A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer (KEYNOTE-A18/ENGOT-cx11/GOG-3047)
Phase: PHASE3
Conditions: Uterine Cervical Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Title: 
A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy 
With or Without Pembrolizumab for the Treatment of High-risk, Locally 
Advanced Cervical Cancer (KEYNOTE-A18/ENGOT-cx11/GOG-3047) 
NCT Number: 
NCT04221945 
Document Date: 
A18-04 / ENGOT-CX11 / GOG-3047 08 November 2022 
 

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08-NOV-2022
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 3, Double-Blind Study of Chemoradiotherapy With or 
Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer 
(KEYNOTE-A18/ENGOT-cx11/GOG-3047)
Protocol Number: A18-04 / ENGOT-CX11 / GOG-3047
Compound Number: MK-3475
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
126191
EudraCT
2019-003152-37
EU CT
2022-501972-25-00
Approval Date: 08 November 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
08-NOV-2022
To amend the SAP to take into account emerging external data in LACC from the 
CALLA study. In addition, changes were made throughout to align with the EU CTR.
Amendment 03
18-MAR-2022
To incorporate PET scans into RECIST 1.1 evaluations to evaluate the burden of 
disease more accurately, and to add flexibility for the timing of efficacy analyses.
Amendment 02
04-JUN-2021
To update the dose modification and toxicity management guidelines for irAEs, and 
country-specific treatment administration details were provided for Japan.
Amendment 01
06-JAN-2021
Changes were made to the objectives/endpoints and statistical analysis plan that 
include changing the PFS by BICR to PFS by investigator and adding PFS by BICR as 
a secondary endpoint. Numerous administrative changes were also made.
Original Protocol
14-NOV-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
To amend the SAP to take into account emerging external data in LACC from the CALLA study. In addition, changes were made 
throughout to align with the EU CTR.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.2 Schema, Figure 1
4.2.1.1 Efficacy Endpoints
Used term ‘primary endpoints’ instead of 
‘dual-primary endpoints’ for PFS and OS
Change of multiplicity strategy in the SAP.
2.2.3 Ongoing Clinical 
Studies
Added emerging data from the CALLA study.
These emerging data for durvalumab + CCRT 
versus placebo + CRT in women with high-
risk LACC are pertinent to KEYNOTE-A18,
and are the basis for the SAP changes in this 
amendment.
4.1 Overall Design
9.1 Statistical Analysis Plan 
Summary
Updated the approximate number of OS events at 
FA from 322 to 240 based on new assumptions.
OS assumptions revised based on these 
emerging external data.
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Section # and Name
Description of Change 
Brief Rationale 
9.1 Statistical Analysis Plan 
Summary 
Changed the multiplicity, OS assumptions, and 
statistical power and properties with a new design 
outlined below:

Updated alpha passing strategy, focusing
initial alpha allocation on the PFS endpoint 
and testing OS in a conditional step-down 
manner.

Updated the OS rate in the control group after 
incorporating the emerging external data.

Updated the OS efficacy boundaries, powers, 
and expected number of events at IAs and FA
accordingly.
The emerging external data from the CALLA 
study (see Section 2.2.3) suggested a longer 
OS in the control arm compared with the 
KEYNOTE-A18 study’s original assumption
(see Section 9.9). The targeted number of OS 
events (based on original assumptions) cannot 
be achieved within a reasonable timeframe and 
the OS endpoint would likely be 
underpowered based on the original 
multiplicity strategy (ie, with initial 
alpha=0.0125). Focusing initial alpha 
allocation on the PFS endpoint and testing OS 
in a conditional step-down manner would give 
a higher POS on PFS and transfer to a higher 
POS on OS.
9.4.1 Primary
Removed the statement regarding claiming study
success based on either PFS or OS.
Change of multiplicity strategy.
9.7.2 Efficacy Interim 
Analyses
Stated that subsequent analysis may be triggered 
by OS events, if the PFS hypothesis is rejected in 
an earlier IA.
Updated the expected number of OS events at IAs 
and FA in Table 11.
Added a footnote in Table 11 stating that IA2 and 
FA may be kept at least 8 months apart as 
planned.
To focus on the more relevant endpoint when 
another endpoint has achieved success in an 
earlier analysis.
Due to new OS assumptions based on 
emerging external data.
Clarification regarding timing of analyses.
