm 
A 
discontinue
d)
Experi
mental
MK-7684A
Drug
Solution
MK-7684 
200 mg + 
pembrolizumab 
200 mg/20 mL 
vial
200 MG/
200 MG
IV 
Infusion
Q3W (Day 1 of each 
cycle) until 
discontinuation 
criteria are met
Test Product
IMP
Central
A
(Protocol 
Amendmen
t 04: Arm 
A 
discontinue
d)
Experi
mental
Saline 
placebo
Drug
Solution
Not applicable
Not 
applicable
IV 
Infusion
At Cycle 1 (and Q3W 
as needed beyond 
Cycle 1)
Placebo
NIMP/
AxMP
local
A
Experi
mental
Etoposide
Drug
Solution
100 mg (may 
vary according 
to supplier/ 
country)
100 mg/m2
IV 
Infusion
Q3W (Days 1, 2, 3 of 
each cycle for up to 
4 cycles)
Background 
Treatment
NIMP/
AxMP
Central or 
local
A
Experi
mental
Cisplatin
Drug
Solution
50 mg (may 
vary according 
to supplier/ 
country)
75 mg/m2
IV 
Infusion
Q3W (Day 1 of each 
cycle for up to 
4 cycles)
Background 
Treatment
NIMP/
AxMP
Central or 
local
A
Experi
mental
Carboplatin
Drug
Solution
600 mg (may 
vary according 
to supplier/ 
country)
AUC 
5 mg/mL/min
IV 
Infusion
Q3W (Day 1 of each 
cycle for up to 
4 cycles)
Background 
Treatment
NIMP/
AxMP
Central or 
local
B
Active 
Compar
ator
Atezolizumab
Drug
Solution
1200 mg
1200 mg
IV 
Infusion
Q3W (Day 1 of each 
cycle) until 
discontinuation 
criteria are met
Comparator
IMP
Central
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Arm Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administ
ration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
B
Active 
Compar
ator
Saline 
placebo
Drug
Solution
Not applicable
Not 
applicable
IV 
Infusion
At Cycle 1 (and Q3W 
as needed beyond 
Cycle 1)
Placebo
NIMP/
AxMP
Local
B
Active 
Compar
ator
Etoposide
Drug
Solution
100 mg (may 
vary according 
to supplier/ 
country)
100 mg/m2
IV 
Infusion
Q3W (Days 1, 2, 3 of 
each cycle for up to 4 
cycles)
Background 
Treatment
NIMP/
AxMP
Central or 
local
B
Active 
Compar
ator
Cisplatin
Drug
Solution
50 mg (may 
vary according 
to supplier/ 
country)
75 mg/m2
IV 
Infusion
Q3W (Day 1 of each 
cycle for up to 
4 cycles)
Background 
Treatment
NIMP/
AxMP
Central or 
local
B
Active 
Compar
ator
Carboplatin
Drug
Solution
600 mg (may 
vary according 
to supplier/ 
country)
AUC 
5 mg/mL/min
IV 
Infusion
Q3W (Day 1 of each 
cycle for up to 
4 cycles)
Background 
Treatment
NIMP/
AxMP
Central or 
local
All 
participants
Active 
Compar
ator
Atezolizumab
Drug
Solution
1200 mg
1200 mg
IV 
Infusion
Q3W (Day 1 of each 
cycle) until 
discontinuation 
criteria are met
Comparator
IMP
Central
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.
In this protocol, placebo for MK-7684A or atezolizumab is diluent alone (normal saline); diluent is used for blinding purposes and does not contain active ingredients.
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All supplies indicated in Table 4 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of investigational agents are provided in the 
Pharmacy Manual. Concomitant chemotherapeutic agents (etoposide and cisplatin or 
carboplatin) will be prepared and administered as per the approved product label(s).
Protocol Amendment 04 Implementation: Due to discontinuation of experimental arm (Arm 
A: MK-7684A), atezolizumab will be prepared and administered per approved local label. 
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 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to MK-7684A study 
intervention and atezolizumab study intervention, respectively.
Protocol Amendment 04 implementation: All active participants in the experimental arm 
(Arm A: MK-7684A) stopped ongoing treatment with MK-7684A and were offered an 
option to move to the comparator arm (Arm B: atezolizumab monotherapy) for the remainder 
of the study.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. ECOG performance status at Baseline (0 or 1)
2. LDH at Baseline (≤ULN or >ULN)
3. Liver metastases at Screening (yes or no)
4. Brain metastases at Screening (yes or no)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. Atezolizumab and 
MK-7684A will be supplied to the sites in an open-label manner. The study site’s unblinded 
pharmacist will obtain each participant’s study identification number and study drug 
assignment from the IRT system. MK-7684A, atezolizumab, and placebo (when needed) will 
be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or qualified 
study-site personnel. Blinded MK-7684A, atezolizumab, and placebo infusions are packaged 
identically. The participant, the investigator, and Sponsor personnel or delegate(s) who are 
involved in the study intervention administration or clinical evaluation of the participants are 
unaware of the intervention assignments. The chemotherapy agents will be open-label.
In addition to emergency unblinding for severe or life-threatening AEs with potential 
immunologic etiology, non-emergency unblinding to MK-7684A versus atezolizumab 
administration may occur on an individual participant basis and only after consultation with 
the Sponsor at the time of (1) centrally verified disease progression and participant has 
discontinued all study treatments, (2) when the participant has discontinued all study 
treatments and a new anticancer treatment is going to be started or (3) Grade 2 infusion 
reaction to the immunotherapy/placebo agent when placebo was also required. 
Non-emergency unblinding, only after consultation and approval from the Sponsor, is 
implemented through IRT by following the instructions in the IRT site user manual.
See Section 8.1.10 for a description of the method of unblinding a participant during the 
study should such action be warranted.
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Protocol Amendment 04 implementation: Following eDMC interim review of data, all 
participants have been unblinded.
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. 
Treatment intervention interruptions for greater than 21 days of the originally scheduled dose 
for situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention require discussion between the 
investigator and the Sponsor.
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 site should ensure and confirm that the study intervention is administered at the correct 
dose to the assigned study participant.
The total volume of study intervention infused will be compared with the total volume 
prepared to determine compliance with each dose administered. 
Refer to Section 6.6.1 and Section 6.6.2 for Dose Modification and Toxicity Management 
Guidelines for irAEs associated with pembrolizumab monotherapy, coformulations, or IO 
combinations and for other allowed dose interruptions.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medication or vaccination specifically prohibited, discontinuation 
from study intervention may be required. The investigator is to discuss prohibited 
medication/vaccination 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.
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Antineoplastic systemic chemotherapy (including chemotherapy, biological therapy, 
immunotherapy, and targeted therapies) not specified in this protocol
•
Investigational agents not specified in this protocol
•
Radiation therapy (including PCI or consolidative thoracic radiation therapy). Note: 
Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed after 
Sponsor consultation.
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•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
•
Phenytoin during therapy with cisplatin/carboplatin
•
Trilaciclib administration
•
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 chemotherapy
-
Premedication for IV contrast allergies
-
Short-term oral or IV use in doses >10 mg/day prednisone equivalent for asthma or 
COPD exacerbations
-
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
For each chemotherapy agent used in the study, site staff should refer to the approved 
product labels for prohibited medications and drug-drug interactions.
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 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
Concomitant medications should also include medication regularly administered at intervals 
>28 days prior to the first dose of study intervention.
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Please refer to Appendix 7 for country-specific requirements.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Please refer to Appendix 7 for country-specific requirements.
6.5.1.1
Blinded Study Intervention (MK-7684A and Atezolizumab)
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.
6.5.1.2
Etoposide/Platinum Chemotherapeutic Agents
For supportive care measures for the management of AEs that may result from treatment with 
chemotherapy, refer to the approved product labels for these agents.
During Induction (Cycles 1-4), the use of CSFs (G-CSF or GM-CSF) is highly recommended 
as primary prophylaxis to reduce the risk of febrile neutropenia, especially as many 
participants have multiple comorbidities and advanced disease. The American Society of 
Clinical Oncology guidelines for use of CSFs should be followed.
For all agents and administration, antiemetic therapy should follow MASCC guidelines 
[Roila, F., et al 2016] and should include a 5-HT3 receptor antagonist, dexamethasone (or 
equivalent) and/or aprepitant as per the MASCC guidelines.
In addition, all participants should receive the appropriate corticosteroid premedications as 
per the local approved label.
Additional premedications and pre- and post-cisplatin hydration should be administered as 
per local practice.
6.6
Dose Modification
The dose modification and toxicity management guidelines for immune-related adverse 
events (Table 5) and the infusion reaction dose modification and treatment guidelines 
(Table 6) apply to both atezolizumab and MK-7684A (ie, blinded study intervention).
Protocol Amendment 04 implementation: Due to discontinuation of experimental arm (Arm 
A: MK-7684A) and ongoing participants being offered an option to move to the comparator 
arm (Arm B: atezolizumab monotherapy), the dose management and toxicity management 
guidelines for atezolizumab should follow approved local label.
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6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
MK-7684A or Atezolizumab
AEs associated with study intervention exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
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 
study intervention, 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 study intervention, study intervention 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, study intervention 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 study intervention.
Restarting Study Interventions:
Participants may restart study intervention 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, study intervention may be 
restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
MK-7684A or atezolizumab are provided in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
MK-7684A or Atezolizumab
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.  Study intervention 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 study intervention has been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With Study 
Intervention
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 Study 
Intervention
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2a
Withhold
·
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
·
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable)
Grade 3b or 4c
Permanently 
discontinue
·
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of b-cell 
failure
Withholdd
·
Initiate insulin replacement 
therapy for participants with 
T1DM
·
Administer antihyperglycemic 
in participants with 
hyperglycemia
·
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
·
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
·
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hyperthyroidism
Grade 2
Continue
·
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
·
Monitor for signs and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hypothyroidism
Grade 2, 3 or 4
Continue
·
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
·
Monitor for signs and symptoms of 
thyroid disorders
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With Study 
Intervention
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
Asymptomatic cardiac 
enzyme elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1 
using CTCAE v4.0)
Withhold
·
Based on severity of AE 
administer corticosteroids
·
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, TEN, 
or DRESS
Withhold
·
Based on severity of AE 
administer corticosteroids
·
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Confirmed SJS, TEN, 
or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With Study 
Intervention
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
·
Based on severity of AE 
administer corticosteroids
·
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the evente 
Recurrent Grade 3 or 
Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 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 study intervention is at the discretion of the investigator or treating physician. If control achieved or ≤Grade 2, study 
intervention 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 or Atezolizumab
Administration of study intervention 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 for the study 
intervention-associated infusion reaction are provided in Table 6.
Table 6
MK-7684A or Atezolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the opinion 
of the investigator
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 h
Stop Infusion
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the opinion 
of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 
50 mL/h). Otherwise dosing will be held 
until symptoms resolve and the 
participant should be premedicated for 
the next scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate premedication 
should be permanently discontinued from 
further study intervention.
Participant may be premedicated 
1.5 h (±30 min) prior to infusion of 
study intervention with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine).
Acetaminophen 500 to 1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the opinion 
of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer Institute; 
NSAIDs= nonsteroidal anti-inflammatory drugs.
Note:  Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for MK-7684A or Atezolizumab
Study intervention 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 for Q3W, 21 days of the 
originally scheduled dose and within 42 days 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.
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6.6.2
Management of Adverse Events and Dose Modifications for 
Etoposide/Platinum Chemotherapeutic Agents
If a participant experiences a ≥10% weight change during Cycles 1 to 4, the doses of 
etoposide and cisplatin/carboplatin should be recalculated.
Study intervention-related toxicities must be resolved to baseline or Grade ≤1 before 
administering the next dose. Exceptions include alopecia, Grade 2 fatigue, and endocrine-
related AEs requiring treatment or hormone replacement, which may be Grade ≤2. For 
creatinine clearance, ANC, platelet, hemoglobin, total bilirubin, and AST/ALT, the 
guidelines provided below may be followed. Participants must not receive the next cycle of 
chemotherapy if any of the following apply:
•
ANC <1,500/mm3
•
Platelet count <100,000/mm3
•
Hemoglobin level <8 g/dL
•
Total bilirubin level >1.5 × ULN
•
AST and ALT levels ≥2.5 × ULN, or ≥5 × ULN if liver metastases are present
Dose modifications due to AEs will depend on the investigator’s assessment of causality. and 
use a stepwise dose reduction according to Table 7. Recommended dose modifications for 
key chemotherapy toxicities (etoposide and cisplatin/carboplatin) are outlined in Table 8 and 
Table 9. These serve as a guide and do not replace investigator judgment and applicable local 
label recommendations, if more stringent. A participant is allowed to switch from cisplatin to 
carboplatin if the participant develops unexpected toxicities with the use of cisplatin 
(including hearing loss), becomes ineligible for further cisplatin therapy, and/or the 
investigator (after consultation with the Sponsor) considers switching to carboplatin to be in 
the best interest of the participant. 
A maximum of 2 dose reductions per chemotherapy agent are permitted; if additional 
reductions are required, that particular agent must be discontinued. In the absence of the 
agent thought to be causing toxicity, treatment can continue with blinded study intervention 
with or without the remaining chemotherapeutic drug.
Once the dose has been decreased, it should remain reduced for all subsequent 
administrations or be further reduced, if necessary. There will be no dose escalations in this 
study.
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Table 7
Dose Modifications for Chemotherapeutic Agents
Etoposide
Cisplatin
Carboplatin
Dose Level 0 
(starting dose)
100 mg/m2/day
75 mg/m2
AUC 5 mg/mL/min
Dose Level -1
75 mg/m2/day
56 mg/m2
AUC 4 mg/mL/min
Dose Level -2
50 mg/m2/day
38 mg/m2
AUC 3 mg/mL/min
Dose Level -3
Discontinue
Discontinue
Discontinue
Abbreviation: AUC=area under the curve
Table 8
Recommended Chemotherapy Dose Modifications for Hematologic Toxicity
Intervention-related Toxicitya
Etoposide
Cisplatin
Carboplatin
Dose Level (DL) from Table 7
Neutrophils (ANC) <500/mm3 without fever
DL -1
DL -1
DL -1
Febrile neutropenia (fever ≥38.5°C and ANC <1,000/mm3)
DL -1
DL -1
DL -1
Platelets <50,000/mm3 without significant bleeding or requiring 
packed platelet transfusion
DL -1
DL -1
DL -1
Platelets <50,000/mm3 with Grade ≥2 hemorrhage or requiring 
packed platelet transfusion
DL -2
DL -2
DL -2
Grade 4 anemia
DL -1
DL -1
DL -1
Abbreviations: ANC=absolute neutrophil count, DL=dose level
Note: For grading, see CTCAE v5.0.
Note: If toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the dose of one 
of the chemotherapy agents. Investigators may decide to use supportive measures/treatment and/or secondary 
prophylaxis as per institutional standards (eg, filgrastim, pegfilgrastim, transfusions) instead of dose reductions for the 
next cycle, if considered in the best interest of the participant.
a
Should the hematologic toxicity recur, the dose of the agent could be reduced further. However, not more than 2 dose 
reductions per chemotherapy agent are permitted.
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Table 9
Recommended Chemotherapy Dose Modifications for Nonhematologic 
Toxicity
Intervention-related 
Toxicitya
CTCAE Grade
Etoposide
Cisplatin
Carboplatin
Dose Level (DL) from Table 7
Nausea/vomiting
Grade ≥3b
DL 0
DL -1
DL -1
Mucositis
Grade ≥3b
DL -1
DL -1
DL -1
Diarrhea
Grade ≥3b
DL -1
DL -1
DL -1
Peripheral neuropathy
Grade 2
No modification
DL -1c
No modification
Grade 3
No modification
Discontinued
DL -1
Grade 4
No modification
Discontinue
Discontinue
Total bilirubin
Grade 2
DL -2
No modification
No modification
Grade 3
Discontinue
No modification
No modification
Grade 4
Discontinue
No modification
No modification
AST or ALT Elevation
Grade 3
DL -1
DL -1
DL -1
Grade 4
Discontinue
Discontinue
Discontinue
Other nonhematologic 
toxicity (except fatigue and 
transient arthralgia and 
myalgia)
Grade ≥3
DL -1
DL -1
DL -1
ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE= Common Terminology Criteria for Adverse 
Events; DL=dose level 
Note: If considered in the best interest of the participant, and consistent with local practice, investigators may decide to
use supportive measures/treatment, and/or secondary prophylaxis instead of dose reductions for the next cycle. Also, if 
toxicity can clearly be attributed to one of the drugs, the investigator may choose to only reduce the dose of one of the 
chemotherapy agents.
a
Should the toxicity recur, the dose of the agent could be reduced further. However, not more than 2 dose reductions per 
chemotherapy agent are permitted.
b
This applies to toxicity of Grade 3 and lasting 72 hours or beyond despite aggressive supportive management, or 
toxicity of Grade 4.
c
If Grade 2 neurotoxicity recurs after DL -1, drug will be given at DL -2 or switch can be made to the appropriate dose 
of carboplatin at the discretion of the investigator in consultation with the Sponsor. If Grade 2 neurotoxicity persists 
after 2 dose level reductions and 21-day hold, switch can be made to the appropriate dose of carboplatin at the 
discretion of the investigator in consultation with the Sponsor.
