Conditions: High-grade Serous Ovarian Carcinoma Ovarian Carcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 160
Healthy volunteers: no

Brief summary:
The primary objective is to evaluate in participants with high-grade serous ovarian cancer (HGSOC), whether the reduction from baseline in circulating tumor DNA (ctDNA) at Cycle 3 (ΔctDNA) is larger in participants receiving MK-4830 + pembrolizumab in combination with standard of care (SOC) therapy than in those receiving pembrolizumab + SOC therapy.

Detailed description:

Arms:
arm 1: Before surgery participants will receive pembrolizumab 200 mg, paclitaxel 175 mg/m\^2, carboplatin Area Under the Curve (AUC) 5 to 6, (or docetaxel 75 mg/m\^2), and MK-4830 800 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for 3 cycles. After surgery participants will receive pembrolizumab 200 mg, paclitaxel 175 mg/m\^2, carboplatin AUC 5 to 6, (or docetaxel 75 mg/m\^2), MK-4830 800 mg, and avastin (or biosimilar) by IV infusion on Day 1 of each 21-day cycle (Q3W) for 3 cycles. arm 2: Before surgery participants will receive pembrolizumab 200 mg, paclitaxel 175 mg/m\^2, carboplatin AUC 5 to 6 and (or docetaxel 75 mg/m\^2) by IV infusion on Day 1 of each 21-day cycle (Q3W) for 3 cycles. After surgery participants will receive pembrolizumab 200 mg, paclitaxel 175 mg/m\^2, carboplatin AUC 5 to 6, (or docetaxel 75 mg/m\^2) and avastin (or biosimilar) by IV infusion on Day 1 of each 21-day cycle (Q3W) for 3 cycles.

Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Avastin intervention 5: MK-4830 intervention 6: Docetaxel
Intervention descriptions: intervention 1: 200 mg by IV infusion on Day 1 of each 21-day cycle intervention 2: 175 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle intervention 3: AUC 5 to 6 by IV infusion on Day 1 of each 21-day cycle intervention 4: According to local practice and at the choice of the investigator. intervention 5: 800 mg by IV infusion on Day 1 of each 21-day cycle intervention 6: 75 mg/m\^2 by IV infusion on Day 1 of each 21-day cycle

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized, Phase 2 Study of 
Pembrolizumab And Chemotherapy With or 
Without MK-4830 as Neoadjuvant Treatment 
for High-Grade Serous Ovarian Cancer
NCT05446870
10-APR-2024


PRODUCT: MK-4830  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Randomized, Phase 2 Study of Pembrolizumab And Chemotherapy With 
or Without MK-4830 as Neoadjuvant Treatment for High-Grade Serous Ovarian Cancer
Protocol Number: 002-04
Compound Number: MK-4830
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
160197
EudraCT
2021-005458-27
EUCT
2023-505005-16
Approval Date: 10 April 2024
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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 04
10-APR-2024
To address a health authority request
Amendment 03
07-NOV-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
Amendment 02
22-MAR-2022
To address health authority comments.
Amendment 01
02-FEB-2022
To allow exploratory histological confirmation of high-grade serous carcinoma of 
tumor samples from enrolled participants to be conducted.
Original Protocol
21-DEC-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendment:
To address a health authority request.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Title page
Added EU CT number.
This change was made to address Health 
Authority feedback to align with Regulation 
(EU) 536/2014
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Section 4.4, 
Beginning and 
End of Study 
Definition
Added text estimating the duration of the study.
Refer to title page rationale.
Section 8.4.4, 
Regulatory 
Reporting 
Requirements for 
SAE
Added text for SUSAR reporting in the EU.
Refer to title page rationale.
Section 10.1.1, 
Code of Conduct 
for Clinical 
Studies
Added text that the study will be conducted in 
compliance with Regulation (EU) 536/2014.
Refer to title page rationale.
Section 10.1.3, 
Data Protection
Added text on privacy rules.
Refer to title page rationale.
Section 10.1.6, 
Compliance with 
Study 
Registration and 
Results Posting 
Requirements
Revised text to include reference to Regulation 
536/2014.
Refer to title page rationale.
Section 10.1.7, 
Compliance with 
Law, Audit, and 
Debarment
Added text on serious breach reporting.
Refer to title page rationale.
Section 10.1.8, 
Data Quality 
Assurance
Added text to specify record retention period 
for EU.
Refer to title page rationale.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................20
1.3.1
Imaging Assessments for Neoadjuvant/Adjuvant Treatment Period With 
Interval Debulking Surgery..........................................................................30
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................33
2.2.1.1
MK-4830 Background .......................................................................33
2.2.1.2
Pembrolizumab Background..............................................................34
2.2.1.3
Overview of Ovarian Cancer .............................................................35
2.2.1.4
Current Standard of Care and Unmet Medical Need.........................36
2.2.2
ctDNA..........................................................................................................37
2.2.3
Microsampling.............................................................................................38
2.2.4
Preclinical and Clinical Studies ...................................................................38
2.2.5
Ongoing Clinical Studies.............................................................................38
2.2.6
Information on Other Study-related Therapy ..............................................39
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................40
4
STUDY DESIGN............................................................................................................42
4.1
Overall Design......................................................................................................42
4.2
Scientific Rationale for Study Design.................................................................44
4.2.1
Rationale for Endpoints ...............................................................................46
4.2.1.1
Efficacy Endpoints.............................................................................46
4.2.1.1.1
RECIST 1.1..............................................................................46
4.2.1.2
Safety Endpoints................................................................................46
4.2.1.3
Pharmacokinetic Endpoints ...............................................................46
4.2.1.4
Pharmacodynamic Endpoints.............................................................46
4.2.1.5
Planned Exploratory Biomarker Research.........................................47
4.2.1.5.1
Translational Oncology Research............................................48
4.2.1.6
Future Biomedical Research..............................................................49
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4.2.2
Rationale for the Use of Comparator...........................................................49
4.3
Justification for Dose...........................................................................................50
4.3.1
Starting Dose for This Study........................................................................50
4.3.1.1
MK-4830............................................................................................50
4.3.1.2
Rationale for Chemotherapy Dosing Regimen..................................50
4.3.1.3
Pembrolizumab ..................................................................................50
4.3.2
Maximum Dose/Exposure for This Study ...................................................51
4.4
Beginning and End-of-Study Definition ............................................................51
4.4.1
Clinical Criteria for Early Study Termination .............................................51
5
STUDY POPULATION ................................................................................................51
5.1
Inclusion Criteria.................................................................................................52
5.2
Exclusion Criteria................................................................................................55
5.3
Lifestyle Considerations......................................................................................58
5.3.1
Meals and Dietary Restrictions....................................................................58
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................58
5.3.3
Activity Restrictions ....................................................................................58
5.4
Screen Failures.....................................................................................................58
5.5
Participant Replacement Strategy......................................................................58
6
STUDY INTERVENTION............................................................................................59
6.1
Study Intervention(s) Administered...................................................................59
6.1.1
Treatment .....................................................................................................62
6.2
Preparation/Handling/Storage/Accountability .................................................62
6.2.1
Dose Preparation..........................................................................................62
6.2.2
Handling, Storage, and Accountability........................................................62
6.3
Measures to Minimize Bias: Randomization and Blinding..............................63
6.3.1
Intervention Assignment..............................................................................63
6.3.2
Stratification.................................................................................................63
6.3.3
Blinding........................................................................................................63
6.4
Study Intervention Compliance..........................................................................63
6.5
Concomitant Therapy..........................................................................................64
6.5.1
Rescue Medications and Supportive Care ...................................................66
6.6
Dose Modification (Escalation/Titration/Other)...............................................66
6.6.1
Immune-related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................66
6.6.2
Chemotherapy Dose Modifications .............................................................74
6.6.3
Definition of Dose-limiting Toxicity...........................................................74
6.7
Intervention After the End of the Study............................................................76
6.8
Clinical Supplies Disclosure................................................................................76
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6.9
Standard Policies..................................................................................................76
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................76
7.1
Discontinuation of Study Intervention...............................................................76
7.2
Participant Withdrawal From the Study...........................................................77
7.3
Lost to Follow-up .................................................................................................78
8
STUDY ASSESSMENTS AND PROCEDURES........................................................78
8.1
Administrative and General Procedures ...........................................................79
8.1.1
Informed Consent.........................................................................................79
8.1.1.1
General Informed Consent.................................................................79
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................80
8.1.2
Inclusion/Exclusion Criteria ........................................................................80
8.1.3
Participant Identification Card.....................................................................80
8.1.4
Medical History ...........................................................................................80
8.1.4.1
Ovarian Cancer History .....................................................................81
8.1.5
Debulking Surgery.......................................................................................81
8.1.5.1
Tumor Tissue Biopsy and Sample Collection ...................................81
8.1.6
Prior and Concomitant Medications Review...............................................82
8.1.6.1
Prior Medications...............................................................................82
8.1.6.2
Concomitant Medications..................................................................82
8.1.7
Assignment of Screening Number...............................................................82
8.1.8
Assignment of Treatment/Randomization Number.....................................82
8.1.9
Study Intervention Administration ..............................................................82
8.1.9.1
Timing of Dose Administration.........................................................83
8.1.9.1.1
Pembrolizumab ........................................................................83
8.1.9.1.2
MK-4830..................................................................................83
8.1.9.1.3
Paclitaxel (or Docetaxel)..........................................................83
8.1.9.1.4
Carboplatin...............................................................................84
8.1.9.1.5
Avastin (or Biosimilar) ............................................................84
8.1.9.1.6
Antiemetic Therapy .................................................................84
8.1.10
Discontinuation and Withdrawal .................................................................84
8.1.10.1
Withdrawal From Future Biomedical Research ................................85
8.1.11
Participant Blinding/Unblinding..................................................................85
8.1.12
Calibration of Equipment.............................................................................85
8.1.13
Microsampling Device.................................................................................85
8.2
Efficacy/Immunogenicity Assessments ..............................................................86
8.2.1
Tumor Imaging and Assessment of Disease................................................86
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8.2.1.1
Initial Tumor Scans............................................................................86
8.2.1.2
Tumor Scans During the Study..........................................................87
8.2.1.3
End-of-Treatment Tumor Scans ........................................................87
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................87
8.3
Safety Assessments...............................................................................................88
8.3.1
Physical Examinations.................................................................................88
8.3.2
Vital Signs....................................................................................................89
8.3.3
Electrocardiograms ......................................................................................89
8.3.4
Clinical Safety Laboratory Assessments .....................................................89
8.3.5
Pregnancy Testing........................................................................................90
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................90
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................90
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................91
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......92
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...93
8.4.4
Regulatory Reporting Requirements for SAE .............................................93
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................93
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying
as AEs or SAEs............................................................................................94
8.4.7
Events of Clinical Interest............................................................................94
8.5
Treatment of Overdose........................................................................................94
8.6
Pharmacokinetics.................................................................................................95
8.7
Pharmacodynamics..............................................................................................95
8.8
Biomarkers ...........................................................................................................95
8.8.1
Planned Genetic Analysis Sample Collection..............................................95
8.9
Future Biomedical Research Sample Collection...............................................96
8.10
Medical Resource Utilization and Health Economics.......................................96
8.11
Visit Requirements...............................................................................................96
8.11.1
Screening......................................................................................................96
8.11.2
Treatment Period..........................................................................................97
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........97
8.11.4
Post-treatment Visits....................................................................................97
8.11.4.1
Safety Follow-up................................................................................97
8.11.4.2
Long-term Follow-up.........................................................................97
9
STATISTICAL ANALYSIS PLAN .............................................................................97
9.1
Statistical Analysis Plan Summary.....................................................................98
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9.2
Responsibility for Analyses/In-house Blinding .................................................98
9.3
Hypotheses/Estimation ........................................................................................99
9.4
Analysis Endpoints...............................................................................................99
9.4.1
Efficacy Endpoints.......................................................................................99
9.4.2
Biomarker Endpoints ...................................................................................99
9.4.3
Safety Endpoints..........................................................................................99
9.5
Analysis Populations..........................................................................................100
9.5.1
Efficacy and Safety Analysis Population...................................................100
9.5.2
Biomarker Analysis Population.................................................................100
9.6
Statistical Methods.............................................................................................100
9.6.1
Statistical Methods for Biomarker/Efficacy Analyses...............................100
9.6.1.1
Primary Objective............................................................................100
9.6.1.2
Secondary Objectives.......................................................................101
9.6.1.3
Exploratory Objectives ....................................................................101
9.6.2
Statistical Methods for Safety Analyses ....................................................102
9.7
Interim Analyses ................................................................................................103
9.8
Multiplicity .........................................................................................................103
9.9
Sample Size and Power Calculations ...............................................................103
9.10
Subgroup Analyses.............................................................................................104
9.11
Compliance (Medication Adherence)...............................................................104
9.12
Extent of Exposure.............................................................................................104
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................105
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......105
10.1.1
Code of Conduct for Clinical Trials...........................................................105
10.1.2
Financial Disclosure...................................................................................107
10.1.3
Data Protection...........................................................................................108
10.1.3.1
Confidentiality of Data ....................................................................108
10.1.3.2
Confidentiality of Participant Records.............................................108
10.1.3.3
Confidentiality of IRB/IEC Information..........................................109
10.1.4
Committees Structure.................................................................................109
10.1.4.1
Standing Internal Data Monitoring Committee ...............................109
10.1.5
Publication Policy......................................................................................109
10.1.6
Compliance with Study Registration and Results Posting Requirements .109
10.1.7
Compliance with Law, Audit, and Debarment ..........................................110
10.1.8
Data Quality Assurance .............................................................................111
10.1.9
Source Documents .....................................................................................111
10.1.10
Study and Site Closure...............................................................................112
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10.2
Appendix 2: Clinical Laboratory Tests............................................................113
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................115
10.3.1
Definition of Medication Error, Misuse, and Abuse..................................115
10.3.2
Definition of AE ........................................................................................115
10.3.3
Definition of SAE ......................................................................................117
10.3.4
Additional Events Reported in the Same Manner as SAE.........................118
10.3.5
Recording AE and SAE .............................................................................118
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................122
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................123
10.5
Appendix 5: Contraceptive Guidance..............................................................124
10.5.1
Definitions..................................................................................................124
10.5.2
Contraception Requirements......................................................................125
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................126
10.7
Appendix 7: Country-specific Requirements..................................................131
10.7.1
France.........................................................................................................131
10.7.2
Italy ............................................................................................................131
10.8
Appendix 8: Abbreviations ...............................................................................132
10.9
Appendix 9: mTPI Table...................................................................................136
11
REFERENCES.............................................................................................................137
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values ...........................................54
Table 2
Study Interventions....................................................................................60
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................68
Table 4
Pembrolizumab Monotherapy, Coformulations or IO Combinations 
(MK-4830) Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................72
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................92
Table 6
Analysis Strategy for Primary Objectives................................................102
Table 7
Illustrative Simulation of the Relationship Between Post-treatment 
ctDNA Values and Treatment Assignment in cLDA Model for Varied 
Fold Change in the Mean ctDNA for MK-4830 Containing Arm 
Versus Not ...............................................................................................103
Table 8
Protocol-required Safety Laboratory Assessments..................................113
Table 9
Dose-finding Rules per mTPI Design......................................................136
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................18
Figure 2
Interval Debulking Surgery........................................................................19
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized, Phase 2 Study of Pembrolizumab And Chemotherapy With 
or Without MK-4830 as Neoadjuvant Treatment for High-Grade Serous Ovarian Cancer
Short Title: Genomic and immune markers of response in ILT4- and pembrolizumab-treated 
ovarian cancer
Acronym: None
Hypotheses, Objectives, and Endpoints:
In participants with high-grade serous ovarian cancer:
Objectives
Endpoints
Primary
Objective: Among patients with detectable 
ctDNA at baseline, to evaluate whether the 
reduction from baseline in circulating tumor 
DNA at Cycle 3 (ΔctDNA) is larger in 
participants receiving MK-4830 + 
pembrolizumab in combination with 
standard of care (SOC) therapy than in 
those receiving pembrolizumab + SOC
therapy.
ctDNA, the continuous mean 
mutant/tumor molecules per mL. 
Secondary
Objective: Among patients with detectable 
ctDNA at baseline, to evaluate the 
association between neoadjuvant ΔctDNA
at Cycle 3 from baseline and surgical 
outcomes.
ctDNA
pCR, all surgical specimens collected 
during the interval debulking surgery are 
microscopically negative for residual 
tumor.
CRS, tiered response score based omental 
assessment of residual disease.
Objective: To estimate the difference in 
pCR and CRS following neoadjuvant 
treatment between arms.
pCR
CRS
Objective: To evaluate the safety and 
tolerability of the study intervention 
administered.
Adverse events (AEs)
Study intervention discontinuation due to 
AEs
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
First-line treatment of advanced HGSOC
Population
Participants with advanced HGSOC who are 
candidates for interval debulking surgery.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 35 months 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 160 participants will be randomly assigned.
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Intervention Groups and Duration:
Eligible participants will be randomized to one of the following study intervention arms:
•
Arm 1:
Neoadjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg 
Q3W plus MK-4830 (800 mg Q3W) before surgery.
Adjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg Q3W) 
plus MK-4830 (800 mg Q3W) ± Avastin® (or biosimilar) after surgery
•
Arm 2:
Neoadjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg 
Q3W) prior to surgery.
Adjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg Q3W) 
± Avastin (or biosimilar) after surgery.
*
At the investigator’s discretion and determined prior to the participant being 
randomly assigned to study intervention, one of the following regimens should be 
selected:
•
Carboplatin AUC 5 or AUC 6 Q3W plus paclitaxel 175 mg/m2 Q3W
The optional use of Avastin (or biosimilar) in the adjuvant phase (ie, after surgery in Cycles 
4 to 6) is permitted according to local practice and at the choice of the investigator; however, 
the investigator must decide on the use of Avastin (or biosimilar) after surgery and it must be 
selected in IRT (interactive response technology) prior to starting treatment in the adjuvant 
phase. 
A safety lead-in will be performed to determine the tolerability of pembrolizumab + 
MK-4830 + carboplatin/paclitaxel when Avastin (or biosimilar) is added. Participants treated 
with pembrolizumab + MK-4830 + carboplatin/paclitaxel + Avastin (or biosimilar) will be 
closely followed for DLTs for the first cycle after the first dose of study intervention (the 
DLT evaluation period). Note: Use of Avastin (or biosimilar) is not permitted in the 
neoadjuvant phase (ie, prior to surgery in Cycles 1 to 3).
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Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Arm 1
Carbo
AUC 5 or
AUC 6
Q3W
IV
Day 1 of each 
3-week cycle
Bgd
Paca
175 mg/m2
Q3W
IV
Day 1 of each 
3-week cycle
Bgd
Pembro
200 mg
Q3W
IV
Day 1 of each 
3-week cycle
Test 
Prod
MK-4830
800 mg
Q3W
IV
Day 1 of each 
3-week cycle
Test 
Prod
Avastin
(or biosimilar)
Variable
Q3W
IV
Day 1 of each 
3-week cycleb
Bgd
Arm 2
Carbo
AUC 5 or
AUC 6
Q3W
IV
Day 1 of each 
3-week cycle
Bgd
Paca
175 mg/m2
Q3W
IV
Day 1 of each 
3-week cycle
Bgd
Pembro
200 mg
Q3W
IV
Day 1 of each 
3-week cycle
Test 
Prod
Avastin
(or biosimilar)
Variable
Q3W
IV
Day 1 of each 
3-week cycleb
Bgd
Abbreviations: AUC = area under the concentration-time curve; Bgd = background; 
Carbo = carboplatin; IV = intravenous; Pac = paclitaxel; Pembro = pembrolizumab; Prod = product;
Q3W = every 3 weeks; QW = once weekly.
a.
Docetaxel may be considered for participants who experience either a severe hypersensitivity 
reaction to paclitaxel or an AE requiring discontinuation of paclitaxel only after consultation 
with the Sponsor. The recommended dose will be carboplatin AUC 5 Q3W and docetaxel 75 
mg/m2 Q3W [Vasey, P. A., et al 2004]. 
b.
The option to use Avastin (or biosimilar) in the adjuvant phase (ie, after surgery in Cycles 4 to 
6) is permitted according to local practice and at the choice of the investigator; however, the 
investigator must decide on the use of Avastin (or biosimilar) after surgery but prior to the 
participant starting study intervention in the adjuvant phase.
Note: Use of Avastin (or biosimilar) is not permitted in the neoadjuvant phase (ie, prior to 
surgery in Cycles 1 to 3).
Other current or former name(s) or alias(es) for study intervention(s) are 
as follows: pembrolizumab (MK-3475, KEYTRUDA®)
Total 
Number of 
Intervention 
Groups/
Arms
2
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PRODUCT:  MK-4830  
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10-APR-2024
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 up to 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 AEs and spontaneously reported pregnancy.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations is in Appendix 8.
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10-APR-2024
1.2
Schema
The study design is depicted in Figure 1 and Figure 2.
Figure 1
Study Design
Abbreviations: AE = adverse event; AUC = area under the concentration-time curve; ECOG = Eastern 
Cooperative Oncology Group; FIGO = International Federation of Gynecology and Obstetrics;
IV = intravenous; Q3W = every 3 weeks; Tx = treatment.
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PRODUCT:  MK-4830  
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PROTOCOL/AMENDMENT NO.:  002-04
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10-APR-2024
Figure 2
Interval Debulking Surgery
Abbreviations: C1D1 = Cycle 1, Day 1; C2D1 = Cycle 2, Day 1; C3D1 = Cycle, 3 Day 1; C4D1 = Cycle 4, 
Day 1; FFPE = formalin-fixed-paraffin-embedded; Q3W = every 3 weeks; R = Randomization.
*Note: The investigator must decide on the use of Avastin (or biosimilar) after surgery but prior to starting 
study intervention in the adjuvant phase. The use of Avastin (or biosimilar) is not permitted in the neoadjuvant 
phase (ie, prior to surgery in Cycles 1 to 3).
08KDDB