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Section # and Name
Description of Change 
Brief Rationale 
9.8 Multiplicity
9.8.1.1 Progression-free 
Survival
9.8.1.2 Overall Survival
Updated alpha passing strategy, focusing initial 
alpha allocation on the PFS endpoint and testing
OS in a conditional step-down manner. Updated 
corresponding Figure 2 and statistical properties in 
Table 12 and Table 13.
The new multiplicity strategy gives a higher 
POS on PFS and transfer to a higher POS on 
OS. 
9.8.1.1 Progression-free 
Survival
Removed note after Table 12.
Note is no longer applicable due to change in 
multiplicity. 
9.9 Sample Size and Power 
Calculations
Updated the OS assumptions and OS designed 
power.
To take the emerging external data into 
account.
Title Page
Added EU CT number. 
Alignment with the EU CTR.
4.4 Beginning and End of 
Study Definition
Added that 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; and 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.
Alignment with the EU CTR.
5 Study Population
Added a new paragraph stating that the collection 
and use of demographic data are to follow all local 
laws and participant confidentiality guidelines 
while supporting the study of the disease, its 
related factors, and the IMP under investigation.
To clarify the collection, use, and 
confidentiality of demographic data provided 
by the participants as required by the EU CTR.
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Section # and Name
Description of Change 
Brief Rationale 
6.1 Study Intervention(s) 
Administered
Added footnote to Table 3 stating that placebo for 
pembrolizumab is diluent alone (normal saline 
and/or dextrose); diluent is used for blinding 
purposes and does not contain active ingredients.
Alignment with the EU CTR.
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Added that investigators need to document if an 
SAE was associated with a medication error, 
misuse, or abuse.
Alignment with the EU CTR.
10.3.1 Definitions of 
Medication Error, Misuse, 
and Abuse
Added a new section with definitions of 
medication error, misuse, and abuse.
To provide definitions of medication error, 
misuse, and abuse in alignment with the EU 
CTR.
Title Page 
10.1.1 Code of Conduct for 
Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. 
This conversion resulted only in an entity 
name change and update to the address.
1.1 Synopsis: Intervention 
Groups and Duration
In the intervention groups table:

Updated ‘Use’ for pembrolizumab from ‘Exp’
(ie, Experimental) to ‘Test Product’

Updated ‘Use’ for placebo from ‘Exp’
(ie, Experimental) to ‘Placebo’
For consistency with Section 6.1, Table 3.
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
In the ‘Notes’ column for the row labeled, ‘CT –
chest, MRI – abdomen & pelvis’, clarified that the 
EOT scan must be performed within ±4 weeks of 
treatment discontinuation.
In the ‘Notes’ column for the row labeled, 
‘EORTC QLQ-C30, EORTC QLQ-CX24, PGI-S, 
PGI-C*, EQ-5D-5L’, clarified that only 
1 collection is required for each scheduled 
evaluation time point.
In the ‘Notes’ column for the row labeled, ‘Newly 
Obtained Tissue Collection’, clarified that the 
sample at time of disease progression may be 
collected during any cycle.
For clarity and alignment with Section 8.2.1.4.
Clarification to ensure that sites only collect 
PROs once per imaging evaluation time point.
To ensure that it is clear that the sample at 
disease progression may be collected at any 
cycle, including before Cycle 5.
4.4.1 Clinical Criteria for 
Early Study Termination
Removed list of reasons that recruitment at a 
particular study site(s) may be stopped and added 
a cross-reference to the information in 
Appendix 10.1.10.
To correct grammar and ensure clarity and 
intent of the section.
5.1 Inclusion Criteria
In Table 2, removed mention of creatinine levels 
from the ‘Laboratory Value’ column in the row 
for creatinine clearance and GFR and from 
footnote ‘b’.
Due to request from multiple Health 
Authorities to use CrCl or GFR, regardless of
creatinine levels, as the renal inclusion 
criterion.
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Section # and Name
Description of Change 
Brief Rationale 
6.5 Concomitant Therapy
Clarified that the listed prohibited concomitant 
medications are prohibited during the treatment 
period. 
In the sentence regarding COVID-19 vaccines, 
added ‘replication-incompetent’ before 
‘adenoviral vaccines’.
Revised the statement regarding permitted use of 
systemic glucocorticoids: ‘To treat asthma or
COPD exacerbations (only short-term oral or IV 
use in doses >10 mg/day prednisone equivalent)’.