d
If Grade 3 neurotoxicity occurs, cisplatin will be discontinued and, upon improvement, a switch can be made to the 
appropriate dose of carboplatin at the discretion of the investigator in consultation with the Sponsor.
Creatinine clearance:
Creatinine clearance (CrCl) will be based on either the Cockcroft-Gault formula or another 
acceptable standard formula.
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For participants receiving cisplatin, the scheduled dose of cisplatin may only be administered 
if the calculated CrCl is ≥50 mL/min:
•
If CrCl falls to <50 mL/min, delay the start of that cycle for ≤21 days. In the interim, 
monitor renal function weekly and consider IV hydration. When CrCl improves to 
≥50 mL/min, decrease cisplatin to DL -1. Alternatively, if in the investigator’s judgment 
it is in the best interest of the participant, cisplatin can be switched to carboplatin if the 
calculated CrCl is appropriate, and in consultation with the Sponsor.
•
At the second occurrence of CrCl <50 mL/min, decrease cisplatin to DL -2 upon 
improvement of CrCl to ≥50 mL/min. Alternatively, if in the investigator’s judgment it is 
in the best interest of the participant, cisplatin can be switched to carboplatin if the 
calculated CrCl is appropriate, and in consultation with the Sponsor.
•
At the third occurrence of CrCl <50 mL/min, cisplatin should be discontinued. If in the 
investigator’s judgment it is in the best interest of the participant, cisplatin can be 
switched to carboplatin if the calculated CrCl is appropriate, at the discretion of the 
investigator and in consultation with the Sponsor.
For participants receiving carboplatin, the scheduled of carboplatin may only be administered 
if the calculated CrCl is ≥40 mL/min:
•
If CrCl falls to <40 mL/min, delay the start of that cycle for ≤21 days. In the interim, 
monitor renal function weekly and consider IV hydration. When CrCl improves to 
≥40 mL/min, decrease carboplatin to DL -1.
•
At the second occurrence of CrCl <40 mL/min, decrease carboplatin to DL -2 upon 
improvement of CrCl to ≥40 mL/min.
•
At the third occurrence of CrCl <40 mL/min, carboplatin should be discontinued.
For participants receiving etoposide, the full dose of etoposide may only be administered if 
the calculated CrCl is ≥50 mL/min. If CrCl falls between 15 mL/min and <50 mL/min, then 
participants should receive only 75% of the recommended dose.
6.6.2.1
Dose Modifications for Overlapping Toxicities
Participants may have chemotherapy discontinued and continue on blinded study 
intervention. Similarly, participants may discontinue blinded study intervention and continue 
on chemotherapy alone during the first 4 cycles, if appropriate.
Reduction of 1 chemotherapy agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced, interrupted, or discontinued according to recommended dose 
modifications. Chemotherapy may be interrupted for a maximum of 6 weeks from the last 
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dose if due to an AE. If the toxicity is related to the combination of etoposide/platinum 
chemotherapy and blinded study intervention, all 3 agents should be reduced (if applicable), 
interrupted, or discontinued according to the recommended dose modifications.
6.6.2.2
Other Allowed Dose Interruptions With Chemotherapeutic Agents
These serve as a guide and do not replace investigator judgment and applicable local label 
recommendations, if more stringent. During Cycles 1 through 4 of blinded study intervention 
and etoposide/platinum:
•
If etoposide dosing is delayed or interrupted, the platinum agent and the blinded study 
intervention should also be delayed/interrupted. If etoposide/platinum is delayed or 
interrupted during Cycles 1 through 4, participants should be seen weekly until toxicity 
resolves.
•
If cisplatin/carboplatin dosing is delayed or interrupted, etoposide, and blinded study 
intervention should also be delayed/interrupted. If etoposide/platinum is delayed or 
interrupted during Cycles 1 through 4, participants should be seen weekly until toxicity 
resolves.
•
If blinded study intervention is delayed or interrupted, etoposide/platinum therapy can 
continue as scheduled. Blinded study intervention administration should be attempted at 
the next cycle of therapy.
•
Each chemotherapy cycle may not be delayed by more than 3 weeks (>21 consecutive 
days) despite supportive treatment (ie, chemotherapy may be interrupted for a maximum 
of 6 weeks from last dose). If only one of the agents is thought to be causing the specified 
toxicity leading to a 21-day delay of administration of the next cycle, that 
chemotherapeutic agent can be stopped and treatment can continue with blinded study 
intervention, with or without the remaining chemotherapy drug.
•
Etoposide/platinum administration 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, 21 days, of the originally scheduled dose and within 42 days 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.
6.7
Intervention After the End of the Study
There is no study-specified intervention after 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. The emergency 
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unblinding call center should only be used in cases of emergency (see Section 8.1.10). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
At implementation of Amendment 05, the below changes apply. The changes listed below 
supersede any protocol content/instructions from previous amendments.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy) should be considered for discontinuation from the study. Those benefiting from 
atezolizumab, but unable to access it as SOC outside the study, may continue on study 
and receive treatment with atezolizumab until discontinuation criteria are met. The final 
required study visit will be the Safety Follow-up Visit.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow up for survival status. Participants currently in imaging follow-up 
or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. Standard safety reporting 
should, however, continue, as applicable.
•
Participants remaining on study at the time of Amendment 05 should continue to be 
monitored in the study through the AE reporting period (Section 8.4).
Existing protocol content is retained for historical reference.
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 before 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 8.11.3 unless the participant has 
withdrawn from the study Section 7.2.
Protocol Amendment 04 implementation: Per eDMC recommendation, there will be no 
collection of efficacy data, and the final visit in the study will be the safety follow-up visit. 
Participants who discontinue study intervention and have completed safety follow up will be 
considered to have completed the study.
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.
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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.
•
Radiographic disease progression outlined in Section 8.2.1.4 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond investigator assessed disease progression).
•
Any progression or recurrence of 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.
•
Interruption of platinum-based chemotherapy for more than 6 weeks from the last dose 
without Sponsor consultation.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Use of prohibited medications or vaccinations as described in Section 6.5.
•
The participant interrupts blinded study intervention administration for more than 12 
consecutive weeks from last dose for an AE/toxicity or for more than 6 weeks from last 
dose for administrative reasons without Sponsor consultation.
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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention. 
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
At implementation of Amendment 05, the below changes apply. The changes listed below 
supersede any protocol content/instructions from previous amendments.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy) should be considered for discontinuation from the study. Those benefiting from 
atezolizumab, but unable to access it as SOC outside the study, may continue on study 
and receive treatment with atezolizumab until discontinuation criteria are met. The final 
required study visit will be the Safety Follow-up Visit.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow up for survival status. Participants currently in imaging follow-up 
or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. Standard safety reporting 
should, however, continue, as applicable.
•
Participants remaining on study at the time of Amendment 05 should continue to be 
monitored in the study through the AE reporting period (Section 8.4).
Existing protocol content is retained for historical reference.
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
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•
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 not exceed the amount specified in the laboratory manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.2
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
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Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2.1
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.3
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.
8.1.4
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.5
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions, tobacco use, clinically important conditions 
diagnosed within 10 years, any prior cancer other than ES-SCLC even if diagnosed greater 
than 10 years before Screening, and family history of premature cardiovascular disease. For 
participants having received blood transfusion within 120 days before Screening, the reason 
for blood transfusion (eg, bleeding, myelosuppression) must be recorded in the medical 
history.
Details regarding ES-SCLC will be recorded separately and not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
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participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5.1
Tobacco Use Assessment
Definitions for cigarette use are as follows [Land, S. R., et al 2016]:
•
Current smokers: persons who report smoking ≥100 cigarettes during their lifetime and 
who, at the time of screening, reported smoking every day or some days within the last 
year
•
Former smokers: persons who report smoking ≥100 cigarettes during their lifetime and 
who, at the time of screening, had stopped smoking 1 year prior
•
Never-smokers: persons who report smoking <100 cigarettes during their lifetime
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before 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.
8.1.6.2
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. 
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused for 
different participants.
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 in Section 8.11.1.
8.1.8
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.
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A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
Study intervention(s) 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.
8.1.9.1
Timing of Dose Administration
8.1.9.1.1
MK-7684A Administration
MK-7684A will be administered Q3W starting C1D1 until any of the reasons for intervention 
discontinuation are met.
To maintain the blinding, participants randomized to Intervention Group A will receive 
60 minutes of saline placebo infusion during Cycle 1. After 30 minutes have passed from the 
beginning of the saline placebo infusion, the MK-7684A infusion, which will be 
administered over 30 minutes, will start (see Figure 2).
Protocol Amendment 04 implementation: All active participants in the experimental arm 
(Arm A: MK-7684A) stopped ongoing treatment with MK-7684A and were offered an 
option to move to the comparator arm (Arm B: atezolizumab monotherapy) for the remainder 
of the study.
Atezolizumab Administration
Protocol Amendment 04 implementation: For participants that have been moved from 
experimental arm (Arm A: MK-7684A) to the comparator arm (Arm B: atezolizumab 
monotherapy), the initial infusion of atezolizumab is to be administered over 60 minutes. If 
the first atezolizumab infusion is well tolerated, subsequent infusions can be administered 
over 30 minutes.
Atezolizumab will be administered Q3W starting C1D1 until any of the reasons for 
intervention discontinuation are met.
The initial infusion of atezolizumab is to be administered over 60 minutes. Subsequent 
infusions can be administered over 30 minutes.
To maintain the blinding, participants randomized to Intervention Group B will receive 
60 minutes of atezolizumab infusion during Cycle 1. After 30 minutes have passed from the 
beginning of the atezolizumab infusion, the saline placebo, which will be administered over 
30 minutes, will start (see Figure 2).
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Figure 2
Intervention Blinding Schema for Initial Infusion
Additional Information for Infusions
If the IO and placebo infusions were well tolerated during Cycle 1 with no infusion reactions, 
placebo will no longer be required and the infusion of either atezolizumab or MK-7684A will 
be given over 30 minutes during Cycle 2 and beyond. If a Grade 1 infusion reaction occurred 
during Cycle 1, the blinding procedure should remain the same as Cycle 1. If Grade 2 
infusion reaction occurred in Cycle 1 or in Cycle 2 and beyond and placebo was also needed, 
consultation with the Sponsor is needed to determine next step and unblinding can be 
considered only after Sponsor agreement and if deemed necessary for participant 
management. In case of Grade 3 or 4 infusion reaction, emergency unblinding is warranted.
8.1.9.1.2
Platinum/Etoposide Chemotherapy Administration
Cisplatin Administration
Cisplatin will be administered as an IV infusion on Day 1 for up to 4 cycles (Cycles 1-4). An 
infusion time of 60 minutes is recommended, but cisplatin may be administered over 
30 to180 minutes based on local standards of care. Cisplatin will be administered 
approximately 30 minutes after the completion of MK-7684A or atezolizumab infusions. 
Additional premedications and hydration should be administered as per standard practice.
BSA will be obtained using the Dubois and Dubois formula. The BSA calculated on Cycle 1, 
Day 1 can be used through the 4 chemotherapy cycles, unless there is a change in 
weight ≥10%.
Carboplatin Administration
Carboplatin will be administered as an IV infusion over approximately 60 minutes on Day 1 
for up to 4 cycles (Cycles 1-4). Carboplatin will be administered approximately 30 minutes 
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after the completion of MK-7684A or atezolizumab infusions. Additional premedications 
should be administered as per standard practice.
Carboplatin will be calculated using the Calvert formula to achieve an area under the plasma 
drug concentration time curve of 5 mg/mL/min. The dose should not exceed 750 mg.
•
Total dose (mg) = (target AUC) x (CrCl + 25)
•
The estimated CrCl in the Calvert formula should not exceed 125 mL/min
•
Maximum carboplatin dose (mg) = target AUC 5 x (125 + 25)
= 5 x 150
= 750 mg
CrCl must be calculated using the Cockcroft-Gault formula:
•
Men: [(140 – age (y)) x weight (kg)]/[72 x serum creatinine (mg/dL)]
•
Women: [(140 – age (y)) x weight (kg)] x 0.85/[72 x serum creatinine (mg/dL)]
Dose may be rounded to the nearest 50 mg at the discretion of the investigator and according 
to institutional standards.
Unless there is a change in weight ≥10%, the same dose of carboplatin can be used 
throughout the 4 cycles (provided there are no additional toxicities).
Etoposide Administration
Etoposide will be administered as an IV infusion on Days 1, 2, and 3 up to 4 cycles 
(Cycles 1-4). Days 1, 2, and 3 must be consecutive days without interruption. An infusion 
time of 30 to 60 minutes is recommended, but etoposide may be administered of 
30 to120 minutes to accommodate local standards of care. Etoposide will be administered 
approximately 30 minutes after completion of platinum (cisplatin or carboplatin) infusions.
Additional premedications should be administered as per standard practice.
BSA will be obtained using the Dubois and Dubois formula. The BSA calculated on Cycle 1, 
Day 1 can be used through the 4 chemotherapy cycles, unless there is a change in 
weight ≥10%.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
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present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
Protocol Amendment 04 implementation: Per eDMC recommendation, there will be no 
collection of efficacy data, and the safety follow-up visit will be the final visit in this study.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the 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 
FBR 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the 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.
8.1.11
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 
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 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 must be discontinued from study 
intervention, but should continue to be monitored in the study. In the event of unblinding due 
to a Grade 2 infusion reaction to the immunotherapy/placebo agent when placebo was also 
required, Sponsor consultation is required to continue on study intervention.
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.
Protocol Amendment 04 implementation: Study has been unblinded as per the 
recommendation by the eDMC and discontinue the experimental arm (MK-7684A).
8.1.12
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.
8.1.13
Tumor Tissue for Biomarker Status
A pretreatment tumor sample must be submitted before or within 4 weeks after 
randomization, if such sample exists, and is to be:
•
A newly obtained core, incisional, or excisional biopsy of a tumor lesion, which was not 
previously irradiated
Or
•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
If a tumor tissue sample is not available, a cytology sample is allowed.
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
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Details pertaining to tumor tissue or cytology sample submission can be found in the 
Laboratory Manual.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. The same scan technique should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new 
tumor burden and improve the accuracy of the response assessment based on scans.
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility. 
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain x-rays acquired for 
correlation, should also be submitted to the iCRO.
Other imaging modalities that may be collected, submitted to the iCRO, and included in the 
response assessment include, but are not limited to, PET-CT, X-ray, etc. Other types of 
medical imaging (such as ultrasound) should not be submitted to the iCRO and will not be 
included in response assessment.
At screening, participant eligibility will require radiographic documentation of at least one 
lesion that meets the requirements for selection as a target lesion, as defined by RECIST 1.1 
as assessed by the investigator/site.
All scheduled scans for participants will be submitted to the iCRO. In addition, a scan that is 
obtained at an unscheduled time point, for any reason (including suspicion of progression or 
other clinical reason), should also be submitted to the iCRO if it shows disease progression, 
or if it is used to support a response assessment. All scans acquired within the protocol-
specified window of time around a scheduled scan visit are to be classified as pertaining to 
that visit.
When the investigator identifies disease progression, the iCRO will verify this progression 
and e-mail the results to the study site and Sponsor (see Section 8.2.1.4 and Figure 3). In 
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clinically stable participants, scans are to continue until disease progression has been verified 
by BICR. If investigator-assessed progression was not verified by BICR, each subsequent 
scan must be submitted to the iCRO. Once progression is verified by BICR, subsequent scans 
(if acquired) should not be submitted to the iCRO. 
Protocol Amendment 04 implementation: Participants currently on study treatment will have 
tumor imaging assessed locally based on site’s standard of care imaging schedule. 