PRODUCT:  MK-4830  
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10-APR-2024
1.3
Schedule of Activities
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Administrative Procedures
Informed Consent
X
Documented informed consent must be 
obtained before any protocol-specific 
screening procedures are performed.
If the investigator plans to treat beyond 
disease progression, additional consent is 
required.
Informed Consent 
for Future 
Biomedical 
Research
X
Participants may participate in main study 
without consenting to FBR.
Inclusion/
Exclusion Criteria
X
X*
Refer to Appendix 7 for country-specific 
requirements.
*Confirm that participants are still eligible 
to receive Avastin (or biosimilar) in the 
adjuvant phase (if administered)
Participant ID Card
X
X
Update with randomization number at C1D1
Demographics and 
Medical History
X
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Ovarian Cancer 
History
X*
X**
*Assess and record tumor burden per 
imaging. 
**Additional details on OC should be 
recorded, including BRCA and HRD status, 
if known, at any point during treatment.
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications, including those 
administered at the time of surgery, will be 
recorded for 30 days after last dose (or for 
up to 90 days after last dose for SAEs).
Interval debulking 
surgery
X
Surgery should occur between 3 to 6 weeks 
following C3D1.
Study intervention may resume when 
clinically appropriate but no later than 
7 weeks following surgery. 
Intervention 
Randomization 
(using IRT)
X
Randomization via IRT may occur up to 
3 days prior to C1D1.
Vital Status
X
X
X
On Sponsor request, participants may be 
contacted for survival information at any 
time during the study.
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Participant contact
X*
X*
X**
* Staff to contact participants within 3 days 
after clinic visit to ensure
 
devices were collected and picked up by the 
courier.
** Staff to contact participants for 
pregnancy status.
Interventions
MK-4830 (Arm 1 
only)
X
X
X
X
X
X
800 mg Q3W
Pembrolizumab
X
X
X
X
X
X
200 mg Q3W
Carboplatin
X
X
X
X
X
X
AUC 5 or AUC 6 Q3W
Paclitaxel
X
X
X
X
X
X
175 mg/m2 Q3W
Docetaxel (75 mg/m2 Q3W) may be 
considered in special cases only after 
Sponsor consultation and approval.
Avastin or 
biosimilar 
(optional)
X
X
X
Avastin (or biosimilar) use must be selected 
in IRT prior to starting study intervention in 
the adjuvant phase.
Participants will be followed for DLTs for 
the first cycle in the adjuvant phase.
CCI
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PROTOCOL/AMENDMENT NO.:  002-04
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Efficacy Procedures
Pathological Tumor 
Assessment (pCR 
and CRS)
X
Detailed pathological assessment of all 
tumor tissue, including tissue from 
omentum, collected during interval 
debulking for CRS determination and pCR.
Tumor Imaging 
(chest, abdomen, 
and pelvis)
X
X
X
X
See Section 1.3.1. Presurgery scan for 
surgical assessment should be performed a 
minimum of 21 days (+5 days) after C3D1. 
A scan should be performed prior to 
resuming study intervention in Cycle 4 
(-5 days)
Brain Imaging (for 
participants with 
brain metastases at 
baseline [to show 
stability] or who 
are clinically 
symptomatic)
X
X*
X*
* On-study imaging as clinically indicated
or to confirm CR.
Bone Imaging (for 
participants with 
bone metastases at 
baseline [to show
stability] or who 
are clinically 
symptomatic)
X
X*
X*
* On-study imaging as clinically indicated
or to confirm CR.
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PRODUCT:  MK-4830  
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Safety Procedures
AE Monitoring
X
X
X
X
X
X
X
X
X
X
Report all AEs and SAEs as outlined in 
Section 8.4.1.
Complete PE
X
X
Directed PE
X*
X
* To be performed when clinically 
indicated.
Height
X
Weight
X*
X
X
X
X
X
X
* Perform within 7 days of starting study 
intervention.
Vital Signs
X
X
X
X
X*
X
X
X
X
X
* To be performed prior to and after surgery.
12-lead ECG
X*
X
* Perform within 7 days of starting study 
intervention.
Pregnancy Test 
(WOCBP only)
X*
X
X
X
X
X
X
X
X
X
X
* A negative pregnancy test within either 
24 hours (urine) or 72 hours (serum) prior to 
C1D1 treatment. 
Refer to Appendix 7 for country-specific 
requirements.
Serum FSH 
(WONCBP only)
X
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PRODUCT:  MK-4830  
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PROTOCOL/AMENDMENT NO.:  002-04
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
HIV/HBV/HCV
X
Testing is only required once at screening if 
mandated by local health authority. 
Refer to Appendix 7 for country-specific 
requirements.
Hematology
X*
X
X
X
X
X
X
X
* Perform within 7 days of starting study 
intervention. Following Day 1 of Cycle 1, 
all on-study assessments collected predose.
‡ Participants receiving Avastin (or 
biosimilar) require urinalysis at every dosing 
cycle that Avastin (or biosimilar) is 
administered.
** CA-125 to be collected at the time of 
imaging.
Urinalysis
X*
X
X‡
X‡
X
X
Chemistry
X*
X
X
X
X
X
X
X
T3 or free 
T3/FT4/TSH
X*
X
X
X
X
X
Cortisol (local 
laboratory only)
X*
X
X
X
CA-125 (central 
laboratory)
X*
X**
X**
X
CEA (central 
laboratory)
X*
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PRODUCT:  MK-4830  
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PROTOCOL/AMENDMENT NO.:  002-04
MK-4830-002-04 FINAL PROTOCOL
10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
CA-125 (local 
laboratory)
X*
Sites have the option of assessing CA-125 
and CEA at the local laboratory at screening 
to determine eligibility. A confirmatory 
sample must be submitted to the central 
laboratory.
* Perform within 7 days of starting study 
intervention.
CEA (local 
laboratory)
X*
PT or INR and 
aPTT/PTT
X*
* Perform within 7 days of starting study 
intervention.
Monitor closely in participants receiving 
anticoagulant therapy.
ECOG PS
X*
X
X
X
X
X
X
* Perform within 7 days of starting study 
intervention (C1D1). 
For all other visits, perform prior to study 
intervention administration.
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Biomarkers
Blood for genetic 
analysis
X
Collect prior to administration of study 
intervention. Refer to Section 8.8 for 
additional collection information.
Blood for RNA 
analysis
X
X
X
X
X
Blood for ctDNA
X
X
X
X
X
X
Plasma for BMx 
analysis
X
X
X
X
Blood for BMx 
analysis
X
Microsampling Device Collection
 
microsampling 
device (In Clinic)
X
X
X
X
Collect prior to administration of study 
intervention. Two 
 devices to be 
collected in clinic 
 
microsampling 
device (At Home)
X
X
Two 
 devices to be collected within +3 
days of C1D1 and C3D1.
 device (In 
Clinic) for 
participants at 
select 
investigational sites
X
X
X
X
Collect prior to administration of study 
intervention. Refer to laboratory manual for 
list of select sites.
CCI
CCI
CCI
CCI
CCI
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PRODUCT:  MK-4830  
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Device collection 
failure assessment
X
X
X
X
Collect information when the device(s) fails 
to collect the full volume of blood due to 
cartridge or device failure.
Tissue Collection
Tumor tissue at 
baseline
X
Prior to randomization, archival or newly 
obtained tissue at Screening must be 
confirmed to be of sufficient quality and 
quantity to analyze the primary endpoint by 
the designated laboratory.
Tumor tissue at 
surgery
X
Newly obtained tumor tissue removed 
during interval debulking must be submitted. 
If participant is unable to undergo interval 
debulking, core or excisional biopsies 
should be obtained, if possible.
Newly obtained 
fresh tumor tissue 
from participants at 
select 
investigational sites
X
X
Refer to the laboratory manual for list of 
select sites. 
Leftover fresh tissue may be frozen for 
translational oncology research as defined in 
Section 4.2.1.5.1, only if there is 
documented optional translational oncology 
research informed consent. If risk of sample 
collection is deemed medically unsafe for 
the study participant, site should consult 
with Sponsor
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PRODUCT:  MK-4830  
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10-APR-2024
Study Period:
Screen-
ing
Intervention
Treatment Cycle = 21 days
EOT
Safety 
Follow-
upa
Long-
term 
Follow-
up
Notes
Neoadjuvant 
Phase
Debulking 
Surgery
Adjuvant Phase
Visit Timing/Cycle 
Number:
–28 to 
–1
1
2
3
–
4
5
6
At 
DC
30 Days 
post last 
dose
Q4W for 
24 Weeks If surgery is delayed (only after Sponsor 
approval), the number of cycles in the 
neoadjuvant and adjuvant phase will alter 
but should not exceed 6 total cycles.
Cycle Day:
1
1
1
–
1
1
1
–
–
–
Screening 
Window (Days):
+3
±3
±3
–
±3
±3
±3
At 
DC
+7
±3
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; AUC = area under the concentration-time curve; BMx = biomarker; 
BRCA = breast cancer susceptibility gene; C1D1 = Cycle 1 Day 1; C3D1 = Cycle 3 Day 1; CA-125 = cancer antigen 125; CEA = carcinoembryonic antigen; 
CRS = chemotherapy response score; ctDNA = circulating tumor DNA; DC = discontinuation; DLT = dose-limiting toxicity; ECG = electrocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance score; EOT = end-of-treatment; FBR=future biomedical research; FSH=follicle-stimulating 
hormone; FT4 = free thyroxine; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HRD = homologous repair 
deficiency; ICF = informed consent form; ID=identification; INR = International Normalized Ratio; IRT = interactive response technology; OC = ovarian 
cancer; pCR = pathological complete response; PE = physical examination; PT = prothrombin time; PTT = partial thromboplastin time; Q3W = every 3 
weeks; RNA = ribonucleic acid; SAE=serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing 
potential; WONCBP = women of nonchild-bearing potential.
a.
If the Discontinuation Visit (Section 8.11.3) occurs ≥30 days from the last dose of study intervention, the Safety Follow-up Visit does not need to be 
performed.
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1.3.1
Imaging Assessments for Neoadjuvant/Adjuvant Treatment Period With 
Interval Debulking Surgery
Neoadjuvant / Adjuvant Treatment Period With Interval Debulking
Imaging Visit
Description
Baseline
Perform imaging within 28 days prior to starting chemotherapy.
Peri-surgery

Presurgery: Imaging performed a minimum of 21 days (+5 days) after 
C3D1

Postsurgery: Imaging performed prior to resuming study intervention in
C4D1 (-5 days)
Note: If surgery is delayed, imaging should be delayed until prior to surgery 
(a minimum of 21 days after the last cycle of study intervention in the 
neoadjuvant phase) and then performed prior to the first dose of study 
intervention in the adjuvant phase. If cytoreduction is attempted but not 
performed (with or without biopsy collection) or deemed inappropriate, the 
next scheduled imaging assessment after C3D1 would occur at the EOT
visit.
End-of-Treatment
Imaging performed at the time of treatment discontinuation (±4 weeks) and 
prior to starting a new anticancer treatment. If previous imaging was 
obtained within 4 weeks (28 days) before the date of discontinuation, then 
imaging at treatment discontinuation is not mandatory.
Abbreviations: C3D1 = Cycle 3, Day 1; C4D1 = Cycle 4, Day 1; EOT = end-of-treatment. 
NOTES: 

Chest, abdomen, and pelvis imaging – required at baseline and every timepoint according to the schedule 
above.