Clarification of the time frame during which
the listed concomitant medications are 
prohibited.
Clarification regarding permitted COVID-19 
vaccines.
Participants may receive short-term steroids 
for asthma exacerbations.
8.4.7 Events of Clinical 
Interest
Revised list item #2 to introduce the acronym 
‘DILI’.
To define what a potential DILI is and to align 
with this acronym being used in Table 6.
5.1 Inclusion Criteria
8.1.1 Informed Consent
8.1.1.1 General Informed 
Consent
8.8.1 Planned Genetic 
Analysis Sample Collection
8.10.1 Screening
10.1.8 Data Quality 
Assurance
Updated informed consent language to refer to 
documented informed consent instead of written 
or signed informed consent, and other minor 
editorial changes to consent language.
Alignment of informed consent language 
across the protocol and with program 
standards.
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Section # and Name
Description of Change 
Brief Rationale 
8.8.1 Planned Genetic 
Analysis Sample Collection
Added that the planned genetic analysis sample 
should be obtained predose on Day 1, but may be 
collected at the next scheduled blood draw, if 
needed.
Clarification of biomarker sample collection.
8.10.4.2 Efficacy Follow-up 
Visits
Added that Efficacy Follow-up visits should align 
with the posttreatment imaging visit schedule.
To facilitate scheduling of Efficacy Follow-up 
visits and to allow imaging and PROs to be 
performed at the same visit.
10.1.4.2 Scientific Advisory 
Committee
Added additional details about the role of the 
SAC.
Clarification of the role of the SAC.
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-up, and 
Reporting
Changed ‘Sponsor’s product’ to ‘study 
intervention’ throughout section. 
To be consistent with other protocol sections
(eg, Study Intervention Table).
10.7.2.3 Japan
Added that cisplatin used in this study is 
categorized as ‘test product(s)’ in Japan.
Since cisplatin is not approved for the study 
population in Japan at the dosage and 
administration specified in the protocol, 
cisplatin is categorized as ‘test product(s)’ in 
Japan, per Japan Protocol Clarification Letter, 
04-MAY-2022.
10.7.2.4 Czech Republic
Added that live vaccines must not be administered 
for 90 days after the last dose of study intervention 
in Czech Republic.
To align with Health Authority standard 
requirements.
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Section # and Name
Description of Change 
Brief Rationale 
10.7.2.7 China
Added that the dose formulation for cisplatin may 
be powder for infusion or injection solution in 
China.
The dose formulation in China may not be as 
stated in Section 6.1, Table 3.
Throughout Document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................21
1.1
Synopsis.................................................................................................................21
1.2
Schema ..................................................................................................................28
1.3
Schedule of Activities...........................................................................................29
2
INTRODUCTION..........................................................................................................43
2.1
Study Rationale....................................................................................................45
2.2
Background ..........................................................................................................47
2.2.1
Pharmaceutical and Therapeutic Background .............................................47
2.2.2
Preclinical and Clinical Studies ...................................................................48
2.2.3
Ongoing Clinical Studies.............................................................................48
2.3
Benefit/Risk Assessment......................................................................................49
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................50
4
STUDY DESIGN............................................................................................................55
4.1
Overall Design......................................................................................................55
4.2
Scientific Rationale for Study Design.................................................................56
4.2.1
Rationale for Endpoints ...............................................................................57
4.2.1.1
Efficacy Endpoints.............................................................................57
4.2.1.2
Safety Endpoints................................................................................58
4.2.1.3
Patient-reported Outcomes.................................................................58
4.2.1.3.1
EORTC QLQ-C30 ...................................................................58
4.2.1.3.2
EORTC QLQ-CX24 ................................................................59
4.2.1.3.3
Patient Global Impression of Severity and Patient Global 
Impression of Change ..............................................................59
4.2.1.3.4
EQ-5D-5L ................................................................................59
4.2.1.4
Pharmacodynamic Endpoints.............................................................60
4.2.2
Rationale for the Use of Comparator/Placebo .............................................62
4.3
Justification of Dose.............................................................................................62
4.3.1
Maximum Dose/Exposure for This Study ...................................................63
4.4
Beginning and End of Study Definition .............................................................63
4.4.1
Clinical Criteria for Early Study Termination .............................................64
5
STUDY POPULATION ................................................................................................64
5.1
Inclusion Criteria.................................................................................................64
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5.2
Exclusion Criteria................................................................................................67
5.3
Lifestyle Considerations......................................................................................70
5.3.1
Meals and Dietary Restrictions....................................................................70
5.4
Screen Failures.....................................................................................................70
5.5
Participant Replacement Strategy......................................................................70
6
STUDY INTERVENTION............................................................................................70
6.1
Study Intervention(s) Administered...................................................................71