Participants currently in efficacy follow-up are considered to have completed the study and 
therefore should obtain imaging as per local standard of care. BICR verification of 
progression is no longer applicable.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review screening scans to confirm the participant has measurable 
disease per RECIST 1.1.
All participants are required to have brain scans during Screening. The specific methods 
permitted for this study are described in the SIM.
All participants are required to have bone scans at Screening to assess for bone lesions. Bone 
scan refers to imaging methods used to assess bone metastasis(ses). The specific methods 
permitted for this study are described in the SIM.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 6 weeks (42 days ±7 days) from the date of 
randomization. Subsequent tumor scans should be performed every 6 weeks (42 days 
±7 days) or more frequently if clinically indicated. After 48 weeks (336 days ±7 days), 
participants who remain on treatment will have scans performed every 9 weeks (63 days 
±7 days). Scan timing should follow calendar days and should not be adjusted for delays in 
cycle starts. 
Scans are to be performed until disease progression is identified by the investigator and 
verified by BICR, or notification by the Sponsor, or until any of these conditions are met:
•
the start of new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
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Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 
4 weeks later; scans may resume at the subsequent scheduled time point.
Refer to the SoA (Section 1.3) for on-study brain and bone scan requirements.
Protocol Amendment 04 implementation: Participants currently on study treatment will have 
tumor imaging assessed locally based on site’s standard of care imaging schedule. 
Participants currently in efficacy follow-up are considered to have completed the study and 
therefore should obtain imaging as per local standard of care. BICR verification of 
progression is no longer applicable.
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 verified by BICR
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
Protocol Amendment 04 implementation: Participants currently on study treatment will have 
tumor imaging assessed locally based on site’s standard of care imaging schedule. 
Participants currently in efficacy follow-up are considered to have completed the study and 
therefore should obtain imaging as per local standard of care. BICR verification of 
progression is no longer applicable
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8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Upon investigator-assessed disease progression, the indicative scan is to be submitted 
immediately to iCRO for BICR verification of progression. After submission of scan(s), the 
iCRO will e-mail the assessment to the site and Sponsor.
Protocol Amendment 04 implementation: Participants currently on study treatment will have 
tumor imaging assessed locally based on site’s standard of care imaging schedule. No need to 
submit scans to iCRO, and VOP request and central review of imaging will no longer be 
applicable.
If disease progression is not verified, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
- Resume imaging per protocol schedule (≥4 weeks to next scan)
-
- Send scans to iCRO
-
- Continue local assessment
-
- Do not change investigator assessment of progression
-
- 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
•
Obtain scans locally per original protocol schedule
•
Do not send scans to iCRO
Figure 3 illustrates the study intervention decision process involving verification of disease 
progression for participants.
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•
For 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 3
Study Intervention Decision-Making Process
8.2.2
Patient-reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-LC13, and EuroQol EQ-5D-5L questionnaires will be 
administered by trained site personnel and completed electronically by participants. The 
questionnaire should be administered as described in Section 1.3.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
Protocol Amendment 04 implementation: Patient-reported Outcomes Assessments will no 
longer be collected for any participants.
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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 the Laboratory 
Manual.
Planned time points for all safety assessments are provided in the SoA.
Protocol Amendment 04 implementation: Safety assessments and safety related data 
collection including laboratory assessments should be followed per SoA for participants who 
continue study therapy.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee (consistent with local requirements) will perform a 
complete physical examination. During Screening, clinically significant abnormal findings 
should be recorded as medical history. The time points for full physical exams are described 
in Section 1.3; height and weight will also be measured and recorded as indicated. 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/symptoms 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 (consistent with local requirements) will perform a directed 
physical examination per institutional standard before study intervention administration. New 
clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs/symptoms related to previous 
serious illnesses.
8.3.2
Vital Signs
Vital signs (ie, systolic and diastolic BP [mm Hg], temperature [in centigrade], heart rate 
[beats per minute], RR [breaths per minute], and pulse oximetry [oxygen saturation 
percentage]) will be assessed at the visits designated in the SoA (Section 1.3) by a validated 
method.
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8.3.3
Audiometry
Participants receiving cisplatin should be monitored for audiological complications. 
Audiometry testing will be performed at Screening and at Safety Follow-up or per local 
standard, by the investigator or medically qualified designee (consistent with local 
requirements). Assessments may be repeated as clinically indicated. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
8.3.4
Electrocardiograms
ECG will be obtained as designated in the SoA (Section 1.3). Complete, standardized, 
12-lead ECG recordings that permit all 12 leads to be displayed on a single page with an 
accompanying lead II rhythm strip below the customary 3 × 4 lead format are to be used. In 
addition to a rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously. Participants must be in the recumbent position for a period of 5 minutes 
before the ECG. The Fridericia correction method for calculating QTc will be used.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Appendix 3) and the CRF Completion Guidelines. In these instances, the AE corresponding 
to the ECG abnormality will be recorded in the appropriate CRF.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
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.
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8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
CBC with differential and clinical chemistry results must be reviewed before administration 
of study intervention. Electrolytes such as potassium, calcium, and magnesium should be 
monitored and abnormalities, when considered clinically significant, should be corrected in 
all participants before starting study intervention.
Laboratory procedures can be conducted up to 72 hours before dosing.
Please refer to Appendix 7 for country-specific requirements.
8.3.6
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum) should be conducted at every protocol treatment 
cycle as per SoA.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
each study intervention(s) as noted in Section 5.1. The length of time required to 
continue pregnancy testing for each study intervention is as follows:
◦
Etoposide, cisplatin, or carboplatin: 180 days
◦
Blinded study intervention (MK-7684A or atezolizumab): 5 months
-
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.
8.3.7
Performance Assessments
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with grades 0 to 5.
The investigator or qualified designee will assess ECOG PS as specified in the SoA 
(Section 1.3). ECOG PS should be completed prior to dose administration.
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.
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Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event causes 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 after cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 
90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.6, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
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•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 10.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
Table 10
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
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
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through Protocol-
specified Follow-
up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
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.
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.
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. SAEs and other reportable safety events, including 
pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
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8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
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), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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.
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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 laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2X 
the ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-7684A by 3 times (ie, 300%). No specific information is available on the 
treatment of overdose of MK-7684A. In the event of overdose, MK-7684A should be 
discontinued and the participant should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
To further evaluate immunogenicity and exposure in this indication, and also to evaluate 
exposure of the proposed dosing regimen, sample collections for analysis of ADA and PK 
are currently planned for investigational agents as shown in the SoA (Section 1.3). Blood 
samples will be obtained to measure PK of investigational agents in the serum. If ongoing 
ADA and/or PK results continue to be consistent with existing ADA and/or PK data from 
other clinical studies with these investigational agents, it may be decided to discontinue or 
reduce further sample collection in this study. 
Based on PK data obtained in this study as well as PK data obtained from other studies, a 
population PK analysis may be performed to characterize PK parameters (CL, V) and 
evaluate the effect of extrinsic and intrinsic factors to support proposed dosing regimen. PK 
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data may also be used to explore the E-R relationships for antitumor activity/efficacy as well 
as safety in the proposed patient population, if feasible. The results of these analyses, if 
performed, will be reported separately.
Protocol Amendment 04 implementation: PK and ADA sampling will no longer be collected 
for any participants.
8.6.1
Blood Collection for PK
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. PK samples should be drawn according to the PK collection schedule 
in the SoA (Section 1.3).
8.6.2
Blood Collection for Anti-drug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. Anti-drug antibody samples should be drawn according to the ADA
collection schedule in the SoA (Section 1.3). 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 as specified in the SoA:
•
Blood for genetic analysis
•
Blood for ctDNA analysis
•
Tumor tissue
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the Laboratory Manual. Please refer to Appendix 7 for country-specific 
requirements.
Protocol Amendment 04 implementation: Biomarker samples will no longer be collected for 
any participants.
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 
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not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be in the 
Operations/Laboratory Manual.
Please refer to Appendix 7 for country-specific requirements.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover samples listed in Section 8.8, Biomarkers (including any extracted material from 
samples)
8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment 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.
Medical resource utilization and health economics associated with medical encounters will 
be collected in the eCRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
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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
Treatment Period/Vaccination Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Participants who discontinue study intervention will continue to be monitored for Efficacy 
and Survival Follow-up as described in Section 8.11.4.
Protocol Amendment 04 implementation: The final visit in the study will be the safety 
follow-up visit. No further monitoring for efficacy and survival follow-up is required.
8.11.4
Posttreatment Visit
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Protocol Amendment 04 implementation: Safety follow-up visit will be the final visit in the
study.
8.11.4.2
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 Efficacy 
Follow-up and should be assessed per the protocol-defined schedule (SoA, Section 1.3) to 
monitor disease status. Every effort should be made to collect information regarding disease 
status until the start of new anticancer therapy, disease progression, withdrawal of consent, 
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 Survival Follow-up.
Protocol Amendment 04 implementation: Efficacy follow-up visits are not required. 
Participants currently on study treatment will have the safety follow-up visit as the final visit. 
Participants currently in efficacy follow-up are considered to have completed the study and 
should obtain imaging and further oncological care as per local standard of care.
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8.11.4.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for vital 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:
1.
For participants who discontinue treatment intervention and who will not enter 
Efficacy Follow-up, the first Survival Follow-up contact will be scheduled 12 weeks 
after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
2.
For participants who completed assessments in Efficacy Follow-up, the first Survival 
Follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
Protocol Amendment 04 implementation: Survival follow-up contacts are not required. 
Participants currently on study treatment will have the safety follow-up visit as the final visit. 
Participants currently in survival follow-up are considered to have completed the study.
8.11.5
Vital Status
Protocol Amendment 04 implementation : There will be no collection of vital status for 
participants. Participants currently on study treatment will have the safety follow-up visit as 
the final visit.
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status. 
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9
STATISTICAL ANALYSIS PLAN
At implementation of Amendment 05, the below changes apply. The changes listed below 
supersede any protocol content/instructions from previous amendments.
•
Participants with access to approved SOC (eg, immunotherapy, chemotherapy, targeted 
therapy) should be considered for discontinuation from the study. Those benefiting from 
atezolizumab, but unable to access it as SOC outside the study, may continue on study 
and receive treatment with atezolizumab until discontinuation criteria are met. The final 
required study visit will be the Safety Follow-up Visit.
•
Participants who complete study treatment or otherwise meet EOT criteria will be 
discontinued from the study after the EOT visit and any required safety follow-up visit.
•
There will be no follow up for survival status. Participants currently in imaging follow-up 
or survival follow-up are considered to have completed the study and therefore should 
obtain imaging and further oncological care as per local SOC. Standard safety reporting 
should, however, continue, as applicable.
•
Participants remaining on study at the time of Amendment 05 should continue to be 
monitored in the study through the AE reporting period (Section 8.4).
Existing protocol content is retained for historical reference.
Protocol Amendment 04 implementation: based on recommendations of the eDMC following 
the interim efficacy/safety analysis (data cutoff 04-JUN-2024) which showed that the 
primary endpoint of overall survival met the pre-specified futility criteria, the study was  
unblinded, the experimental arm (Arm A: MK-7684A) will be discontinued and all ongoing 
participants on MK-7684A treatment will be offered the option to move to the comparator 
arm (Arm B: atezolizumab monotherapy) for the remainder of the study. The prespecified 
final analysis of the study described in the SAP will not be performed. Safety analysis will be 
performed at the end of the study. There will be no further analyses for efficacy and ePRO 
endpoints collected from participants after IA cutoff date.
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 E9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to the conduct of any analysis, will be documented in a sSAP and referenced in the 
CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other 
planned analyses (ie, those specific to the analysis of ePROs) will be documented in an 
sSAP.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Section 9.2 through Section 9.12.
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Protocol Amendment 04 implementation: the prespecified final analysis of the study 
described in the SAP will not be performed. Information regarding planned final analysis in 
Section 9 is being retained for historical purposes. Safety analysis will be performed at the 
end of the study. There will be no further analyses of efficacy and ePRO endpoints collected 
from participants after IA cutoff date.
Study Design Overview
This is a Phase 3, randomized, double-blind, active-controlled, 
multisite study of MK-7684A combined with etoposide/platinum 
chemotherapy followed by MK-7684A compared to atezolizumab 
combined with etoposide/platinum chemotherapy followed by 
atezolizumab in the first-line treatment of ES-SCLC.
Treatment Assignment
Approximately 450 participants will be randomized in a 1:1 ratio 
between 2 treatment groups: (1) the MK-7684A in combination with 
etoposide/platinum arm and (2) the atezolizumab in combination 
with etoposide/platinum arm. Stratification factors are:
•
ECOG performance status at Baseline (0 vs. 1)
•
LDH at Baseline (≤ ULN vs > ULN)
•
Liver metastases at Screening: Yes or No
•
Brain metastases at Screening: Yes or No
This is a randomized double-blind study.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
PRO: Full Analysis Set (FAS) 
Primary 
Endpoints/Hypotheses
Overall survival (OS)
Secondary 
Endpoints/Hypotheses
•
PFS per RECIST 1.1 by BICR
•
ORR per RECIST 1.1 assessed by BICR
•
DOR per RECIST 1.1 assessed by BICR
•
Safety and tolerability
•
ePROs 
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Statistical Methods for 
Key Efficacy Analyses
The primary and secondary hypothesis will be evaluated by 
comparing MK-7684A in combination with etoposide/platinum to 
atezolizumab in combination with etoposide/platinum on OS and 
PFS using stratified log-rank tests. Estimation of the hazard ratio 
(HR) will be performed 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 Tier 1 events in this study. Tier 2 parameters will be assessed via 
point estimates with 95% confidence intervals provided for 
between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters. The 95% confidence 
intervals for the between-treatment differences in percentages will be 
provided using the Miettinen and Nurminen method.
Interim Analyses
Multiplicity
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Sample Size and Power
The planned sample size is approximately 450 participants. 
 