Bone imaging – required at baseline for participants with a history of bone metastases or who are clinically 
symptomatic. If positive for bone metastases at baseline, perform bone imaging according to the schedule 
above.

Brain imaging – required at baseline for participants with a history of brain metastases (to confirm stability) or 
who are clinically symptomatic (to rule out brain metastases). If positive for brain metastases, but eligible as 
noted in the eligibility criteria (Section 5.2, exclusion criterion No. 10) perform brain imaging according to the 
schedule above.

Unscheduled imaging may be performed as clinically indicated.
2
INTRODUCTION
MK-4830 is a novel 
 that is an antagonist of ILT4. MK-4830 is under study 
for the treatment of solid tumors as monotherapy and as combination IO therapy with 
pembrolizumab.
2.1
Study Rationale
Treatment of newly diagnosed advanced OC is determined by the stage and risk of disease 
recurrence at diagnosis. Treatment options include either cytoreductive surgery followed by 
adjuvant chemotherapy (most likely platinum- and taxane-based) or chemotherapy alone. 
Alternatively, when the removal of all cancer during the initial surgery would be problematic 
due to tumor size, chemotherapy may be administered before surgery (neoadjuvant 
chemotherapy) to shrink the tumor, with additional chemotherapy after surgery (adjuvant 
chemotherapy). Clinically, complete remission is achieved in most newly diagnosed patients 
through a combination of cytoreductive surgery and chemotherapy; however, 10% of patients 
might not respond to first-line chemotherapeutic treatment and, of those who do respond, 
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between 55% and 75% will relapse within 2 years [du Bois, A., et al 2009] [Ledermann, J. 
A., et al 2013] [Edwards, S. J., et al 2015]. The overall 5-year survival rate for OC remains 
poor, ranging from 28% to 57% depending on age at diagnosis [Eisenhauer, E. L., et al 2012] 
[Edwards, S. J., et al 2015].
The anti-PD-1 antibody pembrolizumab has shown efficacy in combination with 
chemotherapy in patients with several advanced cancers and has a nonoverlapping toxicity 
profile with chemotherapy. The addition of pembrolizumab to carboplatin and pemetrexed 
improved efficacy and had a favorable benefit-to-risk profile in patients with chemotherapy-
naïve, advanced nonsquamous NSCLC [Langer, C. J., et al 2016]. As neoadjuvant treatment, 
the addition of pembrolizumab to a carboplatin- and anthracycline-based neoadjuvant 
chemotherapy regimen for high-risk, early-stage TNBC provided a statistically significant
improvement in the rate of pCR at the time of definitive surgery [Schmid, P., et al 2020] as 
well as a statistically significant and clinically meaningful improvement in EFS when 
continued as monotherapy in the adjuvant setting [Schmid, P., et al 2021]. These are the first 
published data to prospectively show a benefit of the addition of a PD-1 pathway inhibitor to 
chemotherapy for the neoadjuvant treatment of TNBC. Ongoing studies in several different 
tumor types are currently investigating the benefit of the addition of pembrolizumab to other 
front-line platinum-based chemotherapies, including OC (KEYLYNK-001).
While the advances in immunotherapy have improved treatment outcomes in cancer, tumors 
have several disparate mechanisms to limit immune responses and escape 
immunosurveillance. These resistance mechanisms vary by immune cell population, 
suggesting the need for combination therapy that inhibits multiple interacting pathways. 
Recent advances in targeting the PD-1/PD-L1 axis has demonstrated the potential for 
combination immunotherapy [Upadhaya, S., et al 2021]. 
One such approach centers on the modulation of immune-suppressive and tumor promoting 
myeloid populations [Chaib, M., et al 2020]. MDSCs in the tumor microenvironment 
represent a separate contributing feature of immune suppression and tumor promotion [Gao, 
X., et al 2021]. These MDSC populations contribute greatly to tumor immune evasion 
through multiple mechanisms including suppression of local T-cell activation and 
proliferation [Adah, D., et al 2016]. In OC, MDSCs are associated with immune suppression, 
tumor metastasis, shorter OS, a reduced disease-free interval, and poor prognosis [Singel, K. 
L., et al 2019] [Taki, M., et al 2018] [Banerjee, S., et al 2013], [Cui, T. X., et al 2013] 
[Huang, Q. T., et al 2017] [Mabuchi, S., et al 2021]. Therefore, relief of myeloid immune 
suppression in conjunction with T-cell activation through inhibition of the PD-1/PD-L1 axis, 
may improve antitumor efficacy in OC [Mabuchi, S., et al 2021]. 
MK-4830 is an antagonistic antibody directed toward ILT4, an inhibitory receptor that is 
highly expressed on myeloid cells and thought to be involved in immune tolerance and 
immunosuppression [Gao, A., et al 2018] [Gao, A., et al 2021]. Internal preclinical data 
demonstrate MK-4830 treatment results in tumor growth inhibition in 
 
 supporting the scientific rationale underlying 
this study. The dose-escalation portion of the Phase 1 study (MK-4830-001) has recently
been completed [Siu, L. L., et al 2020] [Siu, L. L., et al 2021]; based on safety and efficacy 
results, several expansion cohorts are planned, including an expansion cohort in OC.
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CA-125 is the best-characterized blood-based biomarker in OC and has been widely studied. 
To improve its clinical utility [Berek, J. S., et al 2018], CA-125 has been used for both 
disease screening and monitoring [Rosenthal, A. N., et al 2017] [Berek, J. S., et al 2018] 
[Jacobs, I. J., et al 2016]. CA-125 levels do correlate with response to chemotherapy
[Crawford, S. M. 2005], and levels of CA-125 prior to interval debulking surgery are 
associated with improved survival [Vasudev, N. S., et al 2011]. Although screening studies 
have demonstrated CA-125 increases the proportion of patients diagnosed with early-stage
disease, the assay characteristics have prevented implementation of a screening program for 
OC. Use of CA-125 for disease monitoring during follow-up does not improve OS. 
Additionally, there are shortcomings of CA-125 monitoring that have resulted in the need to 
evaluate alternative technologies for blood-based biomarker development for both disease 
screening and monitoring tumor burden throughout treatment. 
In recent years, the utility of interrogating genetic material released from tumor cells has 
provided the impetus for novel biomarker discovery and clinical utilization in OC 
[Thusgaard, C. F., et al 2021]. This led to the discovery and approach of liquid biopsies 
[Crowley, E., et al 2013] [Siravegna, G., et al 2017], which covers the approach of using 
tumor-derived circulating cfDNA and RNA, circulating tumor cells, and exosomes for the 
identification of disease. Of these technologies, ctDNA has proven to have the most utility 
due to stability and other technical considerations. 
In OC, ctDNA has been used in an exploratory fashion for screening [Widschwendter, M., et 
al 2017], diagnosis [Vanderstichele, A., et al 2017], and prognosis [Thomsen, C. B., et al 
2019]. More importantly, the ability of ctDNA to interrogate tumor genetics [Lin, K. K., et al 
2019] [Dvorska, D., et al 2019] has provided a noninvasive mechanism for determination of 
tumor biology and potential treatment allocation. Furthermore, ctDNA has provided the 
opportunity to assess mechanisms of treatment response and resistance as shown by the 
identification and detection of reversion mutations to PARP inhibitors [Lin, K. K., et al 
2019]. However, it is in disease monitoring where ctDNA offers much needed clinical utility, 
particularly as a replacement for CA-125. Two recent studies have demonstrated the ctDNA 
technology was better at monitoring treatment response than CA-125 [Widschwendter, M., et 
al 2017]. A recent study in OC using the Signatera assay from Natera Inc. demonstrated the 
ability to generate patient-specific ctDNA assays for disease monitoring. This data further 
highlighted the utility of ctDNA over that of CA-125 to monitor disease burden [Chapman, J. 
S., et al 2021]. More recently, ctDNA was investigated in the neoadjuvant OC setting in the 
CIDOC study (NCT03302884) [Mari, R., et al 2021]. This study demonstrated ctDNA may 
be a promising noninvasive marker to assess peritoneal cancer spreading and to predict 
surgical resection after neoadjuvant chemotherapy. 
These data show the broad utility of ctDNA in OC and paths for future clinical development. 
In this translational study, we will investigate the clinical utility of ctDNA in OC as a blood-
based technology to assess tumor biology and disease monitoring during 
neoadjuvant/adjuvant therapy with pembrolizumab and SOC chemotherapy with or without 
MK-4830. Furthermore, we will interrogate ctDNA as an early blood-based marker in 
relation to surgical outcomes [Siu, L. L., et al 2021]. It is envisaged that incorporation of 
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ctDNA technology will aid in the clinical development of promising agents like MK-4830 in 
addition to enhancing disease biology and mechanisms of drug action and resistance.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-4830 and 
pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ Tregs correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; HCC; 
malignant melanoma; and RCC. TILs can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] 
[Hunder, N. N., et al 2008].
2.2.1.1
MK-4830 Background
MK-4830 is a novel, first-in-class, 
 with high specificity of binding to 
the ILT4 receptor, thus inhibiting its interactions with MHC class I molecules including 
HLA-G. Based on in vitro data, MK-4830 has high affinity and potent receptor blocking 
activity to ILT4. MK-4830 has an acceptable preclinical safety profile and is in clinical 
development as an IV immunotherapy for advanced solid tumors. This mAb is being 
developed as a cancer immunotherapeutic with the potential to be used as an IO combination
with KEYTRUDA® (pembrolizumab; a humanized anti-PD-1 receptor antibody), to increase 
anti-tumor efficacy in patients with various tumor indications.
ILT4, also known as LILRB2, is an inhibitory member of the LILR family that is expressed 
on myeloid and dendritic cells [Colonna, M., et al 1997] [Colonna, M,, et al 1998] [Fanger, 
N. A., et al 1998]. ILT4 binds MHC class I molecules including HLA-G [Allan, D. S., et al 
1999] [Shiroishi, M., et al 2003] [Shiroishi, M., et al 2006]. HLA-G can directly inhibit 
immune cell function including cytolysis, proliferation, maturation, and chemotaxis [Lin, A. 
and Yan, W. H. 2015] [Morandi, F., et al 2014]. ILT4 and HLA-G are reported to have high 
expression in multiple tumor types [Liu, J., et al 2014] [Loumagne, L., et al 2014]. The 
interaction of ILT4 with HLA-G promotes signaling through immunoreceptor tyrosine-based 
inhibitory motifs via activation of SHP-1. This signaling can antagonize immunoreceptor 
tyrosine-based activation motif receptor-mediated activation of myeloid cells [Colonna, M,, 
et al 1998]. ILT4 signaling is also associated with induction of tolerogenic phenotypes in 
antigen presenting cells and was shown to promote HLA-G-dependent Type 1 regulatory T-
cell development [Gregori, S., et al 2010].
In addition to HLA-G and other classical and non-classical MHC class I molecules (HLA-A, 
B, C, E, F, G), ILT4 has a range of additional ligands that include the ANGPTL family of 
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soluble signaling molecules and the MHC-like molecules CD1d [Zheng J, Umikawa M, Cui 
C, Li J, Chen X, Zhang C, et. al. 2012] [Li, D., et al 2009]. The range and variable immune 
functions of these ligands suggests a broader integrated immune biology of considerable 
complexity. ILT4 signaling may directly inhibit the function of monocytes, dendritic cells,
and neutrophils, thus impairing the innate and adaptive immune anti-tumor response. 
Consequently, interrogating the breadth of ILT4 immunosuppressive activity has 
implications for ascertaining combination therapies and identifying cancer histologies for 
clinical investigation. 
In OC, expression of the ILT4 ligand, HLA-G, is associated with advanced stage disease, 
high-grade histology, and worse prognosis [Sheu, J. J. C. 2007] [Song, M. J., et al 2021] 
[Andersson, E., et al 2016]. HLA-G is more frequently expressed in advanced serous
metastatic cells than in primary tumor lesions and inversely correlated with the frequency of 
tumor-infiltrating immune cells [Andersson, E., et al 2016]. HLA-G is also associated with 
direct immune evasion [Menier, C., et al 2009]. 
MK-4830 is a 
 anti-ILT4 antagonistic mAb on an 
/Lambda framework. MK-4830 
was selected based on its specificity to ILT4, its ability to block HLA-G binding to ILT4 and 
its ability to rescue ILT4-related inhibitory function. The 
 isotype was chosen to 
minimize effector function and framework-mediated cross-linking ability leading to agonist 
activity.
 