6.2
Preparation/Handling/Storage/Accountability .................................................75
6.2.1
Dose Preparation..........................................................................................75
6.2.2
Handling, Storage, and Accountability........................................................75
6.3
Measures to Minimize Bias: Randomization and Blinding..............................76
6.3.1
Intervention Assignment..............................................................................76
6.3.2
Stratification.................................................................................................76
6.3.3
Blinding........................................................................................................76
6.4
Study Intervention Compliance..........................................................................76
6.4.1
Pembrolizumab or Placebo ..........................................................................76
6.4.2
Chemoradiotherapy......................................................................................77
6.4.2.1
Concurrent Chemotherapy.................................................................77
6.4.2.2
External Beam Radiotherapy .............................................................78
6.4.2.3
Brachytherapy....................................................................................79
6.5
Concomitant Therapy..........................................................................................79
6.5.1
Rescue Medications and Supportive Care ...................................................81
6.6
Dose Modification (Escalation/Titration/Other)...............................................82
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................82
6.6.2
Radiation Dose Modifications .....................................................................88
6.6.3
Cisplatin Dose Modifications ......................................................................89
6.7
Intervention After the End of the Study............................................................90
6.8
Clinical Supplies Disclosure................................................................................90
6.9
Standard Policies..................................................................................................90
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................90
7.1
Discontinuation of Study Intervention...............................................................90
7.2
Participant Withdrawal From the Study...........................................................91
7.3
Lost to Follow-up .................................................................................................92
8
STUDY ASSESSMENTS AND PROCEDURES........................................................92
8.1
Administrative and General Procedures ...........................................................93
8.1.1
Informed Consent.........................................................................................93
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8.1.1.1
General Informed Consent.................................................................93
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................94
8.1.1.3
Consent for Optional Collection of Tumor Samples .........................94
8.1.2
Inclusion/Exclusion Criteria ........................................................................94
8.1.3
Participant Identification Card.....................................................................94
8.1.4
Medical History ...........................................................................................95
8.1.4.1
Cervical Cancer History.....................................................................95
8.1.5
Prior and Concomitant Medications Review...............................................95
8.1.5.1
Prior Medications...............................................................................95
8.1.5.2
Concomitant Medications..................................................................95
8.1.5.3
Subsequent Anticancer Therapy ........................................................95
8.1.6
Assignment of Screening Number...............................................................96
8.1.7
Assignment of Randomization Number.......................................................96
8.1.8
Study Intervention Administration ..............................................................96
8.1.8.1
Timing of Dose Administration.........................................................96
8.1.9
Discontinuation and Withdrawal .................................................................98
8.1.9.1
Withdrawal From Future Biomedical Research ................................98
8.1.10
Participant Blinding/Unblinding..................................................................99
8.1.10.1
Nonemergency Unblinding................................................................99
8.1.11
Calibration of Equipment...........................................................................100
8.1.12
Tumor Tissue for Biomarker Analyses......................................................100
8.2
Efficacy Assessments .........................................................................................100
8.2.1
Tumor Imaging and Assessment of Disease..............................................100
8.2.1.1
Initial Tumor Imaging......................................................................101
8.2.1.2
Tumor Imaging During the Study....................................................101
8.2.1.3
Optional Biopsy for Confirmation of Disease Progression .............102
8.2.1.4
End-of-Treatment and Follow-up Tumor Imaging..........................102
8.2.1.5
RECIST 1.1 Assessment of Disease................................................102
8.2.2
Patient-reported Outcomes.........................................................................103
8.3
Safety Assessments.............................................................................................103
8.3.1
Physical Examinations...............................................................................103
8.3.1.1
Full Physical Examination...............................................................103
8.3.1.2
Directed Physical Examination........................................................103
8.3.1.3
Gynecological Examination.............................................................104
8.3.2
Vital Signs..................................................................................................104
8.3.3
Audiometry ................................................................................................104
8.3.4
Electrocardiograms ....................................................................................104
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8.3.5