 
 
 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment for this protocol, and the randomization will be implemented 
in an interactive voice response system.
Protocol Amendment 04 implementation: following eDMC review of data at IA, the study 
was unblinded.
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
•
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause.
Secondary
•
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.
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•
Objective Response Rate (ORR)
The ORR is defined as the percentage of participants who achieve a confirmed complete 
response (CR) or partial response (PR) per RECIST 1.1 as assessed by BICR.
•
Duration of Response (DOR)
For participants with 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
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, laboratory values, and vital signs.
9.4.3
Patient-reported Outcome Endpoints
The following secondary PRO endpoints will be evaluated as described in Section 4.2.2.3 
and analyzed as described in Section 9.6.3:
•
Change from baseline in Global Health Status/QoL scale (EORTC QLQ-C30 Items 29 
and 30)
•
Physical functioning scale (EORTC QLQ-C30 Items 1 through 5)
•
Single-item symptom scales: cough (EORTC QLQ-LC13 Item 31), chest pain (EORTC 
QLQ-LC13 Item 40), and dyspnea (EORTC QLQ-C30 Item 8)
Time-to-true deterioration (TTD) in
•
Global Health Status/QoL scale (QLQ-C30 items 29-30)
•
Single-item symptom scales: cough (QLQ-LC13 item 31), chest pain (QLQ-LC13 item 
40), and dyspnea (QLQ-C30 item 8)
•
Physical functioning scale (QLQ-C30 items 1-5)
Based on prior literature [Osoba, D., et al 1998] [King, M. T. 1996], a 10-point or greater 
worsening from baseline for each scale represents a clinically relevant deterioration. TTD is 
defined as the time to first onset of 10 or more (out of 100) deterioration from baseline in a 
given scale/subscale/item and confirmed by a second adjacent 10 or more deterioration from 
baseline. 
 