. 
In addition, MDSCs promote immunosuppression in the tumor microenvironment via 
inhibition of local T-cell activation and proliferation. Therefore, relief of myeloid 
immunosuppression may potentiate T-cell activation and improve the efficacy of T-cell 
targeted therapies such as pembrolizumab, even in tumors that do not normally respond to 
PD-1 antagonism alone. This would suggest that removal of immune suppression, induced by
ILT4 blockade using MK-4830, combined with the T-cell check point inhibitor, 
pembrolizumab, will offer substantially augmented anti-tumor efficacy compared with either 
treatment alone. This scientific rationale provides justification to pursue MK-4830 and 
pembrolizumab as combination therapy.
For more details refer to the MK-4830 IB.
2.2.1.2
Pembrolizumab Background
Pembrolizumab is a potent
 with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
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The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, 
J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which 
PD-1 down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, 
because both molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 
2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in OC.
For more details on specific indications refer to the pembrolizumab IB.
2.2.1.3
Overview of Ovarian Cancer
OC is one of the leading causes of cancer death among women [Sung, H., et al 2021]. In 
2021, the estimated number of new cases and deaths from OC in the US is 21,410 and
13,770, respectively [Siegel, R. L., et al 2021]. Worldwide, OC represents one of the 10 most 
common cancer diagnoses and one of the leading causes of cancer-related deaths in women 
[Sung, H., et al 2021]. Due to lack of tumor-specific signs and symptoms and effective 
screening tests for early detection, over 75% of OC patients are first diagnosed at advanced 
stages. Based on the US data from 2010 to 2016, at initial diagnosis, 58% had distant 
metastasis, 21% had regional disease and only 16% had localized disease [Siegel, R. L., et al 
2021]. The overall 5-year survival rate of OC is approximately 49% counting all stages of 
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disease, whereas, the 5-year survival rate for patients with distant metastasis is only 30% 
[Siegel, R. L., et al 2021].
OC is a heterogeneous disease, with distinct histopathologic features, genetic alterations, and 
clinical behaviors. Epithelial OC is the most common (90% of OC) and most lethal of the 
gynecologic malignancies [Gilks, C. B. and Prat, J. 2009]. Currently, epithelial OC are 
classified into 5 main subtypes based on histopathology, immunohistochemistry, and 
molecular-genetic characteristics: HGSOC (~70% of epithelial OC), endometrioid carcinoma 
(~10% of epithelial OC), clear cell carcinoma (~10% of epithelial OC), mucinous carcinoma 
(~3% of epithelial OC), and low-grade serous carcinoma (<5% epithelial OC) [Gilks, C. B. 
and Prat, J. 2009] [Prat, J. and FIGO Committee on Gynecologic Oncology 2014]. The 
distinction of epithelial OC subtype at diagnosis/staging is a critical factor that will guide 
treatment, as each tumor type responds differently to chemotherapy [Gilks, C. B. and Prat, J. 
2009]. Primary peritoneal carcinoma and fallopian tube carcinoma are rare and distinct tumor 
types that have typically been managed and studied together with epithelial OC as they share 
similar clinical and pathological characteristics with HGSOC [Cannistra, S. A., et al 2011].
2.2.1.4
Current Standard of Care and Unmet Medical Need
The current SOC for advanced epithelial OC (FIGO Stage II to Stage IV) includes primary 
cytoreductive/debulking surgery followed by postoperative front-line (ie, adjuvant) systemic 
treatment with IV carboplatin and paclitaxel administered Q3W for 6 cycles; however, 
weekly paclitaxel has also been frequently used to replace Q3W paclitaxel. In addition, 
where locally approved for front-line treatment, IV bevacizumab can be added to IV 
carboplatin and paclitaxel for up to 6 cycles in the adjuvant setting and then continued as a 
single agent in the maintenance setting. The utilization of bevacizumab in the first-line and 
maintenance settings is variable based on local guidelines and patient characteristics [Hall, J. 
P., et al 2020]. This leads to a heterogeneous population that has implications for clinical 
study design, efficacy assessment of agents in early development, and the contribution of 
anti-angiogenesis pathways for translational data analyses. In a recent analysis of real-world 
data on OC treatment obtained from 340 physicians from the US and select European 
countries, only 26% of patients received a bevacizumab-containing regimen in the first-line 
setting [Hall, J. P., et al 2020]. In suitable cases, postoperative chemotherapy, usually 
cisplatin plus paclitaxel, can be delivered via the intraperitoneal route. Finally, in cases with 
bulky disease that is initially unresectable, 3 cycles of standard platinum/taxane-based 
chemotherapy can be administered as neoadjuvant therapy prior to cytoreductive/debulking 
surgery (ie, interval cytoreductive/debulking surgery) followed by an additional 3 cycles of 
standard platinum/taxane-based chemotherapy [Morgan, R. J ., et al 2016] [Ledermann, J. A., 
et al 2013].
The goal of cytoreductive/debulking surgery is to achieve resection of all macroscopically 
visible tumors, while the goals of postoperative first-line chemotherapy are: 1) to help 
achieve complete remission in those with residual disease, and 2) to prevent disease 
recurrence for those with complete tumor resection. However, after these primary treatments, 
only a small proportion of patients will achieve long-term disease-free and survival status. A 
meta-analysis on data from 3 randomized studies following the standard primary treatment 
with surgery and platinum/taxane-based chemotherapy (N=3126), showed that only 24% of
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patients were recurrence-free after a median follow-up time of 53.9 months. The remaining 
76% had recurrent disease (17.2%) or had died (58.8%) [du Bois, A., et al 2009]. 
Maintenance treatment for adult ovarian cancer patients follows first-line platinum-based 
chemotherapy and is composed of bevacizumab and/or PARPi-based regimens. The specific 
maintenance regimen will depend upon patient characteristics, homologous recombination 
deficiency status, and the response to first-line therapy among others [Mirza, M. R., et al 
2021] [Advani, S. H., et al 2021] [Hall, J. P., et al 2020], [Gupta, S., et al 2019]. 
Consequently, the maintenance setting treatment in an unselected population is 
heterogeneous with respect to therapy utilization and clinical outcomes. Due to lack of 
baseline clinical or safety datasets on the efficacy of MK-4830 with selected first-line OC
patient populations, coupled with the design considerations of treatment heterogeneity in the 
maintenance setting, this study will complete after platinum-based therapy. Participants will 
discontinue study intervention and undertake maintenance therapy as per local treatment 
guidelines. 
While the current SOC is initially effective for the treatment of epithelial OC, approximately 
70% of patients will experience a relapse within 3 years of treatment cessation [du Bois, A., 
et al 2009] [Ledermann, J. A., et al 2013]. Thus, there is an unmet medical need for therapies
that, when used in combination with the current SOC, significantly increases the proportion 
of patients with complete remission and prevents disease recurrence in patients with 
advanced epithelial OC. Increasing our understanding of the biology and immunology of OC 
will aid in the development and integration of those new therapies.
2.2.2
ctDNA
ctDNA is the release of genomic DNA from tumor cells mainly via apoptosis, necrosis, and 
secretion [Chen, Q., et al 2019]. ctDNA can be readily detected in plasma and other fluids 
like the cerebrospinal fluid, saliva, and urine. However, blood is becoming the predominant
sample for ctDNA interrogation. Blood-based interrogation of ctDNA offers many patient 
and logistical advantages over tissue-based methods. Constantly improving technology and 
assay development has meant that the ability of ctDNA to be used as an analyte for 
translational and biomarker cancer research has expanded significantly. 
The US FDA has already approved several single-gene assays or multigene panels to detect 
tumor genetic alterations in plasma ctDNA for use as companion diagnostics that is then 
matched to specific molecularly-targeted therapies. Proposed uses of ctDNA in OC range 
from early detection through to identification of tumor genetics and biology [Sharbatoghli, 
M., et al 2020] [Yu, M., et al 2021] [Chen, Q., et al 2019], [Cheng, X., et al 2017] [Elias, K. 
M., et al 2018]. Recent data has also demonstrated ctDNA as a predictor of neoadjuvant 
therapy and surgical outcomes [Mari, R., et al 2021]. This is of particular interest in the 
neoadjuvant setting as it potentially enables a rapid determination of clinical activity for new 
therapeutics and may enhance criteria for predicting surgical outcomes like CRS. 
The next technical advances for clinical applications likely include early cancer detection 
and, in the adjuvant or maintenance setting, making treatment decisions based upon detection 
of ctDNA as a surrogate for disease burden in patients that is indicative of early relapse prior 
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to image detection. Detection of minimal residual disease using flow cytometry or PCR-
based methods has been well-established within hematological malignancies like AML 
[Voso, M. T., et al 2019] or lymphoma [Jung, D., et al 2020]. However, similar technologies 
with high levels of specificity and sensitivity have been lacking for solid tumors. Some 
technologies like circulating tumor cells [Wu, C. Y., et al 2020] or exosomes [Garcia-Silva, 
S., et al 2021] have shown promise but will be technically difficult to implement or develop 
routine clinical assays. ctDNA represents a readily executable analyte with an expanding 
array of assay technologies for MRD detection from bespoke personalized assays [Bratman, 
S. V., et al 2020] to tumor-specific methylation-based patterning [Luo, H., et al 2021]. The 
use of ctDNA as a surrogate for disease burden in OC may prove more informative than CA-
125 in disease monitoring [Chapman, J. S., et al 2021]. 
2.2.3
Microsampling
Smaller collection volumes are critical in vulnerable populations such as pediatrics and 
oncology due to blood volume collection restrictions. To meet this demand, microsampling 
technologies are being developed and have been approved for collecting biological samples 
for clinical use. These approaches reduce sample volume, reduce pain associated with 
collection, and may enable collection outside of planned clinical visits. Providing 
opportunities to collect samples remotely can reduce patient burden and enable patients to 
enroll in clinical studies without being geographically colocated with clinical sites 
[Dockendorf, M. F., et al 2019] [Dockendorf, M. F., et al 2021]. The need to develop remote 
sampling capabilities was highlighted during the disruption in clinical studies from the 
COVID-19 pandemic [Brown, L., et al 2021]. Finally, the ability to collect samples outside 
the traditional clinic visit allows interrogation of biological changes that occur outside the 
logistical constraint of clinical site visits. Historically, new sampling technology has been 
successfully implemented across the pharmaceutical industry in multiple clinical studies for 
PK analysis [Kothare, P. A., et al 2016] [Li, C. C., et al 2018]. DBS microsampling 
applications for drug quantitation are well accepted and specific considerations for validation 
of DBS assays are included in the FDA bioanalytical method validation guidance released in 
May 2018 [Food and Drug Administration 2018]. New devices such as the 
 and 
provide high sample quality without the pain associated with fingerstick based
collection methods. MSD has experience implementing these new approaches across several 
clinical studies in infectious disease for drug level measurements. It is desirable to assess 
these novel technologies to determine the utility of these approaches for applications beyond 
PK.
2.2.4
Preclinical and Clinical Studies
Refer to the respective IBs for a summary of preclinical and clinical study data for MK-4830 
and pembrolizumab.
2.2.5
Ongoing Clinical Studies
Refer to the respective IBs for a summary of ongoing clinical studies for MK-4830 and
pembrolizumab.
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2.2.6
Information on Other Study-related Therapy
For additional information on carboplatin, paclitaxel (or docetaxel, if applicable), and 
Avastin (or biosimilar), refer to the respective approved product labels.
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 discussed in Section 2.2.1.4, the chemotherapy backbone carboplatin and paclitaxel 
represent one of the preferred treatment options for the first-line treatment of advanced OC
[Dewdney, S. B., et al 2010] [Machida, H., et al 2020] [Patel, A., et al 2021]. Given the high 
rate of relapse following initial treatment for OC [Ledermann, J. A., et al 2013], there is an 
unmet medical need for an effective and tolerable first-line treatment regimen. Furthermore, 
there is a need for the identification of biomarkers that will quickly predict response to 
treatment. The use of ctDNA as a surrogate for disease burden in OC may prove more 
informative than CA-125 in disease monitoring [Chapman, J. S., et al 2021].
OC is thought to be an immune responsive disease. Furthermore, in OC, the expression of the 
ILT4 ligand, HLA-G, is associated with advanced stage disease, high-grade histology, and 
worse prognosis [Sheu, J. J. C. 2007] [Song, M. J., et al 2021] [Andersson, E., et al 2016]. 
HLA-G was more frequently expressed in advanced serous metastatic cells than in primary 
tumor lesions and inversely correlated with the frequency of tumor-infiltrating immune cells 
[Andersson, E., et al 2016]. HLA-G was also associated with direct immune evasion [Menier, 
C., et al 2009]. Finally, the therapeutic benefit of adding pembrolizumab to chemotherapy, 
including in combination with platinum agents, has been shown in several indications (eg, 
NSCLC, HNSCC, TNBC; refer to the pembrolizumab IB). 
Data from KEYNOTE-100, in participants with recurrent OC, suggest improved efficacy for 
pembrolizumab monotherapy in those participants whose tumors express PD-L1 with the 
cutoff of CPS ≥10. KEYLYNK-001 is currently investigating the clinical activity of 
pembrolizumab in combination with platinum-based chemotherapy with or without olaparib. 
The combination of pembrolizumab and chemotherapy has been clinically established in 
several tumor types including TNBC in the neoadjuvant setting as demonstrated by 
KEYNOTE-522 [Schmid, P., et al 2020]. A recent study demonstrated that pembrolizumab 
may be safely added to preoperative treatment in neoadjuvant OC and worthy of additional 
investigation [Ray-Coquard, I. L., et al 2021] [Matulonis, U. A., et al 2020].
The MK-4830 Phase 1 study has demonstrated clinical activity in OC [Siu, L. L., et al 2021]
and acceptable safety when combined with pembrolizumab. In the 84 participants with 
multiple tumor types treated with MK-4830 (cutoff data was 10-JUL-2020), no DLTs were 
observed, and an MTD was not reached in either the monotherapy or the pembrolizumab 
combination therapy group.
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Therefore, targeting the ILT4 and PD-1/PD-L1 pathway in addition to one of the preferred 
chemotherapy regimens for OC is an attractive target for therapeutic intervention. The 
benefit-risk for this study is considered to be favorable.
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.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In participants with high-grade serous ovarian cancer:
Objectives
Endpoints
Primary
Objective: Among patients with detectable 
ctDNA at baseline, to evaluate whether the 
reduction from baseline in circulating tumor 
DNA at Cycle 3 (ΔctDNA) is larger in 
participants receiving MK-4830 + 
pembrolizumab in combination with 
standard of care (SOC) therapy than in 
those receiving pembrolizumab + SOC 
therapy.
ctDNA, the continuous mean 
mutant/tumor molecules per mL. 
Secondary
Objective: Among patients with detectable 
ctDNA at baseline, to evaluate the 
association between neoadjuvant ΔctDNA 
at Cycle 3 from baseline and surgical
outcomes.
ctDNA
pCR, all surgical specimens collected 
during the interval debulking surgery are 
microscopically negative for residual 
tumor.
CRS, tiered response score based omental 
assessment of residual disease.
Objective: To estimate the difference in 
pCR and CRS following neoadjuvant 
treatment between arms.
pCR
CRS
Objective: To evaluate the safety and 
tolerability of the study intervention 
administered.
Adverse events (AEs)
Study intervention discontinuation due to 
AEs
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Objectives
Endpoints
Tertiary/Exploratory
Objective: 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-4830 in 
combination with pembrolizumab and SOC.
Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
Objective: To evaluate the ability of 
molecular (genomic, metabolic, and/or 
proteomic) data from microsampling, 
collected in the clinic and at home, to 
replicate molecular data obtained from 
traditional blood collection.
Genetic (DNA) mutations from tumor, 
tumor and blood RNA variation, 
proteomics and metabolomics, and other 
blood-derived biomarkers (eg, cfDNA) 
using traditional blood collection and 
microsampling.
Objective: To evaluate microsampling 
device use, feasibility of collection, and 
accuracy of collecting microsamples both at 
the clinic and at home.
Compliance in use of device 
Device performance
Quality of samples collected
Sample volumes collected
Objective: To evaluate whether baseline 
ctDNA levels are associated with 
neoadjuvant chemotherapy and surgical 
outcomes.
Mean mutant/tumor molecules per mL
pCR
CRS
Objective: To evaluate ctDNA and CA-125 
as markers for disease monitoring.
ctDNA
CA-125
Measures of clinical response (eg, 
complete response [CR] and partial 
response [PR]) and surgical outcome
Objective: To evaluate additional measures 
of clinical response, such as objective 
response rate as assessed by the investigator 
according to RECIST 1.1 in participants 
with measurable disease in each arm 
separately.
Measures of clinical response (eg, CR and 
PR)
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, randomized, active-controlled, parallel-group, multisite, open-label, 
neoadjuvant and adjuvant study of pembrolizumab and SOC therapy with MK-4830 versus 
pembrolizumab and SOC therapy in participants with high-grade serous OC.
Approximately 160 participants will be randomly assigned in a 1:1 ratio to 1 of 2 treatment 
arms:
Arm 1:
Neoadjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg Q3W) 
plus MK-4830 (800 mg Q3W) prior to surgery
Adjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg Q3W) plus 
MK-4830 (800 mg Q3W) ± Avastin (or biosimilar) after surgery
Arm 2:
Neoadjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg Q3W)
Adjuvant phase: 3 cycles of carboplatin/paclitaxel* plus pembrolizumab (200 mg Q3W) ± 
Avastin (or biosimilar) after surgery
*
At the investigator’s discretion and determined prior to the participant being 
randomly assigned to study intervention, one of the following regimens should be 
selected:
Carboplatin AUC 5 or AUC 6 Q3W plus paclitaxel 175 mg/m2 Q3W
Docetaxel may be considered for participants who experience either a severe 
hypersensitivity reaction to paclitaxel or an AE requiring discontinuation of 
paclitaxel only after consultation and approval with the Sponsor. The 
recommended dose, as determined by the SGCTG group [Vasey, P. A., et al 
2004], is as follows:
Docetaxel 75 mg/m2 Q3W plus carboplatin AUC 5 or AUC 6 Q3W
Participants will receive 3 cycles of study intervention prior to interval debulking surgery 
(neoadjuvant treatment) and another 3 cycles of study intervention after interval debulking 
surgery (adjuvant treatment) Figure 1. Interval debulking surgery should be completed no 
more than 6 weeks after last dose of neoadjuvant treatment. Participants should resume study 
intervention when clinically appropriate but no more than 7 weeks following interval 
debulking surgery. Sponsor consultation and approval is required for surgeries delayed 
>6 weeks after Day 1 of Cycle 3. 
Participants for whom interval debulking is either attempted and not performed or deemed 
inappropriate may continue on-study intervention for up to 6 cycles following Sponsor 
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consultation and approval. Such participants should resume study intervention as planned at 
the next treatment cycle (ie, no more than 3 weeks after Day 1 of Cycle 3).
The optional use of Avastin (or biosimilar) in the adjuvant phase (ie, Cycles 4 to 6) is 
permitted according to local practice and at the choice of the investigator; however, the 
investigator must decide on the use of Avastin (or biosimilar) after surgery and it must be 
selected in IRT prior to starting treatment in the adjuvant phase. If surgery is delayed
(following Sponsor consultation and approval), Avastin (or biosimilar) cannot be started until 
after surgery. Note: Use of Avastin (or biosimilar) is not permitted in the neoadjuvant phase 
(ie, prior to surgery in Cycles 1 to 3).
For participants who will receive Avastin (or biosimilar) in the adjuvant phase, there is a
Safety Lead-in to demonstrate a tolerable safety profile for Arm 1 when Avastin (or 
biosimilar) is added. Participants treated with pembrolizumab + MK-4830 + 
carboplatin/paclitaxel + Avastin (or biosimilar) will be closely followed for DLTs for the 
first cycle after the first dose of study intervention in the adjuvant phase (the DLT evaluation 
period). The number of participants with DLTs (Section 6.6.3) will be monitored according 
to the mTPI [Ji, Y., et al 2007] table as outlined in Table 9 (Appendix 9) with a target DLT 
rate of 30%. If a DU is reached or a D is indicated Table 9, the use of Avastin (or biosimilar) 
will be prohibited for the remainder of the study.
This study will use an siDMC to monitor safety (Appendix 1). The siDMC will review safety 
data from all participants on a frequent basis throughout the study as outlined in the siDMC 
charter. The siDMC may meet on an ad hoc basis to review additional safety data as needed.
After Cycle 6, participants will have completed study intervention and may begin 
maintenance therapy at the discretion of the investigator, per institutional guidelines and 
local regulatory approvals. Participants who have completed study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Long-
term Follow-up as outlined in Section 8.11.4.2.
Tumor marker data (ie, CA-125) will not be used for defining PD to evaluate 
progression-related study objectives; however, CA-125 may be used to make clinical 
decisions, including the decision to discontinue a participant from study intervention
(Section 7.1). Clinical criteria such as the Gynecologic Cancer Intergroup criteria [Rustin, G. 
J., et al 2011] will also be considered for the management of clinical events (eg, bowel 
obstruction) without radiographic disease progression. Participants who discontinue due to 
CA-125 increase and concurrent malignant bowel obstruction will have post-treatment
follow-up imaging to evaluate disease status until disease progression is radiographically 
documented per RECIST 1.1 by the investigator as outlined in Section 8.2.1.4.
Participants will be followed for 30 days after the last dose of study intervention in Cycle 6 
(Section 8.11.4.1). AE monitoring will be ongoing throughout the study and graded in 
severity according to the guidelines outlined in the NCI CTCAE v5.0. AEs and SAEs will be 
reported by the investigator or delegate as outlined in Section 8.4.1.
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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.
4.2
Scientific Rationale for Study Design
Patients with advanced OC have a poor 5-year survival rate (30%), which represents an area 
of unmet medical need that may benefit from novel IO and chemotherapy options, improved 
patient treatment selection, and more advanced monitoring while on-treatment. Determining 
patient selection criteria and treatment combinations requires the development of 
translational datasets and establishment of key technology to achieve those goals. 
The neoadjuvant/adjuvant setting with interval debulking surgery is a recognized SOC
treatment algorithm for first-line advanced OC. The neoadjuvant setting allows for rapid 
assessment of translational and clinical objectives through sample collection and 
determination of pathological responses at surgery. Three cycles of neoadjuvant standard 
platinum/taxane-based chemotherapy prior to cytoreductive/debulking surgery (ie, interval 
cytoreductive/debulking surgery) followed by an additional 3 cycles of standard 
platinum/taxane-based chemotherapy is an accepted clinical design [Morgan, R. J ., et al 
2016] [Ledermann, J. A., et al 2013]. Three cycles of neoadjuvant therapy are a suitable 
number of treatment cycles to evaluate treatment-related-related changes in the tumor 
microenvironment and immune system generated by checkpoint inhibition.
This clinical study will test the utility of ctDNA as a measure of clinical response and 
minimal residual disease (in conjunction with other exploratory immune markers) in 
treatment-naïve HGSOC treated with a combination of SOC therapy and a novel 
immunotherapy combination of PD-1 and ILT4 inhibitors. 
Cancer cells shed ctDNA, which represents an increasingly important blood-based analyte 
for interrogation of tumor presence, tumor biology, genetics, and disease burden. Clinical 
evidence has demonstrated that ctDNA provides a blood-based mechanism to detect minimal 
residual disease and serve as a predictor for both response, treatment resistance, and disease 
progression months prior to RECIST 1.1 assessment or surgery [Ignatiadis, M., et al 2021]. 
Furthermore, ctDNA has the potential to complement other established blood-based markers 
like CA-125 [Soletormos, G., et al 2016]. Analysis of ctDNA has a potential regulatory role 
as a surrogate biomarker for clinical and surgical outcomes, and disease progression. It is 
envisaged that by exploring ctDNA in the neoadjuvant and surgical OC setting will help 
define criteria for rapid appraisal of treatment outcomes. 