Clinical Safety Laboratory Assessments ...................................................104
8.3.5.1
Pregnancy Testing............................................................................105
8.3.6
Performance Assessments..........................................................................105
8.3.6.1
Eastern Cooperative Oncology Group Performance Scale..............105
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................105
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................106
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....107
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.108
8.4.4
Regulatory Reporting Requirements for SAE ...........................................108
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................108
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................108
8.4.7
Events of Clinical Interest..........................................................................109
8.5
Treatment of Overdose......................................................................................109
8.6
Pharmacokinetics...............................................................................................109
8.7
Pharmacodynamics............................................................................................109
8.8.1
Planned Genetic Analysis Sample Collection............................................110
8.9
Future Biomedical Research Sample Collection.............................................110
8.10
Visit Requirements.............................................................................................110
8.10.1
Screening....................................................................................................111
8.10.2
Treatment Period........................................................................................111
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ..............................................................................111
8.10.4
Posttreatment Visits ...................................................................................112
8.10.4.1
Safety Follow-up Visit.....................................................................112
8.10.4.2
Efficacy Follow-up Visits................................................................112
8.10.4.3
Survival Follow-up Contacts ...........................................................112
8.10.5
Survival Status ...........................................................................................113
9
STATISTICAL ANALYSIS PLAN ...........................................................................113
9.1
Statistical Analysis Plan Summary...................................................................113
9.2
Responsibility for Analyses/In-house Blinding ...............................................116
9.3
Hypotheses/Estimation ......................................................................................116
9.4
Analysis Endpoints.............................................................................................116
9.4.1
Primary.......................................................................................................116
9.4.2
Secondary...................................................................................................117
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9.5
Analysis Populations..........................................................................................118
9.5.1
Efficacy Analysis Population.....................................................................118
9.5.2
Safety Analysis Population........................................................................118
9.5.3
Patient-reported Outcome Analysis Population.........................................119
9.6
Statistical Methods.............................................................................................119
9.6.1
Statistical Methods for Efficacy Analyses.................................................119
9.6.1.1
Progression-free Survival.................................................................119
9.6.1.2
Overall Survival...............................................................................121
9.6.1.3
Progression-free Survival at 2 Years ...............................................121
9.6.1.4
Overall Survival at 3 Years..............................................................121
9.6.1.5
Objective Response Rate .................................................................122
9.6.1.6
Duration of Response.......................................................................122
9.6.2
Statistical Methods for Safety Analyses ....................................................123
9.6.3
Statistical Methods for PRO Analyses.......................................................125
9.6.4
Summaries of Baseline Characteristics and Demographics.......................125
9.7
Interim Analyses ................................................................................................126
9.7.1
Safety Interim Analyses.............................................................................126
9.7.2
Efficacy Interim Analyses..........................................................................126
9.8
Multiplicity .........................................................................................................127
9.8.1
Efficacy Analyses ......................................................................................128
9.8.1.1
Progression-free Survival.................................................................128
9.8.1.2
Overall Survival...............................................................................129
9.8.2
Safety Analyses..........................................................................................129
9.9
Sample Size and Power Calculations ...............................................................130
9.10
Subgroup Analyses.............................................................................................130
9.11
Compliance (Medication Adherence)...............................................................131
9.12
Extent of Exposure.............................................................................................131
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................132
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......132
10.1.1
Code of Conduct for Clinical Trials...........................................................132
10.1.2
Financial Disclosure...................................................................................134
10.1.3
Data Protection...........................................................................................134
10.1.3.1
Confidentiality of Data ....................................................................135
10.1.3.2
Confidentiality of Participant Records.............................................135