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of efficacy endpoints are based on the intention-to-treat (ITT) population. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment group to which they are randomized. 
9.5.2
Safety Analysis Populations
Safety Analyses will be conducted in the All Participants as Treated (APaT) population, 
which consists of all randomized participants who received at least 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
This will be the treatment group to which they are randomized except for participants who 
take incorrect study intervention for the entire treatment period; such participants will be 
included in the treatment group corresponding to the study intervention actually received. 
Any participant who receives the incorrect study intervention for 1 cycle, but receives the 
correct treatment for all other cycles, will be analyzed according to the correct treatment 
group and a narrative will be provided for any events that occur during the cycle for which 
the participant is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Populations
The PRO analyses are based on the PRO Full Analysis Set (PRO FAS) Population, defined 
as all randomized participants who have at least one PRO assessment available for the 
specific endpoint and have received at least one dose of the study intervention. Participants 
will be analyzed in the treatment group to which they are randomized.
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 sSAP.
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]. If 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 pre-specified in the sSAP, prior to the database lock for the first analysis 
when each applicable endpoint will be analyzed, and decisions regarding the pooling will be 
based on a blinded review of response and event counts by stratum.
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9.6.1.1
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
hypotheses of treatment difference in survival will be tested by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron’s method of tie handling will be used to 
estimate the magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from 
the stratified Cox model with a single covariate for treatment will be reported. The 
stratification factors used for randomization will be applied to both the stratified log-rank test 
and the stratified Cox model. Participants without documented death at the time of analysis 
will be censored at the date the participant was last known to be alive.
9.6.1.2
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, 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, progressive disease (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.
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Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS
9.6.1.3
Objective Response Rate (ORR)
The stratified Miettinen and Nurminen’s method will be used for the comparison of ORR 
between 2 treatment groups. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen’s 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. Additional supportive unstratified analyses may also be provided. A sensitivity 
analysis will be performed for the comparison of ORR based on investigator's assessment.
The point estimate of ORR will be provided by treatment group, together with 95% CI using 
exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, 
E. S. 1934].
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 CR or PR will be 
included in this analysis. Censoring rules for DOR are summarized in Table 12.
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For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided.
 