The advent of targeting immune checkpoints such as CTLA-4 and PD-1 has led to several 
treatment advances in oncology [Marin-Acevedo, J. A., et al 2021]. Inhibitors against 
additional checkpoints such as TIGIT and LAG3 [Rodriguez-Abreu, D., et al 2020] have 
shown initial clinical activity. These targets are predominantly T-cell targets with some 
expression in other immune cell types. 
The myeloid ILT4 pathway has more recently been defined as a new checkpoint target for 
therapeutic intervention [Gao, A., et al 2021]. Unlike the aforementioned targets, there is 
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little known about the functionality of this pathway in the broader oncology space,
particularly mechanisms of response and resistance. Unlike PD-1 which has 2 identified 
ligands, PD-L1 and PD-L2, ILT4 has considerably more complexity with several ligands 
identified [Gao, A., et al 2018]. Thus, delineating pathway biology is paramount for 
understanding mechanisms or response and resistance. MK-4830 has demonstrated clinical 
activity in a Phase 1 study [Siu, L. L., et al 2021] and is currently being investigated in 
several expansion cohorts, including late-stage OC. 
The complexity by which tumors escape immune surveillance suggests that multiple 
checkpoints may need to be targeted. Clinical evidence has demonstrated, in a wide range of 
tumor types, that many patients fail to respond to PD-1 inhibitors [Chen, S., et al 2021]. The 
combination of anti-PD-1 and anti-ILT4 agents is consistent with the hypothesis that 
removing multiple inhibitory signals of immune evasion could potentially result in an added 
benefit [Siu, L. L., et al 2021].
As with many oncology pathways under interrogation, early determination of clinical activity
is usually performed in the advanced setting beyond first-line therapy in heavily treated 
patients. This has implications for immune system status and tumor biology. This study
design enables a rapid read on activity and a treatment naïve population in which to study the 
immunology of the ILT4 pathway.
The SOC treatment paradigm for OC of interval debulking surgery along with neoadjuvant 
therapy is an appropriate clinical space for the above mentioned translational of 
investigations [Elies, A., et al 2018] [Machida, H., et al 2020] [Melamed, A., et al 2016],
[Qin, M., et al 2018]. Neoadjuvant chemotherapy offers the opportunity to test upfront 
chemosensitivity and response to new agents to identify early clinical activity and patients at 
higher risk of relapse. The advent of newer and effective treatment options targeting different 
tumor biologies (eg, PARP inhibitors) has opened the way to clinical trials investigating
these agents as a substitute or in addition to chemotherapy in the neoadjuvant setting in all 
comers or molecularly selected OC patients. Thus, neoadjuvant treatment before debulking 
surgery could also represent an optimal approach for testing new and effective treatments and 
biomarkers, with the potential to accelerate drug development due to availability of pre- and 
post-treatment tumor tissue [Cowan, R., et al 2016]. The latter point is of particular 
importance for agents like MK-4830 that are new classes of agents early in clinical 
development.
This study will also evaluate the potential of microsampling to obtain low volume and low 
risk blood samples to conduct multi-omic disease analyses. Reduction of collected blood 
volumes and the ability to have “at home” collection using this approach may allow 
incorporation of new translational and biomarker technologies into clinical care in the future. 
The recent advent of the COVID-19 pandemic has highlighted the need for reliable at home 
blood collection approaches such as the microsampling device that is incorporated into this 
study.
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Surgical outcomes will be measured using pCR criteria and CRS [Ivantsov, A. O. 2018] 
[Bohm, S., et al 2015]. CRS is an acceptable exploratory surgical criterion for assessing the 
completeness of neoadjuvant treatment followed by interval debulking surgery. It is a 3-
tiered scoring system (CRS1-3) based on the pathological analysis of surgically removed 
omental masses, with CRS3 (complete or near-complete response) characterized by the lack 
of residual tumor cells in the omentum or presence of tumor foci up to 2 mm maximum size. 
CRS3 is found after neoadjuvant chemotherapy in approximately 30% to 40% patients with 
high-grade serous OC and is reproducibly related with the improvement of the disease 
prognosis. In addition to CRS, complete pathological responses will be recorded [Bohm, S., 
et al 2015] and will be defined as all surgical specimens collected during interval debulking 
surgery are microscopically negative for residual tumor.
RECIST 1.1 will be used when assessing images for efficacy measures (Section 8.2.1.4).
This study will use objective response based on RECIST 1.1 criteria as assessed by the 
investigator as an exploratory endpoint. Objective response is defined as a confirmed CR or 
confirmed PR per RECIST 1.1 as assessed by investigator recorded between the start of and 
end-of-treatment, or disease progression or death due to any cause within that period, 
whichever occurs first.
4.2.1.1.1
RECIST 1.1
RECIST 1.1 will be used by the investigator when assessing images for primary efficacy
(Section 8.2.1.4). Although traditional RECIST 1.1 references 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.
4.2.1.2
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, 
causality, and outcome of AEs/SAEs, and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE v5.0.
4.2.1.3
Pharmacokinetic Endpoints
PK endpoints will not be evaluated in this study.
4.2.1.4
Pharmacodynamic Endpoints
The primary objective of this study will be to measure changes in ctDNA as a translational 
primary endpoint to establish the clinical validity of ctDNA kinetics in the neoadjuvant and 
adjuvant setting. The aim is to determine if quantification of ctDNA can perform as a 
surrogate for clinical and surgical response to the neoadjuvant combination therapies. ctDNA 
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is rapidly becoming an experimental surrogate measure of tumor burden and clinical 
responses in a range of clinical spaces across many tumor types.
4.2.1.5
Planned Exploratory Biomarker Research
The mechanism of action of many antitumor agents 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 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 antineoplastic 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. In addition to studying variation across 
the human genome, BRCA and homologous repair deficiency status will specifically be 
investigated as these are common in patients with HGSOC. 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 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 
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to treatment with antitumor therapies. Specific gene sets (ie, those capturing interferon-
gamma transcriptional pathways) may be evaluated and new signatures may be identified. 
Individual genes may also be evaluated (eg, IL-10). MicroRNA profiling may also be 
pursued as well as exosomal profiling.
Proteomics and IHC using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, for example. 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 
antitumor 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 therapy may identify new approaches for 
predictive biomarkers in blood, representing a major advance from today’s reliance on 
assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.1.5.1
Translational Oncology Research
The tumor microenvironment plays a fundamental role to dictate the efficacy of cancer 
immunotherapy. Multiple cell types are present and cross-talk with each other in the tumor 
milieu. To better understand how different cell types and their interactions affect patient 
responses, as well as to better understand molecular mechanisms of cancer, patient-derived 
ex-vivo and in vivo models will be generated using fresh tumor material from consenting 
patients at select sites in this study. Investigations may include, but are not limited to:
Primary cell line generation, including organoids
Fresh tumor specimens will be digested either mechanically or enzymatically. When 
applicable, different cell populations may be separated by either flow cytometry or mass 
cytometry based sorting. Primary tumor cells will be amplificated by organoid culture or 
adherent 2D culture with tumor type-specific protocols. Cancer associated fibroblast may be 
isolated and cultured on gelatin-coated surface in fibroblast growth medium, or other similar 
reagents. In addition, TILs can be stimulated and amplified through a combination of factors, 
such as CD3/CD2/CD28 activation beads, cytokines and antibodies. Further isolation of 
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tumor-specific T-cell clones may also be performed by stimulation of TILs with matched 
primary tumor cells.
Pharmacological perturbation of single or coculture of primary cells
Various 2-dimensional and 3-dimensional coculture may be performed under applicable 
pharmacological perturbations with applicable biological readouts including, but not limited 
to, cytokine secretion, flow cytometry or other protein-based assays, imaging, microscopy, 
gene expression or other genomic assays.
Different reagents may be applied, including possible future drugs, to evaluate the effect on 
tumor cells. 
Patient-derived xenograft murine tumor model
Primary tumor cells may be implanted into either immunosuppressed or humanized murine 
host to facilitate in vivo studies. Animals may be treated with different combinations of 
pharmacological perturbations to better understand the mechanism of action of possible 
patient responses.
Genetic and transcriptomic analysis
This research may evaluate whether genetic or transcriptomic variations within the collection 
of primary cell lines or murine tumor models correlates with response to the treatment(s) 
under evaluation. If genetic variation is found to predict efficacy the data might inform 
optimal use of therapies in the patient population.
4.2.1.6
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.
4.2.2
Rationale for the Use of Comparator
Carboplatin and paclitaxel represent one of the preferred treatment options for the first-line 
treatment of advanced OC. Docetaxel may be considered for participants who either 
experience a severe hypersensitivity reaction or an AE that requires discontinuation of 
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paclitaxel only after Sponsor consultation and approval. This study will use pembrolizumab 
added to SOC chemotherapy as the comparator arm consistent with the KEYLYNK-001 
study. This will enable delineation of contributing immune effects of inhibiting PD-1 alone 
versus the combination of PD-1 and ILT4 inhibition. Furthermore, our knowledge of PD-1 
inhibition and biology within ovarian cancer itself is limited and the comparator arm will aid 
in understanding that immune and tumor biology. Based upon the MK-4830 Phase 1 study 
data [Siu, L. L., et al 2021] and relationship between the PD-1 and ILT4 pathways, this
combination checkpoint therapy is a potential backbone in several tumor types. Delineating 
the PD-1 and ILT4 biology will contribute to clinical development in those tumors where 
pembrolizumab has established clinical efficacy.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
MK-4830
The planned dose of MK-4830 in this study is 800 mg Q3W. Based on safety and efficacy 
data in Study MK-4830-001, 800 mg demonstrated promising anticancer activity, was 
generally well tolerated, and was determined to be the RP2D [Siu, L. L., et al 2020].
4.3.1.2
Rationale for Chemotherapy Dosing Regimen
The dosing regimens of carboplatin and paclitaxel that will be used in this study are 
reflective of current clinical practice. The dose of docetaxel, if the use of docetaxel is
approved by the Sponsor, reflects the recommended dose for OC as determined by the 
SGCTG group [Vasey, P. A., et al 2004]. The use of Avastin (or biosimilar) is allowed at the 
investigator’s discretion, where approved for the front-line treatment of OC, as per the local 
SOC and approved product label.
4.3.1.3
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:
Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating 
flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W 
representing an approximate 5- to 7.5-fold exposure range (refer to IB, Section 5.2.2)
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W 
Clinical data showing meaningful improvement in benefit-risk including overall survival at 
200 mg Q3W across multiple indications
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Pharmacology data showing full target saturation in both systemic circulation (inferred from 
PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose/exposure of study intervention (pembrolizumab, MK-4830, and 
chemotherapy) in this study is 6 treatment cycles: 3 cycles prior to interval debulking surgery 
(neoadjuvant treatment) and 3 cycles after interval debulking surgery (adjuvant treatment).
The maximum dose/exposure of Avastin (or biosimilar) in this study is 3 treatment cycles: 
3 cycles after interval debulking surgery (adjuvant treatment).
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory test result or at the time of final contact with the last participant, whichever 
comes last.
If the study includes countries in the EEA, the local start of the study in the EEA is defined 
as 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 3 years (~2.5 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.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
4.4.1
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.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
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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.
Female participants of at least 18 years of age with advanced HGSOC, fallopian tube cancer, 
or primary peritoneal cancer will be enrolled in this study.
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 will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has histologically-confirmed FIGO Stage III or Stage IV HGSOC, primary peritoneal 
cancer, or fallopian tube cancer [Prat, J. and FIGO Committee on Gynecologic Oncology 
2014].
2. Is a candidate for carboplatin and paclitaxel chemotherapy, to be administered in the 
neoadjuvant and adjuvant setting.
3. Is a candidate for interval debulking surgery.
4. Has either a CA-125 (kilounits/L):CEA (ng/mL) ratio ≥25 [Vergote, I., et al 2010] or, if 
the CA-125:CEA ratio is <25, then a workup should be negative for the presence of a 
non-OC tumor (eg, breast or GI cancers including CRC).
5. Is able to provide archival tissue or newly obtained core, incisional, or excisional biopsy 
of a tumor lesion. Details pertaining to tumor tissue submission requirements can be 
found in the laboratory manual.
Note: Prior to randomization, archival or newly obtained tissue at Screening must be 
confirmed to be of sufficient quality and quantity to analyze the primary endpoint (which 
requires tissue for analysis) by the designated laboratory. Participants will not be eligible 
for the study if it is not of sufficient quality and quantity, and they cannot provide an 
additional sample that meets the above criteria.
Demographics
6. Is female and at least 18 years of age on the day of providing documented informed 
consent.
7. Has an ECOG PS of 0 or 1, as assessed within 7 days prior to the first dose of study 
intervention on Day 1 of Cycle 1.
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Female Participants
8.   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:
-
Uses 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 is as follows:
◦
MK-4830: 180 days
◦
Pembrolizumab: 120 days
◦
Chemotherapy: 180 days (refer to Appendix 7 for country-specific requirements)
◦
Avastin (or biosimilar if administered): 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 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.
-
Has a negative highly sensitive pregnancy test (urine or serum) as required by local 
regulations) within either 24 hours (urine) or 72 hours (serum) before the first dose of 
study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. Additional 
requirements for pregnancy testing during and after study intervention are in
Section 8.3.5.
-
Has had her medical history, menstrual history, and recent sexual activity reviewed 
by the investigator to decrease the risk for inclusion of a woman with an early
undetected pregnancy.
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Informed Consent
9. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
10. Has an adequate organ function as defined in Table 1; all screening laboratory tests 
should be performed within 7 days prior to the first dose of study intervention on Day 1 
of Cycle 1.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
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.
aCriteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
bCreatinine clearance (CrCl) should be calculated per institutional standard.
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.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a non-HGSOC histology.
2. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
3. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous-cell carcinoma of the 
skin, superficial bladder cancer, in-situ cervical cancer, or other in-situ cancers.
Note: Participants with synchronous primary endometrial cancer or a past history of 
primary endometrial cancer that meet the following conditions are not excluded: Stage 
not greater than IA; no more than superficial myometrial invasion, without vascular or 
lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear 
cell or other FIGO Grade 3 lesions.
Prior/Concomitant Therapy
4. Has received prior treatment for any stage of OC, including radiation or systemic 
anticancer therapy (eg, chemotherapy, hormonal therapy, immunotherapy, investigational 
therapy).
5. Is a participant for whom intraperitoneal chemotherapy is planned or has been 
administered as first-line therapy.
6. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-ILT4, or
anti-HLA-G agent or with an agent directed to another stimulatory or coinhibitory T-cell 
receptor (eg, CTLA-4, OX-40, CD137) or MDSC-directed therapy.
7. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines is allowed. Refer to Section 6.5 for 
information on COVID-19 vaccines.
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Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks before the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study medication.
Note: Participants that require intermittent use of non-systemic steroids such as ocular, 
inhaled, intranasal, topical steroids, or local steroid injections are not excluded from the 
study.
10. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (Note: 
The repeat imaging should be performed during study screening.), clinically stable, and 
without requirement of steroid treatment for at least 14 days before the first dose of study 
intervention.
Note: Participants with known untreated, asymptomatic brain metastases (ie, no 
neurological symptoms, no requirement for corticosteroids, no or minimal surrounding 
edema, and no lesion >1.5 cm) may participate but will require imaging of the brain as a 
site of disease as specified in the SoA.
11. Has resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as 
judged by the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, QTcF prolongation >500 msec, electrolyte disturbances, etc.), or 
participant has congenital long QT syndrome.
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab, carboplatin, paclitaxel (or 
docetaxel, if applicable), Avastin or biosimilar (if using) and/or any of their excipients. 
13. 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.
14. Has an active infection, requiring systemic therapy.
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15. Has a known history of HIV infection. 
Note: No HIV testing is required unless mandated by local health authority.
Refer to Appendix 7 for country-specific requirements.
16. Has a known history of hepatitis B (defined as HBsAg reactive) or known active hepatitis 
C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority. Participants with a history of hepatitis B but who are HBsAg negative 
are eligible for the study.
Refer to Appendix 7 for country-specific requirements.
17. Has received colony-stimulating factors (eg, G-CSF, GM-CSF, or recombinant 
erythropoietin) within 4 weeks (28 days) prior to receiving study intervention on Day 1 of 
Cycle 1.
18. Has had surgery <6 months prior to Screening to treat borderline ovarian tumors, 
early-stage OC, or early-stage fallopian tube cancer.
19. Has a 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.
20. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant's ability to cooperate with the requirements of the study.
21. Has current, clinically relevant bowel obstruction (including subocclusive disease), 
abdominal fistula, or GI perforation, related to underlying epithelial OC.
Note: This applies only to participants who will receive Avastin (or biosimilar) during 
Cycles 4 to 6 and should be confirmed prior to the first dose of Avastin (or biosimilar).
22. Has a history of hemorrhage, hemoptysis, or active GI bleeding within 6 months prior to 
randomization.
Note: This applies only to participants who will receive Avastin (or biosimilar) during 
Cycles 4 to 6 and should be confirmed prior to the first dose of Avastin (or biosimilar).
23. Has uncontrolled hypertension.
Note: This applies only to participants who will receive Avastin (or biosimilar) during 
Cycles 4 to 6 and should be confirmed prior to the first dose of Avastin (or biosimilar). 
Use of antihypertensive medications to control blood pressure is permitted.
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Other Exclusions
24. Has had an allogenic tissue/solid organ transplant.
25. Has either had major surgery within 3 weeks of randomization or has not recovered from 
any effects of any major surgery.
26. In the judgment of the investigator, is unlikely to comply with the study procedures, 
restrictions, and requirements of the study.
5.3
Lifestyle Considerations
There are no lifestyle considerations for this study.
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage AEs
such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
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 for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions 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 intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Arm 
1
Experi
-
mental
Carboplatin
Drug
Solution for 
Infusion
10 mg/mL
AUC5-
AUC6
IV 
Infusion
Q3W; Day 1 of 
each 3-week 
cycle
Background 
Treatment
NIMP/
AxMP
Local or 
Central
Arm 
1
Experi
-
mental
Paclitaxel
Drug
Solution for 
Infusion
6 mg/mL
175 
mg/m2
IV 
Infusion
Q3W; Day 1 of 
each 3-week 
cycle
Background 
Treatment
NIMP/
AxMP
Local or 
Central
Arm 
1
Experi
-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Q3W; Day 1 of 
each 3-week 
cycle
Test product
IMP
Central
Arm 
1
Experi
-
mental
MK-4830
Biological/
Vaccine
Solution for 
Infusion
100
mg/vial
800 mg
IV 
Infusion
Q3W Day 1 of 
each 3-week 
cycle
Test product
IMP
Central
Arm 
1
Experi
-
mental
Avastin (or 
biosimilar)
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
Variabl
e
IV 
Infusion
Q3W; Day 1 of 
each 3-week 
cycle of Cycles 
4 to 6
Background 
Treatment
NIMP/
AxMP
Local or 
Central
Arm 
2
Experi
-
mental
Carboplatin
Drug
Solution for 
Infusion
10 mg/mL
AUC5-
AUC6
IV 
Infusion
Q3W; Day 1 of 
each 3-week 
cycle
Background 
Treatment
NIMP/
AxMP
Local or 
Central
Arm 
2
Experi
-
mental
Paclitaxel
Drug
Solution for 
Infusion
6 mg/mL
175
mg/m2
IV 
Infusion
Q3W; Day 1 of 
each 3-week 
cycle
Background 
Treatment
NIMP/
AxMP
Local or 
Central
Arm 
2
Experi
-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Q3W; Day 1 of 
each 3 week 
cycle
Test product
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 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or
NIMP/
AxMP
Sourcing
Arm 
2
Experi
-
mental
Avastin or 
biosimilar
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
Variabl
e
IV 
Infusion
Q3W; Day 1 of 
each 3 week 
cycle of Cycles 
4 to 6
Background 
Treatment
NIMP/
AxMP
Local or 
Central
Abbreviations: AUC = area under the concentration-time curve; EEA = European Economic Area; IMP = investigational medicinal product; IV = intravenous; NIMP/AxMP =
noninvestigational/auxiliary medicinal product; Q3W = every 3 weeks.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences
with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 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 8.1.9 and the pharmacy manual for details regarding administration of the 
study intervention.
6.1.1
Treatment
In this study, the treatment course for MK-4830 Q3W and/or pembrolizumab Q3W consists 
of 6 treatment cycles. Note: The number of treatment cycles is calculated starting with the 
first dose.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3. Carboplatin, paclitaxel (and potentially docetaxel), and Avastin (or biosimilar)
will be prepared and administered as per the approved product label and per the pharmacy
manual.
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.
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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.
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 Arm 1 and Arm 2, 
respectively.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
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.
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with either pembrolizumab or MK-4830 and for other allowed dose interruptions of 
pembrolizumab and MK-4830.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study-site staff other than the person administering the 
study intervention.
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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.
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic chemotherapy or biological therapy.
•
Immunotherapy not specified in this protocol.
•
Chemotherapy not specified in this protocol.
•
Anticancer hormonal therapy (eg, anti-estrogens).
Note: Hormonal replacement therapy is allowed.
•
Investigational agents other than pembrolizumab and MK-4830.
•
Radiation therapy.
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. 
Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed as long as they are mRNA vaccines, adenoviral vaccines, or 