10.1.3.3
Confidentiality of IRB/IEC Information..........................................135
10.1.4
Committees Structure.................................................................................136
10.1.4.1
Executive Oversight Committee......................................................136
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10.1.4.2
Scientific Advisory Committee........................................................136
10.1.4.3
External Data Monitoring Committee .............................................136
10.1.5
Publication Policy......................................................................................136
10.1.6
Compliance with Study Registration and Results Posting Requirements .137
10.1.7
Compliance with Law, Audit, and Debarment ..........................................137
10.1.8
Data Quality Assurance .............................................................................138
10.1.9
Source Documents .....................................................................................138
10.1.10
Study and Site Closure...............................................................................139
10.2
Appendix 2: Clinical Laboratory Tests............................................................140
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................141
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................141
10.3.2
Definition of AE ........................................................................................141
10.3.3
Definition of SAE ......................................................................................142
10.3.4
Additional Events Reported in the Same Manner as SAE.........................143
10.3.5
Recording AE and SAE .............................................................................144
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................147
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................149
10.5
Appendix 5: Contraceptive Guidance..............................................................150
10.5.1
Definitions..................................................................................................150
10.5.2
Contraception Requirements......................................................................151
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................152
10.7
Appendix 7: Country-specific Requirements..................................................157
10.7.1
Laboratory Testing.....................................................................................157
10.7.2
Country-specific Requirements .................................................................157
10.7.2.1
Germany...........................................................................................157
10.7.2.2
France...............................................................................................158
10.7.2.3
Japan ................................................................................................158
10.7.2.4
Czech Republic................................................................................158
10.7.2.5
Norway.............................................................................................159
10.7.2.6
United Kingdom...............................................................................159
10.7.2.7
China................................................................................................159
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................160
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10.9
Appendix 9: Federation of Gynecology and Obstetrics Staging for Cancer 
of the Cervix Uteri .............................................................................................161
10.10 Appendix 10: Abbreviations .............................................................................162
11
REFERENCES.............................................................................................................166
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LIST OF TABLES
Table 1
Study Schedule of Activities......................................................................29
Table 2
Adequate Organ Function Laboratory Values ...........................................67
Table 3
Study Interventions....................................................................................72
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................83
Table 5
Pembrolizumab/Placebo Infusion Reaction Dose Modification and 
Treatment Guidelines.................................................................................87
Table 6
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................107
Table 9
Efficacy Analysis Methods for Key Efficacy Endpoints.........................123
Table 10
Analysis Strategy for Safety Parameters..................................................125
Table 14
Protocol-required Safety Laboratory Assessments..................................140
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................28
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Randomized, Phase 3, Double-Blind Study of Chemoradiotherapy With or 
Without Pembrolizumab for the Treatment of High-risk, Locally Advanced Cervical Cancer 
(KEYNOTE-A18/ENGOT-cx11/GOG-3047)
Short Title: Chemoradiotherapy With or Without Pembrolizumab for the Treatment of 
High-risk, Locally Advanced Cervical Cancer
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 refers to the modification of RECIST 1.1 to include a maximum of 10 target lesions and a 
maximum of 5 target lesions per organ. Refer to Section 4.2.1.1 for additional details. When 
tumor growth is suspected on imaging or by physical examination, an optional biopsy for
confirmation of suspected disease progression is allowed at investigator discretion. 
Throughout the protocol, the term “histopathologic confirmation” is used when referencing a 
biopsy that confirms suspected disease progression either from a new lesion or a pre-existing 
lesion showing growth.
This study will enroll female participants, at least 18 years of age, with high-risk locally 
advanced cervical cancer and will include the following objectives and endpoints:
Primary Objectives
Primary Endpoints
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to progression-free 
survival per RECIST 1.1 as assessed by 
investigator or by histopathologic 
confirmation of suspected disease 
progression (in the absence of radiographic 
disease progression per RECIST 1.1) as 
assessed by investigator
- Hypothesis (H1): concurrent 
chemoradiotherapy plus pembrolizumab is 
superior to concurrent chemoradiotherapy 
plus placebo with respect to progression-
free survival per RECIST 1.1 by 
investigator or by histopathologic 
confirmation as indicated