 
Table 12
Censoring Rules for DOR
9.6.1.5
Analysis Strategy for Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 13.
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Table 13
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
OS
Testing: stratified log-rank test 
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
Censored at the date 
participant last known to 
be alive
Key Secondary Analyses
PFS per RECIST 1.1 by 
BICR
Testing: stratified log-rank test
Estimation: Stratified Cox model 
with Efron’s tie handling method
ITT
•
 censoring 
rule
•
 
•
 
 
.
Abbreviations: BICR=blinded independent central review; ITT=intent-to-treat; 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, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 14). The tiers differ with 
respect to the analyses that will be performed. Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p values and 95% confidence 
intervals provided for between-group comparisons. Other safety parameters will be 
considered Tier 2 or Tier 3 based on the observed proportions of participants with an event. 
Tier 2 parameters will be assessed via point estimates with 95% confidence intervals 
provided for between-group comparisons; only point estimates by treatment group are 
provided for Tier 3 safety parameters.
Tier 1 Events
Safety parameters or adverse events of special interest (AEOSI) that are identified a priori 
constitute “Tier 1” safety endpoints that will be subject to inferential testing for statistical 
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significance. AEOSI that are immune-mediated or potentially immune-mediated are well 
documented and will be evaluated separately; however, these events have been characterized 
consistently throughout the pembrolizumab clinical development program and determination 
of statistical significance is not expected to add value to the safety evaluation. Finally, the 
addition of MK-7684A to etoposide/platinum treatments included in the study is not 
anticipated to be associated with any new safety signals. Therefore, there are no Tier 1 events 
expected in this study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen (M&N) 
method [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
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 (≥1% 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. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE that is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
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Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3-5 AE (incidence ≥5% of participants in one 
of the treatment groups)
X
X
Serious AE (incidence ≥1% of participants in one of 
the treatment groups)
X
X
AEs (incidence ≥10% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3-5 AE
X
Any Serious AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <10% of participants 
in all of the treatment groups)
X
Change from Baseline Results (lab toxicity shift, vital 
signs)
X
Abbreviations: AE=adverse event; CI=confidence interval; SOC=system organ class.
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses
This section describes the planned analyses for the PRO endpoints.
Mean Change from Baseline
The time point for the mean change from baseline will be determined based on blinded data 
review prior to the database lock for any PRO analysis and documented in the sSAP. 
To assess the treatment effects on the PRO score change from baseline in the Global Health 
Status/QoL scale (EORTC QLQ-C30 Items 29 and 30), Physical functioning scale 
(EORTC QLQ-C30 Items 1 through 5), cough (EORTC QLQ-LC13 Item 31), chest pain 
(EORTC QLQ-LC13 Item 40), dyspnea (EORTC QLQ-C30 Item 8) and EQ-5D-5L visual 
analog scale, a constrained longitudinal data analysis (cLDA) model proposed by Liang and 
Zeger [Liang, K-Y. and Zeger, S. L. 2000] will be applied, with the PRO score as the 
response variable, and treatment, time, treatment by time interaction, and stratification 
factors used for randomization (See Section 6.3.2) as covariates. The treatment difference in 
terms of least square (LS) mean change from baseline will be estimated from this model 
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together with 95% CI. Model-based LS mean with 95% CI will be provided by treatment 
group for PRO scores at baseline and post-baseline time point.
Time-to-True Deterioration (TTD)
For the TTD endpoint defined in Section 9.4.3, the Kaplan-Meier method will be used to 
estimate the TTD curve for each treatment group. The estimate of median time to 
deterioration and its 95% confidence interval will be obtained from the Kaplan-Meier 
estimates. The treatment difference in TTD will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron's method of tie handling and with a 
single treatment covariate will be used to assess the magnitude of the treatment difference 
(ie, HR). The HR and its 95% CI will be reported. The same stratification factors used for 
randomization (See Section 6.3.2) will be used as the stratification factors in both the 
stratified log-rank test and the stratified Cox model.
The approach for the TTD analysis will be based on the assumption of non-informative 
censoring. The participants who do not have deterioration on the last date of evaluation or do 
not have a second PRO assessment to confirm deterioration will be censored. Table 15
provides censoring rule for TTD analysis.
Table 15
Censoring Rules for Time-to-True Deterioration
Scenario
Outcome
Deterioration documented
Event observed at time of assessment (first 
deterioration)
Ongoing or discontinued from study without 
confirmed deterioration
Right censored at time of last assessment
No baseline assessments
Right censored at treatment start date
9.6.4
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed 
using tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age), baseline 
characteristics, and prior and concomitant therapies will be summarized by treatment either 
by descriptive statistics or categorical tables.
9.7
Interim Analyses
Protocol Amendment 04 implementation: the prespecified final analysis of the study 
described in the SAP will not be performed. Safety analysis will be performed at the end of 
the study. The subsections below are retained for reference.
The eDMC will serve as the primary reviewer of the results of the IA (analyses) and will 
make recommendations for discontinuation of the study or modification to the executive 
oversight committee of the Sponsor. If the eDMC recommends modifications to the design of 
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the protocol or discontinuation of the study, this executive oversight committee and 
potentially other limited Sponsor personnel may be unblinded to the treatment level in order 
to act on these recommendations. The extent to which individuals are unblinded with respect 
to results of interim analyses will be documented by the unblinded study team. Additional 
logistic details will be provided in the eDMC Charter.  
Treatment-level results of the IA will be provided by the unblinded statistician to the eDMC. 
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 after the interim analyses.
9.7.1
Efficacy Interim Analyses
 
 
 
 
Table 16
Summary of Interim and Final Analyses Strategy
9.7.2
Safety Interim Analyses
 
 
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9.8
Multiplicity
The study strictly controls type I error at 0.025 1-sided
 
 
Figure 4
Multiplicity Diagram for Type I Error Control
9.8.1
Overall Survival
 
 
 
 
 
CCI
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Table 17
Efficacy Boundaries and Properties for OS Analyses
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9.8.2
Progression-free Survival
 
 
 
 
 
Table 18
Efficacy Boundaries and Properties for PFS Analysis
9.8.3
Safety Analyses
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. eDMC review of 
efficacy data to assess the overall risk/benefit to study participants will not require a 
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multiplicity adjustment typically associated with a planned efficacy IA.
 
 
9.9
Sample Size and Power Calculations
The study will randomize approximately 450 subjects in a 1:1 ratio into the experimental arm 
of MK-7684A in combination with etoposide/platinum and the control arm of atezolizumab 
in combination with etoposide/platinum. OS is primary endpoint for the study, with PFS as 
the secondary endpoint.
CCI
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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 OS, PFS and ORR (with a nominal 95% CI) will be 
estimated and plotted within each category 
 
 
 
 The subgroup analyses for PFS and OS will be conducted using 
an unstratified Cox model, and the subgroup analyses for ORR will be conducted using the 
unstratified M&N method.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles in which the 
participant receives the study medication infusion (see Section 8.6). Summary statistics will 
be provided on the extent of exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional 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), Regulation (EU) 536/2014, 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 
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parties. All trial protocols are and will be assessed for the need and capability to 
enroll underrepresented groups. Participants must meet protocol entry criteria to 
be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
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 
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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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their 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.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
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 before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
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10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
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 [Interim 
Analyses]) and recommend to the EOC whether the study should continue in accordance 
with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
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Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 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 Regulation 536/2014, 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, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: 
(i) the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
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 
(eg, EU CTR: 25 years after the end of the study). No records may be destroyed during the 
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retention period without the written approval of the Sponsor. No records may be transferred 
to another location or party without written notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 19 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Results must be reviewed by the investigator or qualified designee and found to be 
acceptable before each dose of study intervention.
•
Laboratory safety tests will be performed within 72 hours of dosing.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 19
Protocol-required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indicesa:
MCV
MCH
% Reticulocytes
WBC count with 
Differentialb:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNc
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is above 
the ULN)
Albumin
Bicarbonatea
Chloride
Phosphorousa
Creatinined
Sodium
ALT/SGPT
Total Protein
Glucose (fasting or 
nonfasting)
Calcium
Alkaline 
phosphatase
Magnesium
LDH
Routine 
Urinalysise
•
Specific gravity
•
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
•
Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Thyroid Function 
Testsf
•
TSH, total or free T3, free T4
Pregnancy 
Testing
•
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP). A 
serum test is required if a urine test is positive or not evaluable.
Other Screening 
Tests
•
FSH (as needed in WONCBP only)
•
Serology (HIV antibody, HIV RNAg, HBsAg, anti-HBc, HCV antibody, and HCV 
RNAh). Only perform if required by local health authority or institutional 
regulation. Refer to Appendix 7 for country-specific information.
•
Coagulation parametersi (PT/INR and aPTT or PTT)
aPTT=activated partial thromboplastin time; ALT=alanine aminotransferase; anti-HBc=Total hepatitis B 
core antibody; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CrCl=creatinine clearance; 
FSH=follicle-stimulating hormone; GFR=glomerular filtration rate; hCG=human chorionic gonadotropin; 
HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=international normalized ratio; 
LDH=lactate dehydrogenase; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
PT=prothrombin time; PTT=partial prothrombin time; RBC=red blood cell; SGOT=serum glutamic 
oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; TSH=thyroid-stimulating hormone; 
ULN=upper limit of normal; WOCBP=women of childbearing potential; WONCBP=women of 
nonchildbearing potential
Notes:
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
GFR (measured or calculated) and CrCl can be used in place of creatinine.
e
Urine dipstick is the preferred method for testing urinary protein; however, urinalysis may be used if the 
use of urine dipsticks is not feasible.
f
Participants may be dosed in subsequent cycles after C1D1 while thyroid function tests are pending. If 
the local laboratory is unable to perform these tests, the site should submit the sample to the central 
laboratory for testing. Details are provided in the Laboratory Manual.
g
Only required if immunoassay tests are equivocal.
h
Only required to confirm active infection if immunoassay test is positive.
i
Performed as part of the Screening assessment and as clinical 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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not the cancer under study).
•
Is associated with an overdose.
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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 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
- Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
- Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
- Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
- Grade 4: Life threatening consequences; urgent intervention indicated.
- Grade 5: Death related to AE.
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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 IMP)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
-
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; (3) the 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.)
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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 
IRB/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 
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.
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•
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).
-
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).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b.
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited 
to those which inhibit ovulation.
c.
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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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 Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 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.
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3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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 Research3, 4
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 is 
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 that 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 Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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 Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the 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 study use only. If specimens were 
collected from study participants specifically for FBR, 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the 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 Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used 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 
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.
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8. Data Security3, 4
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 Participants3, 4
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 Population3, 4
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 Research3, 4
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
CCI
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10.7.3
France
Section 1.3 Schedule of Activities
Pregnancy testing must be performed at each cycle during treatment as well as at the end of 
study intervention.
HBV, HCV, and HIV testing at screening is mandatory.
Section 5.2 Exclusion Criteria
Exclusion Criterion: Participant has a known history of HIV infection. HIV testing is 
required for participants.
Exclusion Criterion: Participant has a known history of hepatitis B or hepatitis C infection. 
Hepatitis B and C testing is required for participants.
10.7.4
Germany
Section 5.2 Exclusion Criteria
Exclusion Criterion: Participant has a known history of human immunodeficiency virus 
(HIV) infection. HIV testing is required for participants.
Exclusion Criterion: hepatitis B and C testing is required for participants.
Section 6.5.1 Rescue Medications and Supportive Care
Live vaccines must not be administered for 90 days after the last dose of study intervention.
Legally Acceptable Representative protocol sections 
In order for a participant to be eligible to participate in Germany, they must be capable of 
providing documented informed consent; therefore, all references to a participant’s “legally 
acceptable representative” in the protocol are not applicable for participants in Germany.
10.7.5
Ireland
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
10.7.6
Italy
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
CCI
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10.7.7
Japan
10.7.8
Portugal
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
10.7.9
Romania
Section 1.3 Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 5.2 Exclusion Criteria
Exclusion Criterion: Participant has a known history of HIV infection. HIV testing is 
required for participants.
Exclusion Criterion: Participant has a known history of hepatitis B or C infection. Hepatitis B 
and C testing is required for participants.
CCI
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10.7.10
United Kingdom
CCI
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADA
anti-drug antibodies
ADL
activities of daily living
AE
adverse event 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All Participants as Treated
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the curve
BICR
blinded independent central review
BMI
body mass index
BP
blood pressure
BSA
body surface area
BUN
blood urea nitrogen
CD4
cluster of differentiation 4
CD8
cluster of differentiation 8
CD112
cluster of differentiation 112
CD155
cluster of differentiation 155
CD226
cluster of differentiation 226
CI
confidence interval
CL
clearance
Cmax
maximum serum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease 
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CSF
colony-stimulating factor
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Abbreviation
Expanded Term
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE v5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CTR
Clinical Trials Regulation
DCR
disease control rate
DDI
drug-drug interaction
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DRAE(s)
drug-related adverse event(s)
DSP
diastolic blood pressure
E-R
exposure-response
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire C30
EORTC QLQ-LC13
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire Lung Cancer13
EOT
end-of-treatment
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Abbreviation
Expanded Term
ePROs
electronic patient-reported outcomes
EQ-5D
EuroQoL-5D
ESMO
European Society for Medical Oncology
ES-SCLC
extensive-stage small cell lung cancer
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GI
gastrointestinal
GM-CSF
granulocyte macrophage colony-stimulating factor
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
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Abbreviation
Expanded Term
iCRO
imaging CRO
ICU
intensive care unit
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG1
immunoglobulin G1
IgG4
immunoglobulin G4
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
investigational medicinal product
IND
Investigational New Drug
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intention-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IWG
International Working Group
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
LLN
lower limit of normal
M&N
Miettinen and Nurminen
mAb
monoclonal antibody
MASCC
Multinational Association of Supportive Care in Cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
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Abbreviation
Expanded Term
MTD
maximum tolerated dose 
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
Necl5
nectin-like protein 5
NSCLC
non–small cell lung cancer
NDA
New Drug Application 
OR
objective response
ORR
objective response rate
OS
overall survival
OSF
on-site formulation
OTC
over-the-counter
PBPK
physiologically based PK
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic
po
orally
PR
partial response
PRO
patient-reported outcome
PS
performance status
PTT
partial thromboplastin time
PVR
poliovirus receptor
PVRL-2
poliovirus receptor ligand-2
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
QoL
quality of life
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Abbreviation
Expanded Term
RECIST
Response Evaluation Criteria In Solid Tumors
RFS
relapse-free survival
RNA
ribonucleic acid
rP2D
recommended Phase 2 dose
RR
respiratory rate
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SCLC
small cell lung cancer
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TIGIT
T-cell immunoglobulin and immunoreceptor tyrosine based 
inhibitory motif
TIL
tumor-infiltration lymphocytes
TNBC
triple negative breast cancer
TPS
tumor proportion score
TTD
time-to-true deterioration
UC
urothelial carcinoma
ULN
upper limit of normal
UTN
Universal Trial Number
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Abbreviation
Expanded Term
Vc
central volume of distribution
VAS
Visual Analog Scale
WBC
white blood cell
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
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11
REFERENCES
[Aaronson, N. K., et al 1993]
Aaronson NK, Ahmedzai S, Bergman B, 
Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-
life instrument for use in international 
clinical trials in oncology. J Natl Cancer Inst 
1993;85(5):365-76.
[03Q3QL]
[American Cancer Society 
2020]
American Cancer Society. Cancer facts & 
figures: 2020. Atlanta (GA): American 
Cancer Society (ACS); 2020. 76 p.
[05KBKH]
[Bai,S., et al 2012]
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, 
Damico-Beyer LA, et al. A guide to rational 
dosing of monoclonal antibodies. Clin 
Pharmacokinet 2012;51(2):119-35.
[03T78B]
[Beith, J. M., et al 1996]
Beith JM, Clarke SJ, Woods RL, Bell DR, 
Levi JA. Long-term follow-up of a 
randomised trial of combined 
chemoradiotherapy induction treatment, with 
and without maintenance chemotherapy in 
patients with small cell carcinoma of the 
lung. Eur J Cancer. 1996 Mar;32A(3):438-
43.
[04KV0C]
[Chauvin, J. M., et al 2015]
Chauvin JM, Pagliano O, Fourcade J, Sun Z, 
Wang H, Sander C, et al. TIGIT and PD-1 
impair tumor antigen-specific CD8⁺ T cells 
in melanoma patients. J Clin Invest. 2015 
May;125(5):2046-58.
[04GS9H]
[Clopper, C. J. and Pearson, 
E. S. 1934]
Clopper CJ and Pearson ES. The use of 
confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 
1934;26(4):404-13.
[03Y75Y]
[Deng, T., et al 2018]
Deng T, Zhang J, Meng Y, Zhou Y, Li W. 
Higher pretreatment lactate dehydrogenase 
concentration predicts worse overall survival 
in patients with lung cancer. Medicine. 
2018;97(38):e12524.
[05NSXV]
[Dirks, N. L. and Meibohm, 
B 2010]
Dirks NL and Meibohm B. Population 
pharmacokinetics of therapeutic monoclonal 
antibodies. Clin Pharmacokinet 
2010;49(10):633-59.
[058SQX]
08RNJZ