inactivated vaccines. These vaccines will be treated as concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology.
-
For the prevention of emesis.
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-
To premedicate for IV contrast allergies.
-
To treat COPD exacerbations (only short-term oral or IV use in doses >10 mg/day 
prednisone equivalent).
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent.
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use.
-
Intraarticular joint use.
-
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease.
•
Strong and moderate inducers or inhibitors of either CYP3A4 or CYP2C8.
Note: Refer to the local approved product label of each of the chemotherapy agents used 
in this study for specific guidance. A current list of strong/moderate inducers/inhibitors of 
CYP3A4 can be found at the following website:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling 
Note: the use of aprepitant as an antiemetic is allowed during the study
(Section 8.1.9.1.6).
In addition to the medications listed here, site staff should refer to the local approved product 
label for permitted and prohibited medications, as well as drug-drug interactions for each 
chemotherapy agent used in this study.
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention may need to be discontinued.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications 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 ECI are to be recorded. SAEs and 
ECI are defined in Section 8.4.
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6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an AE to a single 
component is likely to be difficult. Therefore, while the investigator may attribute a toxicity 
event to pembrolizumab monotherapy, coformulations, or IO combinations, pembrolizumab 
monotherapy, coformulations, or IO combinations must be held according to the criteria in 
the Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse 
Events.
Holding Study Interventions:
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
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Restarting Study Interventions:
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.  Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.   Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the 
corticosteroid dose is not ≤10 mg/day within 12 weeks of the last treatment.
3.   The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to 
≤Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
   Add prophylactic antibiotics 
for opportunistic infections
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent 
Grade 2, Grade 3 
or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
   Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
   Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or Grade 
3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer antihyperglycemic 
in participants with 
hyperglycemia
   Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
·   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
   Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
   Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
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 
(previously 
CTCAE v4.0 
Grade 1)
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
   Based on severity of AE 
administer corticosteroids
·   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
PersistentGrade2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b     AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x 
baseline if baseline abnormal
c     AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e     Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations or IO Combinations (MK-4830 + 
Pembrolizumab)
Pembrolizumab monotherapy, coformulations or IO combinations (MK-4830 + 
pembrolizumab) may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab monotherapy, 
coformulations or IO combinations (MK-4830 + pembrolizumab) associated infusion 
reactions are provided in Table 4.
Table 4
Pembrolizumab Monotherapy, Coformulations or IO Combinations (MK-4830) 
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.
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
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.
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
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; 
NCI=National Cancer Institute; NSAIDs=nonsteroidal anti-inflammatory drugs; PO=orally.
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 CTCAE v5.0 at http://ctep.cancer.gov
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Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations 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.
6.6.2
Chemotherapy Dose Modifications
Carboplatin and/or paclitaxel (or docetaxel) may be reduced, interrupted, or discontinued at 
the investigator’s discretion per the approved product labels, local regulations, and/or 
institutional standards. If chemotherapy (either carboplatin or paclitaxel [or docetaxel] or 
both) is interrupted or discontinued, pembrolizumab, and/or MK-4830 should be continued. 
If pembrolizumab or MK-4830 is interrupted or discontinued, chemotherapy should be 
continued.
Avastin (or biosimilar), if using, may be interrupted, or discontinued at the investigator’s 
discretion per the approved product label and local regulations. If Avastin (or biosimilar) is 
interrupted or discontinued, chemotherapy, pembrolizumab, and/or MK-4830 should be 
continued. If pembrolizumab or MK-4830 is interrupted or discontinued, Avastin (or 
biosimilar) should be continued as per the approved product label, local regulations, and/or 
institutional standards for a maximum of 3 cycles following surgery.
Interruptions from either carboplatin and paclitaxel (or docetaxel) or Avastin (or biosimilar) 
of greater than 6 weeks (42 days) from the originally scheduled dose require consultation 
between the investigator and the Sponsor. Discontinuation of both carboplatin and paclitaxel 
(or docetaxel) require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on participant management.
Supportive care measures (eg. G-CSF, erythropoietin, blood transfusion) should be used 
according to local standards to manage chemotherapy-induced myelosuppression to prevent 
severe infections linked to febrile neutropenia. To minimize dose reductions, interruptions, 
and discontinuations of chemotherapy, these supportive care measures should be used before 
implementing dose modifications, when appropriate.
6.6.3
Definition of Dose-limiting Toxicity
All toxicities will be graded using NCI CTCAE v5.0 based on the investigator assessment. 
The DLT window of observation will be during the first cycle of Avastin (or biosimilar)
administration (ie, the first cycle after surgery [Cycle 4]) following surgery.
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The occurrence of any of the following toxicities during the DLT observation period will be 
considered a DLT, if assessed by the investigator to be possibly, probably, or definitely 
related to study intervention administration:
▪
Grade 4 nonhematologic toxicity (not laboratory).
▪
Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:
•
Grade 4 thrombocytopenia of any duration
•
Grade 3 thrombocytopenia associated with clinically significant bleeding
▪
Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of antiemetics or antidiarrheals per SOC; Grade 3 rash without use 
of corticosteroids or anti-inflammatory agents per SOC.
▪
Any Grade 3 or Grade 4 nonhematologic laboratory value if:
•
Clinically significant medical intervention is required to treat the participant, or
•
The abnormality leads to hospitalization, or
•
The abnormality persists for >1 week
•
The abnormality results in a DILI (see Section 8.4.7 for criteria)
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc.
▪
Febrile neutropenia Grade 3 or Grade 4:
•
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than 1 hour.
•
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than 1 hour, with life-threatening consequences and urgent intervention 
indicated.
▪
Prolonged delay (>2 weeks) in initiating Cycle 2 due to intervention-related toxicity.
▪
Any intervention-related toxicity that causes the participant to discontinue intervention 
during Cycle 1.
▪
Grade 5 toxicity.
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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
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
For studies using controlled substances, all Federal, State, Province, Country, etc, regulations 
must be adhered to in regard to their shipping, storage, handling, and dispensing of controlled 
substances. Additionally, the investigator should have the appropriate controlled drug 
license(s) as mandated by Federal, State, Province, Country, etc, laws in which the study is 
being conducted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period/vaccination regimen will still continue to be monitored in the 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.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
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Clinical progression without radiographic disease progression defined by elevated CA-125 
[Rustin, G. J., et al 2011] in conjunction with any of the following criteria for malignant 
bowel obstruction:
Any of the following: new or worsening abdominal pain, nausea, or vomiting
Abdominal distension, constipation, and/or diarrhea 
No evidence of metabolic or electrolyte abnormalities leading to impaired intestinal 
motility
Note: Symptoms must be assessed as not related to study intervention and/or concomitant 
medication AND other non-malignant causes must be excluded by supplementary 
diagnostic measures.
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 and 6.6.2, require 
Sponsor consultation and approval 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 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.
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.
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.
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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.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. Delegation of study-site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or equivalent).
All study-related medical decisions must be made by an investigator who is a qualified 
physician .
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before documented ICF may be used for screening or baseline purposes 
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provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
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.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the 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.
8.1.1.2
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.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant 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.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
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8.1.4.1
Ovarian Cancer History
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s OC, including investigator-determined tumor size per RECIST 1.1.
8.1.5
Debulking Surgery
All eligible participants will undergo interval debulking surgery per the local SOC. Interval 
debulking surgery should be performed between 3 to 6 weeks following Day 1 of Cycle 3; 
any delay to interval debulking surgery (eg, due to an AE) requires approval from the 
Sponsor. The last dose of study intervention of the neoadjuvant phase should be administered 
no less than 3 weeks before surgery. Participants should resume study intervention when 
clinically appropriate but no longer than 7 weeks following surgery. Details regarding the 
date of surgery, surgical findings, residual tumor postsurgery, surgical pathology, etc. will be 
recorded in the appropriate eCRF. Surgical resection sample will be reviewed as per standard 
guidelines by the local pathologist to confirm pathological CR and omentum for CRS 
following interval debulking surgery. Debulking surgery may be performed at a 
hospital/surgical unit separate from the investigator site.
Surgery may be performed earlier than Cycle 3 for clinical reasons for participant care in 
accordance with local SOC for disease management. Similarly, surgery may be delayed after 
Cycle 3 for clinical reasons in accordance with local SOC for disease management or due to 
AEs. In these instances, Sponsor consultation and approval are required prior to any change 
in the protocol-defined timing of surgery.
If the investigator determines that a participant has unresectable disease following the 
3 neoadjuvant treatment cycles, the participant may continue treatment in the study without 
undergoing the interval debulking surgery and receive up to 6 cycles of treatment following 
Sponsor consultation and approval. For these participants, a tumor biopsy should be 
collected, if possible (Section 8.1.5.1). Participants should resume study intervention when 
clinically appropriate but no longer than 6 weeks following the last dose of study intervention
of the neoadjuvant phase.
8.1.5.1
Tumor Tissue Biopsy and Sample Collection
Participants are required to submit archival or newly obtained core, incisional, or excisional 
biopsy of a tumor lesion during the screening period for local confirmation of HGSOC 
histology, baseline biomarker assessment, and for generation of the ctDNA assay. The 
surgical resection sample collected during interval debulking will be sent for detailed 
pathological assessment (site pathologist is required to take participants’ samples not only 
from the ovaries/ tube or omentum but also from other organs resected as part of the 
debulking to confirm pCR). This study may also conduct exploratory histological 
confirmation of high-grade serous carcinoma of tumor samples from enrolled participants.
For those participants who were randomized as eligible for interval debulking surgery but 
failed to undergo surgery and are continuing on-study intervention, a core or excisional 
biopsy should be collected, if possible, prior to resuming study intervention in Cycle 4.
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All biopsies should be obtained and prepared according to the instructions outlined in the 
Laboratory Manual for this study.
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 the first dose of study intervention.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study including at the time of surgery and through the Safety Follow-up Visit.
Additionally, the investigator or qualified designee will record medication, if any, taken by 
the participant following PD.
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.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
Study interventions will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual.
Study intervention should begin within 3 days of randomization.
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8.1.9.1
Timing of Dose Administration
Administer study intervention in the following order:
1. Pembrolizumab
2. MK-4830 (Arm 1 only)
3. Paclitaxel (or docetaxel)
4. Carboplatin
5. Avastin (or biosimilar), if using, in Cycles 4 to 6
NOTE: Local practices for the sequence of drug administration for chemotherapies 
(excluding Avastin or biosimilar) can be followed if preferred. The date and time of 
administration must be captured in the eCRF.
On Day 1 of each cycle, study intervention should be administered after all procedures and 
assessments have been completed. Study intervention can be administered ± 3 days of the 
targeted Day 1 for each cycle.
The reason for any variability in administration of study intervention outside of the 
protocol-specified window should be documented in the participant’s chart and recorded on 
the eCRFs.
8.1.9.1.1
Pembrolizumab
Pembrolizumab (200 mg) will be administered as a 30-minute IV infusion Q3W for 6 cycles. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (ie, infusion time is 25 to 40 minutes).
8.1.9.1.2
MK-4830
MK-4830 (800 mg) will be administered as a 30-minute IV infusion Q3W for 6 cycles. 
MK-4830 will be administered 30 minutes after completion of pembrolizumab infusion. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (ie, infusion time is 25 to 40 minutes).
8.1.9.1.3
Paclitaxel (or Docetaxel)
Paclitaxel (175 mg/m2 Q3W) will be administered as an IV infusion for 6 treatment cycles as 
per local practice and labels. The infusion time should follow local practice and labels. All 
participants should be premedicated with oral or IV steroid and antihistamines according to 
the approved product label and/or standard practice. Additional premedications should be 
administered as per standard practice.
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Docetaxel (75 mg/m2 Q3W), if approved by the Sponsor, will be administered as an IV 
infusion as per local practice and labels. The infusion time should follow local practice and 
labels. All participants should be premedicated with an oral steroid according to the approved 
product label and/or standard practice. Additional premedications should be administered as 
per standard practice.
8.1.9.1.4
Carboplatin
Carboplatin (AUC 5 or 6 mg/mL•min Q3W) will be administered as an IV infusion for 
6 treatment cycles as per local practice and labels. The infusion time of carboplatin should 
follow local practice and labels. The carboplatin dose should be calculated using Calvert 
formula (see below) and should not exceed 900 mg.
Calvert Formula:
Total Dose (mg) = target AUC × (GFR + 25)
The estimated GFR used in the Calvert’s formula should not exceed 125 mL/min to calculate 
the maximum carboplatin dose (mg). An example calculation for AUC 6 for a participant 
with a GFR of 125 mg/mL is as follows:
Target AUC 6 (mg/mL•min) × (125 + 25) = 6 × 150 mL/min = 900 mg
8.1.9.1.5
Avastin (or Biosimilar)
If Avastin (or biosimilar) is used, it should be administered, as per local practice and label, 
starting on Day 1 of the first cycle following surgery (ie, Cycle 4), after carboplatin. The 
local practice for the sequence of drug administration can be followed if preferred. The date 
and dose of Avastin (or biosimilar) administered will be recorded in the eCRF.
Note: Use of Avastin (or biosimilar) is not permitted in the neoadjuvant phase (ie, prior to 
surgery in Cycles 1 to 3).
8.1.9.1.6
Antiemetic Therapy
The use of antiemetic therapy should follow Multinational Association of Supportive Care in 
Cancer guidelines [Roila, F., et al 2016] and should include a 5-HT3 receptor antagonist, 
dexamethasone (or equivalent), and/or aprepitant.
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.
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
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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
Microsampling Device
Two 
 devices will be used to obtain capillary blood samples from participants’ 
arms. Additionally, at select participating investigational sites, one 
 device will be 
used to obtain capillary blood samples from participants’ arms. The
 device 
collects a dried blood sample on an absorptive material and the 
 collects a liquid blood 
sample that can be further processed to plasma or serum. Both devices adhere to the skin of
participant’s upper arm and use lancets to pierce the skin and a delicate vacuum to flow 
blood into the tool. Further instructions on the use of both devices will be provided in the 
laboratory manual. 
CCI
CCI
CCI
CCI
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Device failures (ie, lancet does not pierce skin, or device does not collect blood) or AEs 
directly related to both devices should be communicated to the Sponsor by the investigator. 
Additionally, AEs involving the devices should be recorded on the appropriate eCRF. Refer 
to the laboratory manual for additional details.
Timepoints for the collection of these samples can be found in the SoA. Please refer to the 
laboratory manual for detailed instructions on sample collection, storage, and shipment.
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 
safety 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, MRI 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.
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.
If brain scans are required to document the stability of existing metastases, the brain scan 
should be acquired during Screening. The specific methods permitted for this study are 
described in the SIM.
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Bone scans are required at Screening for participants with a history of bone metastases or for 
those participants with indicative clinical signs/symptoms such as bone pain or elevated 
alkaline phosphatase levels.
Bone scan refers to imaging methods used to assess bone metastasis. 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 imaging assessment should be performed at least 21 days (+5 days) after 
Day 1 of Cycle 3 and prior to the debulking surgery. The next on-study imaging assessment 
should be performed after surgery prior to resuming study intervention in Cycle 4 (-5 days; 
Section 1.3).
Note: If surgery is delayed, imaging should be delayed until prior to surgery (a minimum of 
21 days after the last cycle of study intervention in the neoadjuvant phase) and then 
performed prior to the first dose of study intervention in the adjuvant phase. If cytoreduction
is attempted but not performed (with or without biopsy collection) or deemed inappropriate, 
the next scheduled imaging assessment after Cycle 3 Day 1 would be performed a minimum 
of 21 days after Cycle 6 Day 1 (ie, the EOT visit; Section 8.2.1.3).
On-study brain and bone scans should be performed if clinically indicated or to confirm CR 
(if other lesions indicate CR and either brain or bone lesions existed at baseline).
8.2.1.3
End-of-Treatment Tumor Scans
Imaging should be performed at the time of treatment discontinuation (±4 weeks) and prior to 
starting a new anticancer treatment. If previous imaging was obtained within 4 weeks 
(28 days) before the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.
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.
Following surgery, tumor response will be assessed using a more limited application of 
RECIST 1.1 to evaluate participants as either showing progression, or not showing 
progression. In participants who have residual disease, progression is defined as growth of 
residual disease (following RECIST 1.1 methods of measurement) or appearance of new 
lesions. In participants without residual disease, progression is defined as the detection of 
new lesions on subsequent scans.
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If disease progression is established by the investigator, the process continues as follows:
•
Investigator judgment will determine action
•
Obtain scans per original protocol schedule
•
Send scans to iCRO
For the purpose of this decision process, lack of clinical stability is defined as:
•
Unacceptable toxicity
•
Clinical signs or symptoms indicating clinically significant disease progression
•
Decline in performance status
•
Rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
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. Safety monitoring and assessments should be performed in accordance with the 
approved product labels and local practice for paclitaxel (or docetaxel), carboplatin, and 
Avastin (or biosimilar).
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard at the timepoints 
specified in the SoA. Height and weight will also be measured and recorded.
For cycles that do not require a complete physical examination, a brief directed physical 
examination will be conducted by an investigator or medically qualified designee (consistent 
with local requirements) per institutional standard as clinically indicated before study 
intervention administration.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.3.2
Vital Signs
The investigator or qualified designee will assess vital signs at Screening and as specified in 
the SoA. Vital signs will include, temperature, systolic and diastolic blood pressure, pulse 
rate, and respiratory rate.
For participants who will start Avastin (or biosimilar) in the adjuvant phase (ie, after surgery 
in Cycle 4), blood pressure must be measured prior to the first administration of Avastin (or 
biosimilar) to ensure the participants do not have uncontrolled hypertension.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) as outlined in the SoA using an ECG 
machine that automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. 
Additional ECGs may be performed as clinically indicated.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant 
changes occurring during the study in the AE section of the CRF. The laboratory reports 
must be filed with the source documents. Clinically significant abnormal laboratory findings 
are those which are not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose modification), 
then the results must be recorded in the appropriate CRF (eg, SLAB).
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be 
conducted 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:
◦
MK-4830: 180 days
◦
Pembrolizumab: 120 days
◦
Chemotherapy: 180 days
◦
Avastin (or biosimilar if used): 180 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each cycle of study treatment as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
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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.
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 cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
All AEs from the time of intervention randomization through 30 days 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 8.3.5, or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the time
specified above must be reported immediately to the Sponsor if the event is considered 
related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 5.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE 
including 
Cancer and 
Overdose
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or run-
in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event.
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.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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) 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 
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must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. 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 the purposes of this study, an overdose will be defined as follows:

Pembrolizumab: ≥5 times the protocol-specified dose

MK-4830: ≥3 times the protocol-specified dose

Paclitaxel (or docetaxel), carboplatin, and Avastin (or biosimilar): any dose ≥20% 
over the protocol-specified dose
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No specific information is available on the treatment of overdose of MK-4830, 
pembrolizumab, chemotherapy, or Avastin (or biosimilar). In the event of overdose, the 
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
in the laboratory manual.
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 biomarker analysis
Blood for plasma biomarker analysis
Blood for RNA analyses
Blood for ctDNA analyses
Dried whole blood from 
device
Liquid whole blood from 
 device
Archival or newly obtained tissue collection
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the laboratory manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for 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.
CCI
CCI
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Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be in the Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
Leftover samples as outlined in Section 8.8.
8.10
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
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
Within 28 days prior to randomization, potential participants will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to documented 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-day Screening Period, except for 
the following:

Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention on Day 1 of Cycle 1. An exception is HIV and hepatitis testing which 
may be performed up to 28 days prior to randomization if required by the local health 
authority. Refer to Appendix 7 for country-specific requirements.

Evaluation of ECOG PS is to be performed within 7 days prior to the first dose of 
study intervention on Day 1 of Cycle 1.

For WOCBP, a pregnancy test (urine or serum) will be performed within either 
24 hours (urine) or 72 hours (serum) prior to the first dose of study intervention on 
Day 1 of Cycle 1. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required (performed by the local study site laboratory). Refer 
to Appendix 7 for country-specific requirements.