- Progression-free survival: The time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
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-  To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to overall survival 
- Hypothesis (H2): concurrent 
chemoradiotherapy plus pembrolizumab is 
superior to concurrent chemoradiotherapy 
plus placebo with respect to overall survival
- Overall survival: The time from 
randomization to death due to any cause
Secondary Objectives
Secondary Endpoints
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to progression-free 
survival per RECIST 1.1 as assessed by 
blinded independent central review (BICR)
- Progression-free survival: The time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to progression-free 
survival at 2 years per RECIST 1.1 as 
assessed by investigator or by 
histopathologic confirmation of suspected 
disease progression (in the absence of 
radiographic disease progression per 
RECIST 1.1)
- Progression-free survival at 2 years: The 
proportion of participants that are 
progression-free survival event-free at 
2 years 
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to progression-free 
survival at 2 years per RECIST 1.1 as 
assessed by blinded independent central 
review
- Progression-free survival at 2 years: The 
proportion of participants that are 
progression-free survival event-free at 
2 years
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to overall survival at 3 
years
- Overall survival at 3 years: The proportion 
of participants that are overall survival 
event-free at 3 years
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- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to complete response 
rate at 12 weeks after completion of 
concurrent chemoradiotherapy per 
RECIST 1.1 as assessed by investigator in 
all randomly assigned participants with 
measurable disease at study entry
- Complete response rate at 12 weeks after 
completion of concurrent 
chemoradiotherapy 
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to objective response 
rate per RECIST 1.1 as assessed by 
investigator in all randomly assigned 
participants with measurable disease at 
study entry
- Objective response: complete response or 
partial response 
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to complete response 
rate at 12 weeks after completion of 
concurrent chemoradiotherapy per 
RECIST 1.1 as assessed by blinded 
independent central review in all randomly 
assigned participants with measurable 
disease at study entry
- Complete response rate at 12 weeks after 
completion of concurrent 
chemoradiotherapy 
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to objective response 
rate per RECIST 1.1 as assessed by blinded 
independent central review in all randomly 
assigned participants with measurable 
disease at study entry
- Objective response: complete response or 
partial response 
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- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to overall survival and 
progression-free survival per RECIST 1.1 as 
assessed by investigator or by 
histopathologic confirmation of suspected 
disease progression (in the absence of 
radiographic disease progression per 
RECIST 1.1), by PD-L1 status (by 
combined positivity score)
- Overall survival
- Progression-free survival
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to overall survival and 
progression-free survival per RECIST 1.1 as 
assessed by blinded independent central 
review, by PD-L1 status (by combined 
positivity score)
- Overall survival
- Progression-free survival
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to progression-free 
survival after next-line treatment 
(progression-free survival 2) following 
discontinuation of study treatment 
administration as determined by the 
investigator according to the local standard 
of clinical practice
- Progression-free survival 2: The time from 
the date of randomization until disease 
progression on next-line treatment or death 
due to any cause, whichever occurs first
- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to change from 
baseline score in global quality of life and 
physical function using the European 
Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 
(EORTC QLQ-C30) global health 
status/Quality of Life scale and Physical 
Function subscale
- European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire EORTC QLQ-C30 Global 
Score and Physical Function subscale
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- To compare concurrent 
chemoradiotherapy plus pembrolizumab 
with concurrent chemoradiotherapy plus 
placebo with respect to change from 
baseline score in symptom experience using 
the European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire (Symptom Score for Cervical 
Cancer) the EORTC CX24 symptom 
specific scale (11 items)
- The European Organization for Research 
and Treatment of Cancer Quality of Life 
Questionnaire (Symptom Score for Cervical 
Cancer) EORTC QLQ-CX24 symptom 
specific scale
- To evaluate the safety and tolerability of 
pembrolizumab in combination with 
concurrent chemoradiotherapy 
- Adverse events 
- Study treatment discontinuation due to 
adverse events
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
High-risk locally advanced cervical cancer
Population
Women with International Federation of Gynecology and Obstetrics
2014 Stage IB2-IIB (with node-positive disease) and Stage III-IVA 
(either node-positive or node-negative disease) cervical cancer
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration 
of Study
The Sponsor estimates that the study will require approximately 
63 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.
Extension Portion of the Study in China: The study may remain 
open longer than 63 months to complete an extension portion of the 
study in China.
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08-NOV-2022
Number of Participants:
Approximately 980 participants will be randomized as described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin-
istration
Regimen/ 
Treatment Period
Use
Arm 1
Pembro-
lizumab
200 mg
Q3W
IV
5 infusions
Test 
Product
400 mg
Q6W
IV
15 infusions
Test 
Product
Arm 2
Placebo 
0 mg
Q3W
IV
5 infusions
Placebo
0 mg
Q6W
IV
15 infusions
Placebo
For both 
Arm 1 and
Arm 2
Cisplatin
40 mg/m2
Once 
weekly
IV 
5 infusions
(An optional, sixth
infusion may be 
administered 
according to local 
practice)
Back-
ground 
Treatment
For both 
Arm 1 and
Arm 2
Radiation
(EBRT)
Refer to 
Radiation 
Manual
Refer to 
Radiation 
Manual
External 
radiotherapy 
(IMRT or 
VMAT
/non-IMRT
and non-
VMAT) to 
primary 
tumor and 
nodal 
volumes
Within 40 days
Back-
ground 
Treatment
Radiation
(Brachy-
therapy)
Refer to 
Radiation 
Manual
Refer to 
Radiation 
Manual
High, low or 
pulse dose 
rates can be 
used
Brachy-therapy 
should be started 
immediately after 
completion of 
EBRT sessions.