PRODUCT: MK-7684A
175
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Dora, D., et al 2020]
Dora D, Rivard C, Yu H, Bunn P, Suda K, 
Ren S, et al. Neuroendocrine subtypes of 
small cell lung cancer differ in terms of 
immune microenvironment and checkpoint 
molecule distribution. Mol Oncol. 
2020;14:1947-65.
[06DWDD]
[Dostalek,M., et al 2012]
Dostalek M, Gardner I, Gurbaxani BM, Rose 
RH, Chetty M. Pharmacokinetics, 
pharmacodynamics and physiologically-
based pharmacokinetic modelling of 
monoclonal antibodies. Clin Pharmacokinet 
2013;52:83-124.
[03T7LF]
[Foster, N. R., et al 2009]
Foster NR, Mandrekar SJ, Schild SE, Nelson 
GD, Rowland KM Jr, Deming RL, et al. 
Prognostic factors differ by tumor stage for 
small cell lung cancer: a pooled analysis of 
North Central Cancer Treatment Group trials. 
Cancer. 2009 Jun 15;115:2721-31.
[05NT78]
[Fruh, M., et al 2013]
Fruh M, De Ruysscher D, Popat S, Crino L, 
Peters S, Felip E, et al. Small-cell lung 
cancer (SCLC): ESMO Clinical Practice 
Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol. 2013 Oct;24 Suppl 
6:vi99-105.
[0454SV]
[Gaspar, L. E., et al 2012]
Gaspar LE, McNamara EJ, Gay EG, Putnam 
JB, Crawford J, Herbst RS, et al. Small-cell 
lung cancer: prognostic factors and changing 
treatment over 15 years. Clin Lung Cancer. 
2012 Mar;13(2):115-22.
[04JXMV]
[Gazdar, A. F., et al 2017]
Gazdar AF, Bunn PA, Minna JD. Small-cell 
lung cancer: what we know, what we need to 
know and the path forward. Nat Rev Cancer. 
2017 Dec;17:725-37.
[04WRMF]
[Hanna, N. H., et al 2002]
Hanna NH, Sandier AB, Loehrer PJ Sr, 
Ansari R, Jung SH, Lane K, et al. 
Maintenance daily oral etoposide versus no 
further therapy following induction 
chemotherapy with etoposide plus ifosfamide 
plus cisplatin in extensive small-cell lung 
cancer: a Hoosier Oncology Group 
randomized study. Ann Oncol. 2002 
Jan;13(1):95-102.
[04KTRR]
08RNJZ

PRODUCT: MK-7684A
176
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Hanna, N., et al 2006]
Hanna N, Bunn PA, Jr., Langer C, Einhorn L, 
Guthrie T, Jr., et al. Randomized phase III 
trial comparing irinotecan/cisplatin with 
etoposide/cisplatin in patients with 
previously untreated extensive-stage disease 
small-cell lung cancer. J Clin Oncol 
2006;24(13):2038-43.
[03R4D6]
[Hendrikx, J. J. M. A., et al 
2017]
Hendrikx JJMA, Haanen JBAG, Voest EE, 
Schellens JHM, Huitema ADR, Beijnen JH. 
Fixed dosing of monoclonal antibodies in 
oncology. Oncologist. 2017;22:1212-21.
[05JHQC]
[Horn, L., et al 2018]
Horn L, Mansfield AS, Szczesna A, Havel L, 
Krzakowski M, Hochmair MJ, et al. First-
line atezolizumab plus chemotherapy in 
extensive-stage small-cell lung cancer. N 
Engl J Med. 2018 Dec 6;379(23):2220-2229.
[05345T]
[Johnston, R. J., et al 2014]
Johnston RJ, Comps-Agrar L, Hackney J, Yu 
X, Huseni M, Yang Y, et al. The 
immunoreceptor TIGIT regulates antitumor 
and antiviral CD8(+) T cell effector function. 
Cancer Cell. 2014 Dec 8;26(6):923-37.
[04GS9T]
[Keizer,R.J., et al 2010]
Keizer RJ, Huitema ADR, Schellens JHM, 
Beijnen JH. Clinical pharmacokinetics of 
therapeutic monoclonal antibodies. Clin 
Pharmacokinet 2010;49(8):493-507.
[03T7M7]
[King, M. T. 1996]
King MT. The interpretation of scores from 
the EORTC quality of life questionnaire 
QLQ-C30. Quality of Life Research 
1996;5:555-67.
[03Q4R5]
[Land, S. R., et al 2016]
Land SR, Toll BA, Moinpour CM, Mitchell 
SA, Ostroff JS, Hatsukami DK, et al. 
Research priorities, measures, and 
recommendations for assessment of tobacco 
use in clinical cancer research. Clin Cancer 
Res. 2016 Apr 15;22(8):1907-13.
[083RSQ]
08RNJZ