Archival or newly obtained tissue obtained at screening must be confirmed to be of 
sufficient quality and quantity by the designated laboratory.
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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
Visit requirements are outlined in the SoA. Specific procedure-related details are provided in 
Section 8.1.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study intervention due to disease progression/recurrence or start 
of a new anticancer therapy will have Safety Follow-up (Section 8.11.4.1).
The Discontinuation Visit (end-of-treatment) should occur at the time study intervention is 
discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of 
study intervention, at the time of the mandatory Safety Follow-up Visit, the Discontinuation 
Visit procedures and any additional Safety Follow-up procedures should be performed. If the 
Discontinuation Visit occurs ≥30 days from the last dose of study intervention, the Safety 
Follow-up Visit does not need to be performed.
8.11.4
Post-treatment Visits
8.11.4.1
Safety Follow-up
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.
8.11.4.2
Long-term Follow-up
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Long-
term Follow-up and should be assessed every 4 weeks by telephone contact for up to 
24 weeks after the last dose of study intervention to monitor pregnancy status. Every effort 
should be made to collect information regarding pregnancy status until the start of new 
anticancer therapy, disease progression, death, end of study. Information regarding poststudy 
anticancer treatment will be collected if new treatment is initiated.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in a sSAP and referenced in the Clinical Study Report for the study. Details 
around the analysis approach for biomarker endpoints related to the exploratory objectives 
are deemed out of scope for this SAP but may be the subject of sSAPs.
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 to 9.12. 
Study Design Overview
A Randomized, Phase 2 Study of Pembrolizumab And Chemotherapy 
With or Without MK-4830 as Neoadjuvant Treatment for High-Grade 
Serous Ovarian Cancer.
The primary objective is to evaluate whether the reduction from baseline
in ctDNA at Cycle 3 is larger in participants receiving MK-4830 + 
pembrolizumab in combination with SOC therapy arm than in those 
receiving pembrolizumab + SOC arm among treated participants with 
detectable ctDNA at baseline.
Treatment Assignment
Approximately 160 participants will be randomized in a 1:1 ratio 
between 2 treatment groups: (1) Arm 1 and (2) Arm 2. This is an open-
label study.
Primary Endpoint
1.
ctDNA, mean mutant/tumor molecules per mL (continuous).
Secondary Endpoints
1.
pCR, all surgical specimens collected during the interval debulking 
surgery are microscopically negative for residual tumor (binary; pCR 
vs. not).
2.
CRS, tiered response score based omental assessment of residual 
disease (binary; CRS3 vs. non-CRS3).
Statistical Methods for Key 
Efficacy Analyses
For the primary objective, the posterior probability that the coefficient 
for treatment assignment is less than zero in a cLDA model, where 
ctDNA values at baseline and Cycle 3 will be modeled as the response 
vector and treatment assignment (MK-4830 containing vs. not) is 
included as the independent variable with the constraint that the mean 
ctDNA value at baseline is the same for both treatment groups, will be 
used to evaluate whether the reduction in ctDNA from baseline is larger 
amongst the MK-4830 containing arm.
Statistical Methods for Key 
Safety Analyses
Safety will be evaluated using descriptive statistics by treatment group.
Interim Analyses
A preliminary analysis of the primary objective will be conducted at 50% 
enrollment. Final analysis will occur approximately 4 months after 
LPLV.
Multiplicity
No multiplicity adjustment.
Sample Size and Power
The planned sample size is approximately 160 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 
Early Clinical Development Statistics Department of the Sponsor. 
This study is being conducted as an unblinded, open-label study; ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is randomized and treatment is assigned.
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Biomarker assays used to assess the primary, secondary, and tertiary/exploratory objectives 
in this study will be performed by personnel blinded to participants’ treatment and clinical 
outcome data.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. There are no hypotheses to be tested.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Secondary Efficacy Endpoints
pCR: all surgical specimens collected during the interval debulking surgery are 
microscopically negative for residual tumor (binary; pCR vs. not).
CRS: tiered response score based omental assessment of residual disease (to be analyzed as 
binary; CRS3 score vs. non-CRS3).
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints may include measures of clinical outcome and surgical 
response, which are deemed out of scope for this SAP but may be the subject of sSAPs.
9.4.2
Biomarker Endpoints
Primary and Secondary Biomarker Endpoints
The primary and secondary biomarker endpoint is the change in the mean mutant/tumor 
molecules per mL (MTM/mL) at Cycle 3 from baseline (continuous) detailed in 
Section 4.2.1.1.
Exploratory Biomarker Endpoints
Details around other biomarker-related endpoints associated with the exploratory objectives, 
including additional molecular (eg, CA-125, genomic, metabolic, proteomic) endpoints, as 
well as details for the processing and normalization of these complex data sources, are 
deemed out of scope for this SAP, but may be the subject of sSAPs.
9.4.3
Safety Endpoints
Refer to Section 4.2.1.2 for a description of safety measures.
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9.5
Analysis Populations
9.5.1
Efficacy and Safety Analysis Population
The APaT population will be used for the analysis of safety in this study. The APaT 
population consists of all randomized participants who received at least one dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received. For most participants this will be the treatment group to 
which they are randomized. Participants who take incorrect study intervention for the entire 
treatment period will be included in the treatment group corresponding to the study 
intervention actually received. Inclusion of participants who take incorrect study intervention
for a portion of the time in which treatment group will be described in the CSR. 
The APaT population that underwent surgery (ie, that has a surgical outcome) will be used 
for the analysis of efficacy in this study, as efficacy endpoints are surgical outcomes. 
Efficacy analyses associated with change in ctDNA will use the biomarker analysis 
population described in Section 9.5.2.
9.5.2
Biomarker Analysis Population
The subset of the APaT with detectable ctDNA at baseline will be used for the analysis of 
ctDNA.
9.6
Statistical Methods
9.6.1
Statistical Methods for Biomarker/Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in sSAPs.
Those generating the biomarker data will remain blinded to a participant’s treatment and 
clinical status in order to preserve an objective evaluation of the study objectives.
9.6.1.1
Primary Objective
cLDA will be used to evaluate whether the reduction in ctDNA from baseline is larger in the 
MK-4830-containing arm. The cLDA model will include ctDNA values at baseline and post-
treatment as part of the dependent response vector and treatment assignment (MK-4830 
containing vs. not) as the independent variable with the constraint that the mean ctDNA 
value at baseline is the same for both treatment groups. The cLDA model will be 
parameterized in a Bayesian framework, assuming noninformative priors, and the posterior 
probability that the coefficient for treatment assignment is less than zero in the cLDA model 
will be reported. ctDNA may be transformed. Descriptive and visual summaries (ie, spider 
plots and/or boxplots) of the change in ctDNA (MTM/mL) will be provided by treatment 
group.
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9.6.1.2
Secondary Objectives
Logistic regression modeling of pCR (or CRS) will be used to evaluate whether the reduction 
in ctDNA from baseline is associated with improved pCR in each treatment group. The 
logistic regression model will include binary surgical response endpoint pCR (or CRS) as the 
dependent variable and change in ctDNA (MTM/mL) at Cycle 3 from baseline and treatment 
assignment as the independent variables. The posterior probabilities that the coefficient for 
change in ctDNA is less than zero and that the coefficient for treatment assignment 
(MK-4830 containing vs. not) is greater than zero in the multivariable logistic regression 
model will be reported. The logistic regression model will also include a term for baseline 
ctDNA value. ctDNA may be transformed. The association of change in ctDNA with pCR
(or CRS) will also be evaluated using the AUROC in each treatment group pooled and 
separately. Descriptive and visual summaries (ie, spider plots and/or boxplots) of ∆ctDNA 
(MTM/mL) will be provided pooled and/or by treatment group.
pCR (or CRS) rate is estimated as the proportion of participants with pCR (or CRS) in each 
group separately and will be reported with the 95% CI using the exact method based on the 
binomial distribution (Clopper-Pearson). Miettinen and Nurminen’s method will be used to 
estimate the treatment difference between the 2 treatment arms and the associated 95% CI 
will be reported.
9.6.1.3
Exploratory Objectives
Details around the analysis approach for biomarker endpoints related to the exploratory 
objectives are deemed out of scope for this SAP but will be the subject of sSAPs.
Table 6 summarizes the estimation strategy for the primary and secondary objectives detailed 
above.
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Table 6
Analysis Strategy for Primary Objectives
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach
Statistical Method
Analysis Population
Primary Objective
Change in ctDNA from baseline 
at Cycle 3 (continuous; Mean 
Mutant/Tumor Molecules per 
mL [MTM/mL])
P
Bayesian 
parameterization of 
cLDA
Study participants must have 
baseline and on-treatment ctDNA 
assessment; study participants 
must have detectable ctDNA at 
baseline.
S
Summary statistics, 
visual representations
Secondary Objectives
Change in ctDNA from baseline 
at Cycle 3 (continuous; 
MTM/mL); pCR/CRS (binary)
P
Bayesian 
parameterization of 
logistic regression
Study participants must have 
baseline and on-treatment ctDNA 
assessment; study participants 
must have detectable ctDNA at 
baseline; study participants must 
have surgical outcome.
S
AUROC, summary 
statistics, visual 
representations
pCR/CRS (binary)
P
Miettinen and 
Nurminen’s method
APaT; Study participants must 
have surgical outcome.
Abbreviations: APaT = all-participants-as-treated; AUROC = area under the ROC curve;
cLDA = constrained longitudinal data analysis; CRS = chemotherapy response score; ctDNA = circulating 
tumor DNA; MTM=mean mutant/tumor molecules; P = Primary approach; pCR = pathological complete 
response; S = Supportive approach.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, SAEs, laboratory tests, vital signs, etc.
Descriptive summary statistics will be provided by treatment group for safety endpoints. For 
continuous measures such as changes from baseline in laboratory tests and vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided in table format. Additional safety endpoints may also be summarized as deemed 
clinically appropriate.
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9.7
Interim Analyses
A preliminary analysis of the primary objective will be conducted at 50% enrollment to serve 
as a first look at the data and a feasibility assessment of the ctDNA assay. Final analysis will 
occur approximately 4 months after LPLV.
9.8
Multiplicity
No multiplicity adjustment.
9.9
Sample Size and Power Calculations
The study will enroll approximately 160 participants; of which approximately 80% (N~128) 
are expected to be included in the primary analysis population (ie, have detectable ctDNA at 
baseline). Participants with nondetectable ctDNA at baseline will be excluded from the 
primary objective analysis. No formal hypotheses are being tested. 
Table 7 illustrates the relationship between post-treatment ctDNA values and treatment 
assignment in a cLDA model, such that the mean ctDNA value is the same between the 
2 treatment groups based on results from 10,000 simulated datasets of expected sample size. 
Simulations assume ctDNA at baseline is normally distributed on the log10 scale with mean 
1.5 and standard deviation 1.15 and assume various fold changes in the mean ctDNA at post-
treatment timepoint. At the expected sample size and under distributional assumptions from 
limited presurgical ctDNA data in ovarian cancer [Chapman, J. S., et al 2021], dramatic 
differences in the post-treatment mean between treatment groups provide the highest 
probability of detecting a statistically significant difference (Table 7).
Table 7
Illustrative Simulation of the Relationship Between Post-treatment ctDNA Values 
and Treatment Assignment in cLDA Model for Varied Fold Change in the Mean ctDNA for 
MK-4830 Containing Arm Versus Not
Sample Size of Analysis 
Population
Mean Fold Change in Mean 
ctDNA at Post-treatment 
Timepoint for MK-4830 
Containing Arm vs. Nota
Probability Reduction in Mean 
ctDNA Differs Significantly in 
MK-4830 Containing Arm vs. 
Notb
128
1.02
5.2%
0.87
10.2%
0.73
23.4%
0.51
58.9%
0.33
83.5%
cLDA=constrained longitudinal data analysis; ctDNA = circulating tumor deoxyribonucleic acid; MTM=mean mutant/tumor 
molecules.
a.
Mean fold change (mean ctDNA [MTM/mL] at post-treatment timepoint for MK-4830 containing arm/mean ctDNA at post-
treatment timepoint for other arm) of 10,000 simulated datasets
b.
Proportion of 10,000 simulations such that the change in mean ctDNA over time (at post-treatment timepoint) differs 
significantly by nominal α=0.05 using cLDA model such that mean ctDNA at baseline is the same among MK-4830 containing 
arm vs. not 
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9.10
Subgroup Analyses
Not applicable.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles in which the 
participant receives the study medication infusion. Summary statistics will be provided on 
the extent of exposure.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), 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 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.
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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 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.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
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 his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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
Standing Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate siDMC will
monitor the interim data from this study. The siDMC is comprised of members of Sponsor
Senior Management, none of whom are directly associated with the conduct of this study.
The siDMC will monitor the study at an appropriate frequency (as detailed in the charter) for
evidence of adverse effects of study intervention, as described in the detailed monitoring 
guidelines. The siDMC will determine whether the study should continue (or other 
modifications, prespecified or otherwise, should be made) according to the protocol,
considering the overall risk and benefit to study participants. The siDMC will also make
recommendations to the Sponsor protocol team regarding steps to ensure both participant
safety and the continued ethical integrity of the study. Specific details regarding 
responsibilities of the siDMC will be described in a separate charter that is reviewed and 
approved by the siDMC.
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.
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 fulfil
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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 
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) 
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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 
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 
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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 8 will be performed by the local laboratory. 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.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.
Refer to Appendix 7 for country-specific requirements.
Table 8
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
MCHC
Reticulocytesa
WBC count with 
Differential:
Neutrophilsa
Lymphocytesa
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNb
Blood Ureab
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin if total 
bilirubin is above 
the ULN)
Albumin
Bicarbonate or 
CO2c
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasting 
or nonfasting)
Calcium
Alkaline 
phosphatase
GGT
LDH
Magnesium
Uric acid
TSHd
T3 (FT3 is 
acceptable)
FT4
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)
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Laboratory 
Assessments
Parameters
Other 
Screening Tests
FSH (as needed in WONCBP only)
PT/INR and aPTT/PTTe
Serology (HIV antibody, HBsAg, and HCV RNA). NOTE: Certain ex-US 
sites require testing for HIV, HBV, and HCV during Screening. Consult with 
regional health authorities and institutional standards to confirm if such 
testing is applicable.
Cortisol to be determined at Screening, and the morning of surgery, and on 
Day 1 of Cycles 4 and 5. Cortisol measurements should be obtained in the 
morning.
CEA and CA-125 may be analyzed by the local laboratory to verify eligibility 
at Screening. A confirmatory sample must be submitted to the central 
laboratory.
CA-125 will be assessed centrally at all imaging visits.
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; C1D1 = Cycle 1, Day 1; CA-125 = cancer antigen 125; 
CEA = carcinoembryonic antigen; CO2 = carbon dioxide; FSH = follicle-stimulating hormone; FT3 = free 
triiodothyronine; FT4 = free thyroxine; GGT = gamma-glutamyl transferase; HBsAg = hepatitis B surface antigen; 
HBV = hepatitis B virus; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; INR = International Normalized Ratio; LDH = lactate dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCHC = mean cell hemoglobin concentration; MCV = mean corpuscular volume;
PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; RNA = ribonucleic acid;
SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase;
T3 = triiodothyronine; T4 = thyroxine; TFTs = thyroid function tests; TSH = thyroid-stimulating hormone; 
ULN = upper limit of normal; WBC = white blood cell; WOCBP = women of childbearing potential;
WONCBP = women of nonchildbearing potential.
a.
Percentage (%) is preferred but absolute results can be reported per local standard of practice. Report 
the results in the same manner throughout the study.
b.
Urea is acceptable if BUN is not available as per standard of practice. Only 1 specified test should be 
reported.
c.
Test only if either it is the local standard of care or if clinically indicated.
d.
Participants may be dosed in subsequent cycles after C1D1 while TFTs are pending.
e.
Performed as part of the screening assessments and as clinically indicated for participants taking 
anticoagulants.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition 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 non-therapeutic 
effect.
10.3.2
Definition of AE
AE definition
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study intervention.
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic agent, 
medical device, combination product, or protocol specified procedure whether investigational 
or marketed (including placebo, active comparator product, or run-in intervention), 
manufactured by, licensed by, provided by, or distributed by the Sponsor for human use in 
this study.
Events meeting the AE definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator.
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Exacerbation of a chronic or intermittent preexisting condition including either an increase in 
frequency and/or intensity of the condition.
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication.
For all reports of overdose (whether accidental or intentional) with an associated AE, the AE 
term should reflect the clinical symptoms or abnormal test result. An overdose without any 
associated clinical symptoms or abnormal laboratory results is reported using the 
terminology “accidental or intentional overdose without adverse effect.”
Any new cancer (that is not a condition of the study). Progression of the cancer under study 
is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Anticipated day-to-day fluctuations of 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.
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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.
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.
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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 a condition of the study)
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to the 
event.
The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at 
each examination.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be blinded on the copies of the medical records before submission to the Sponsor.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity /toxicity
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
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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.
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.
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- 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.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
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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.
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.
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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).
SAE reporting to the Sponsor via paper CRF
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE paper 
CRF is the preferred method to transmit this information to the Sponsor.
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service.
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
Contacts and instructions for SAE reporting and paper reporting procedures can be found in 
the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
Premenarchal
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the 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
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb
IUSc
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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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.
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.
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.   Confidential Participant Information for Future Biomedical 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 are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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 
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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 utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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
10.7.1
France
5.1 Inclusion Criteria
WOCBP are required to continue using contraception for 210 days (7 months) after 
discontinuation of chemotherapy.
10.7.2
Italy
1.3 Schedule of Activities and 5.2 Exclusion Criteria
HIV, hepatitis B, and hepatitis C testing are required at baseline.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
5-HT3
5-hydroxytryptomine
ADL
activities of daily living  
AE
adverse event 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myelogenous leukemia
ANC
absolute neutrophil count
ANGPTL
angiopoietin-like proteins
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the concentration-time curve
AUROC
area under the ROC curve
AxMP
Auxiliary Medicinal Product
BRCA
breast cancer susceptibility gene
CA-125
cancer antigen-125
CD28
cluster of differentiation 28
CD3
cluster of differentiation 3
CD3ζ
cluster of differentiation 3 zeta
CD8
cluster of differentiation 8
CEA
carcinoembryonic antigen
cfDNA
cell-free DNA
CI
confidence interval
CIDOC
circulating tumor DNA as an early marker of recurrence and treatment 
efficacy in ovarian carcinoma
cLDA
constrained longitudinal data analysis
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
corona virus disease of 2019
CL
clearance
CPS
combined positive score
CR
complete response
CRC
colorectal cancer
CRF
Case Report Form
CRS
chemotherapy response score
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
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group
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Abbreviation
Expanded Term
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CYP
cytochrome P450
D
de-escalate to the next lower dose
DBS
dried blood spot
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid 
DU
the current dose is unacceptably toxic
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection
EEA
European Economic Area
EFS
event-free survival
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
E-R
exposure response
EU
European Union
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FIGO
International Federation of Gynecology and Obstetrics
FoxP3
Forkhead box protein 3
FSH
follicle-stimulating hormone
FSR
first site ready
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
GM-CSF
granulocyte macrophage colony-stimulating factor
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGSOC
high-grade serous ovarian carcinoma
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HR
heart rate
HRD
homologous repair deficiency
HRT
hormone replacement therapy
IB
Investigator’s Brochure
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Abbreviation
Expanded Term
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ICSR
Individual Case Safety Report
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IL-10
interleukin-10
ILT4
immunoglobulin-like transcript 4
IMP
Investigational Medicinal Product
IND
investigational new drug
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
IVD
in vitro diagnostic
LAG3
lymphocyte-activation gene 3
LILR
leukocyte immunoglobulin-like receptor
LILRB2
leukocyte immunoglobulin-like receptor B2
LPLV
last patient last visit
mAb
monoclonal antibody
MDSC
myeloid-derived suppressor cells
MHC
major histocompatibility complex
MRD
measurable residual disease
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NIMP
Noninvestigational Medicinal Product
NSCLC
non–small cell lung cancer
OC
ovarian cancer
OS
overall survival
OTC
over-the-counter
PARP
poly (ADP-ribose) polymerase
CCI
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Abbreviation
Expanded Term
PBMC
peripheral blood mononuclear cells
PBPK
physiologically-based PK
pCR
pathologic complete response
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death 1 ligand 1
PD-L2
programmed cell death 1 ligand 2
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PMBC
peripheral blood mononuclear cells
po
orally
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria In Solid Tumors version 1.1
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
Statistical Analysis Plan
SGCTG
Scottish Gynaecological Cancer Trials Group
SHP-1
Src-homology 2 domain containing phosphatase-1
SHP-2
Src-homology 2 domain containing phosphatase-2
siDMC
Standing Internal Data Monitoring Committee
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TIGIT
T-cell immunoreceptor with Ig and ITIM domains
TIL
tumor-infiltrating lymphocyte
TNBC
triple-negative breast cancer
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
ZAP70
zeta-chain-associated protein kinase
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10.9
Appendix 9: mTPI Table
The first 10 participants treated with pembrolizumab + MK-4830 + carboplatin/paclitaxel + 
Avastin (or biosimilar) will be closely followed for DLTs for the first cycle after the first 
dose of study intervention in the adjuvant phase (the DLT evaluation period). The number of 
participants with DLTs (Section 6.6.3) will be monitored according to the mTPI [Ji, Y., et al 
2007] table as outlined in Table 9 with a target DLT rate of 30%. 
Table 9
Dose-finding Rules per mTPI Design
Number of
Participants with
at Least 1 DLT
Number of Participants Evaluable for DLT at Current Dose
3
4
5
6
7
8
9
10
0
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
2
D
S
S
S
S
S
S
S
3
DU
DU
D
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
5
DU
DU
DU
DU
DU
D
6
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
8
DU
DU
DU
9
DU
DU
10
DU
D = De-escalate to the next lower dose; DLT = dose-limiting toxicity; DU = The current dose is 
unacceptably toxic; E = Escalate to the next higher dose; mTPI = modified toxicity probability interval; 
S = Stay at the current dose.
Note: Target toxicity rate=30%. Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.03 [Ji, 
Y., et al 2007] [Ji, Y. and Wang, S.-J. 2013] [Ji, Y., et al 2010].
08KDDB


PRODUCT:  MK-4830  
137
PROTOCOL/AMENDMENT NO.:  002-04
MK-4830-002-04 FINAL PROTOCOL
10-APR-2024
11
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