PRODUCT: MK-7684A
177
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Leal, T. A., et al 2020]
Leal TA, Wang Y, Dowlati A, Lewis DA, 
Chen Y, Mohindra AR, et al. Randomized 
phase II clinical trial of cisplatin/carboplatin 
and etoposide (CE) alone or in combination 
with nivolumab as frontline therapy for 
extensive-stage small cell lung cancer (ES-
SCLC): ECOG-ACRIN EA5161. Slides 
presented at: 2020 American Society of 
Clinical Oncology (ASCO) Virtual Scientific 
Program; 2020 May 29-31; [online meeting]. 
Abstract no. 9000.
[05LXH3]
[Levin, S. D., et al 2011]
Levin SD, Taft DW, Brandt CS, Bucher C, 
Howard ED, Chadwick EM, et al. Vstm3 is a 
member of the CD28 family and an 
important modulator of T-cell function. Eur J 
Immunol. 2011 Apr;41(4):902-15.
[04GT88]
[Liang, K-Y. and Zeger, S. L. 
2000]
Liang K-Y and Zeger SL. Longitudinal data 
analysis of continuous and discrete responses 
for pre-post designs. Sankhya: the Indian 
Journal of Statistics 2000;62:134-48.
[03RSBZ]
[Liu, S. V., et al 2020]
Liu SV, Horn L, Mok TSK, Mansfield AS, 
De Boer R, Losonczy G, et al. IMpower133: 
characterisation of long-term survivors 
treated with first line chemotherapy ± 
atezolizumab in extensive-stage small cell 
lung cancer. Slides presented at: European 
Society for Medical Oncology (ESMO) 
Virtual Congress; 2020 Sep 19-21; [online 
meeting].
[05NZ78]
[Lozano, E., et al 2012]
Lozano E, Dominguez-Villar M, Kuchroo V, 
Hafler DA. The TIGIT/CD226 axis regulates 
human T cell function. J Immunol. 2012 Apr 
15;188(8):3869-75.
[04J3HX]
[Majem, M. 2017]
Majem M, Rudin CM. Small-cell lung cancer 
in the era of immunotherapy [editorial]. 
Transl Lung Cancer Res. 2017 Dec;6(suppl 
1):S67-70.
[05J80D]
[Maurer, W. and Bretz, F. 
2013]
Maurer W and Bretz F. Multiple testing in 
group sequential trials using graphical 
approaches. Stat Biopharm Res 
2013;5(4):311-20.
[03XQVB]
08RNJZ

PRODUCT: MK-7684A
178
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O and Nurminen M. Comparative 
Analysis of Two Rates. Stat Med 
1985;4:213-26.
[03QCDT]
[Nadler, E., et al 2021]
Nadler E, Vasudevan A, Davies K, Wang Y, 
Johnson A, Ogale S, et al. Real-world 
evidence of cancer immunotherapy (CIT) 
combination treatment in first-line (1L) 
extensive-stage small cell lung cancer (ES-
SCLC). Poster session presented at: 2021 
American Society of Clinical Oncology 
(ASCO) Annual Meeting; 2021 Jun 4-8; 
[online meeting].
[06DVV6]
[National Cancer Institute 
2014]
National Cancer Institute. Scientific 
Framework for Small Cell Lung Cancer 
(SCLC) [Internet]. Bethesda (MD): NCI; 
2014. Available from: 
https://deainfo.nci.nih.gov/advisory/ctac/wor
kgroup/SCLC/SCLC%20Congressional%20
Response.pdf.
[04NP54]
[National Comprehensive 
Cancer Network 2018]
National Comprehensive Cancer Network. 
NCCN clinical practice guidelines in 
oncology: small cell lung cancer; version 
1.2019. Fort Washington (PA): National 
Comprehensive Cancer Network (NCCN); 
2018. 61 p.
[053Q3V]
[Osoba, D., et al 1998]
Osoba D, Rodrigues G, Myles J, Zee B, Pater 
J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin 
Oncol 1998;16(1):139-44.
[03RL72]
[Paz-Ares, L., et al 2019]
Paz-Ares L, Dvorkin M, Chen Y, Reinmuth 
N, Hotta K, Trukhin D, et al. Durvalumab 
plus platinum-etoposide versus platinum-
etoposide in first-line treatment of extensive-
stage small-cell lung cancer (CASPIAN): a 
randomised, controlled, open-label, phase 3 
trial. Lancet. 2019 Nov 23;394(10212):1929-
1939
[05BY5L]
[Pickard, A. S., et al 2007]
Pickard AS, Neary MP, Cella D. Estimation 
of minimally important differences in EQ-5D 
utility and VAS scores in cancer. Health Qual 
Life Outcomes 2007;5:1-8.
[00W0FM]
08RNJZ

PRODUCT: MK-7684A
179
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Rabin, R. and de Charro, F. 
2001]
Rabin R and de Charro F. EQ-5D: a measure 
of health status from the EuroQol group. Ann 
Med 2001;33:337-43.
[03QM46]
[Reck, M., et al 2016]
Reck M, Luft A, Szczesna A, Havel L, Kim 
SW, Akerley W, et al. Phase III Randomized 
Trial of Ipilimumab Plus Etoposide and 
Platinum Versus Placebo Plus Etoposide and 
Platinum in Extensive-Stage Small-Cell Lung 
Cancer. J Clin Oncol. 2016 Nov 25;34:3740-
8.
[04KTS9]
[Reck, M., et al 2019]
Reck M, Liu SV, Mansfield AS, Mok T, 
Scherpereel A, Reinmuth N, et al. 
Impower133: updated overall survival (OS) 
analysis of first-line (1L) atezolizumab 
(atezo) + carboplatin + etoposide in 
extensive-stage SCLC (ES-SCLC). Slides 
presented at: 44th European Society for 
Medical Oncology (ESMO) 2019 Congress; 
2019 Sep 27-Oct 1; Barcelona (Spain).
[05DY9H]
[Roila, F., et al 2016]
Roila F, Molassiotis A, Herrstedt J, Aapro M, 
Gralla RJ, Bruera E, et al. 2016 MASCC and 
ESMO guideline update for the prevention of 
chemotherapy- and radiotherapy-induced 
nausea and vomiting and of nausea and 
vomiting in advanced cancer patients. Ann 
Oncol. 2016 Sep;27(suppl 5):v119-v133.
[04KSW4]
[Rossi, A., et al 2012]
Rossi A, Di Maio M, Chiodini P, Rudd RM, 
Okamoto H, Skarlos DV, et al. Carboplatin-
or cisplatin-based chemotherapy in first-line 
treatment of small-cell lung cancer: the 
COCIS meta-analysis of individual patient 
data. J Clin Oncol. 2012 May 
10;30(14):1692-8.
[04JY5R]
[Rudin, C. M., et al 2015]
Rudin CM, Ismaila N, Hann CL, Malhotra N, 
Movsas B, Norris K, et al. Treatment of 
Small-Cell Lung Cancer: American Society 
of Clinical Oncology Endorsement of the 
American College of Chest Physicians 
Guideline. J Clin Oncol. 2015 Dec 
1;33(34):4106-11.
[04KTSB]
08RNJZ

PRODUCT: MK-7684A
180
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Rudin, C. M., et al 2020]
Rudin CM, Awad MM, Navarro A, Gottfried 
M, Peters S, Csoszi T, et al. Pembrolizumab 
or placebo plus etoposide and platinum as 
first-line therapy for extensive-stage small-
cell lung cancer: randomized, double-blind, 
phase III KEYNOTE-604 study. J Clin 
Oncol. 2020 Jul 20;38(21):2369-2379.
[05HVDK]
[Schiller, J. H., et al 2001]
Schiller JH, Adak S, Cella D, DeVore III RF, 
Johnson DH. Topotecan versus observation 
after cisplatin plus etoposide in extensive-
stage small-cell lung cancer: E7593 - A 
phase III trial of the Eastern Cooperative 
Oncology Group. J Clin Oncol 
2001;19(8):2114-22.
[03RL7T]
[Sierocki, J. S., et al 1979]
Sierocki JS, Hilaris BS, Hopfan S, Martini N, 
Barton D, Golbey RB, et al. cis-
Dichlorodiammineplatinum(II) and VP-16-
213: an active induction regimen for small 
cell carcinoma of the lung. Cancer Treat Rep. 
1979 Sep-Oct;63(9-10):1593-7.
[04JYWT]
[Spiro, S. G., et al 1989]
Spiro SG, Souhami RL, Geddes DM, Ash 
CM, Quinn H, Harper PG, et al. Duration of 
chemotherapy in small cell lung cancer: a 
Cancer Research Campaign trial. Br J 
Cancer. 1989 Apr;59(4):578-83.
[04KTSS]
[Steindl, A., et al 2019]
Steindl A, Schlieter F, Klikovits T, Leber E, 
Gatterbauer B, Frischer JM, et al. Prognostic 
assessment in patients with newly diagnosed 
small cell lung cancer brain metastases: 
results from a real-life cohort. J Neurooncol. 
2019;145:85-95.
[05N8SB]
[Thomas, A., et al 2020]
Thomas A, Mian I, Tlemsani C, Pongor L, 
Takahashi N, Maignan K, et al. Clinical and 
genomic characteristics of small cell lung 
cancer in never smokers: results from a 
retrospective multicenter cohort study. Chest. 
2020 Oct;158(4):1723-33.
[05NDJ8]
[Varghese, A. M., et al 2014]
Varghese AM, Zakowski MF, Yu HA, Won 
HH, Riely GJ, Krug LM, et al. Small-cell 
lung cancers in patients who never smoked 
cigarettes. J Thorac Oncol. 2014 
Jun;9(6):892-6.
[04JXNJ]
08RNJZ

PRODUCT: MK-7684A
181
PROTOCOL/AMENDMENT NO.: 008-05
MK-7684A-008-05 FINAL PROTOCOL
22-JAN-2025
[Xu, Y., et al 2019]
Xu Y, Cui G, Jiang Z, Li N, Zhang X. 
Survival analysis with regard to PD-L1 and 
CD155 expression in human small cell lung 
cancer and a comparison with associated 
receptors. Oncol Lett. 2019;17:2960-8.
[05LDL6]
[Yu, H., et al 2018]
Yu H, Koczara C, Badzio A, Gao D, Rivard 
CJ, Ellison K, et al. Expression of an immune 
checkpoint- Poliovirus Receptor (PVR) in 
small cell lung cancer [abstract]. Presented 
at: American Association for Cancer 
Research (AACR) Annual Meeting; 2018 
Apr 14-18; Chicago, IL. Cancer Res. 
2018;78(13 suppl). Abstract no. 3637.
[06DWZK]
[Zhang, T., et al 2014]
Zhang T, Wang J, Zhou X, Liang R, Bai Q, 
Yang L, et al. Increased expression of TIGIT 
on CD4+ T cells ameliorates immune-
mediated bone marrow failure of aplastic 
anemia. J Cell Biochem. 2014 
Nov;115(11):1918-27.
[04J3J5]
[Zhang, X., et al 2016]
Zhang X, Guo M, Fan J, Lv Z, Huang Q, Han 
J, et al. Prognostic significance of serum 
LDH in small cell lung cancer: a systematic 
review with meta-analysis. Cancer Biomark. 
2016;16:415-23.
[05NSXY]
[Zhao, H., et al 2018]
Zhao H, Ren D, Liu H, Chen J. Comparison 
and discussion of the treatment guidelines for 
small cell lung cancer. Thorac Cancer. 
2018;9:769-74.
[0522ZL]
08RNJZ