Total radiation 
treatment (EBRT 
and brachy-therapy) 
should not exceed 
50 days (with 
extension to a 
maximum of 56 
days for unforeseen 
delays). 
Back-
ground 
Treatment
Abbreviations: EBRT=external beam radiotherapy; Exp=experimental; IMRT=intensity modulated radiotherapy; 
IV=intravenous; Q3W=dosing every 3 weeks; Q6W=dosing every 6 weeks; VMAT=volumetric modulated arc 
therapy
Geographic variance in total radiation dose administered, number of fractions and methodology of application 
may be permitted after consultation with the Sponsor.
Participants must receive 5 infusions of pembrolizumab or placebo at Q3W before moving to Q6W dosing. 
Chemoradiotherapy and brachytherapy are administered during the Q3W dosing regimen. Interruptions of 
cisplatin, EBRT, brachytherapy, pembrolizumab or placebo are allowed according to Section 6.4.
Administration of EBRT must be completed within 40 days from start to finish. The minimum acceptable 
radiation dosing is 80 Gy for volume-directed and 75 Gy for point-directed. Total radiation treatment (EBRT and 
brachytherapy) should not exceed 50 days (with extension to a maximum of 56 days for unforeseen delays).
The maximum dosage for radiation depends on the methodology used. Please refer to the Radiation Manual for 
additional details such as nodal boost dosing requirements.
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08-NOV-2022
Total 
Number of 
Intervention 
Groups/ 
Arms
2 intervention groups
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-specified 
contact.
After a screening phase of up to 42 days, each participant will be assigned 
to receive study intervention until one of the conditions for discontinuation 
of study intervention is met.
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1, 
withdrawal of consent, pregnancy, death, or loss to follow-up.
All participants will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study.
Once the study objectives have been met or the study has ended, 
participants will be discontinued from this study and will be enrolled in an 
extension study to continue protocol-defined assessments and treatment.
Further details of reasons for discontinuation of study intervention during 
the study are provided in Section 7.1.
Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
Abbreviations: EBRT=external beam radiotherapy; FIGO=International Federation of Gynecologists and Obstetricians; 
IMRT=intensity modulated radiotherapy; OS=overall survival; PFS = progression-free survival; QW3=dosing every 
3 weeks; QW6=dosing every 6 weeks; Q12W=every 12 weeks; Q24W=every 24 weeks; VMAT=volumetric modulated arc 
therapy
Note: For cisplatin, an optional, sixth infusion may be administered according to local practice.
Participants must receive 5 infusions of pembrolizumab 200 mg or placebo at Q3W before proceeding to pembrolizumab 
400 mg or placebo Q6W dosing.
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1.3
Schedule of Activities
Table 1
Study Schedule of Activities
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Administrative Procedures
Informed Consent
X
Consent form may be 
obtained any time prior to 
any protocol-specific 
screening procedures being 
performed.
If the investigator plans to 
treat beyond the initial 
radiographic disease 
progression, per RECIST 1.1, 
additional documented 
consent is required at initial 
site-assessed radiographic 
disease progression.
Informed Consent for 
Future Biomedical 
Research (optional)
X
Participant may participate in 
main study without 
documented Future 
Biomedical Research
consent.
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Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Consent for Optional 
Tissue Collection
Optional consent.
Participant ID Card
X
X
Distribute ID card at 
screening and add 
randomization number at 
C1D1.
Eligibility Assessment 
(Inclusion / Exclusion)
X
Demographics
X
Medical History
X
Cervical Cancer History 
X
Prior / Concomitant 
Medication Review
X
X
X
X
X
X
X
Record medications taken 
within 42 days prior to the 
start of study intervention. 
Concomitant medications 
will be recorded for 30 days 
after last dose (or for up to 90 
days after last dose for 
SAEs).
Radiotherapy Planning 
Assessment
X
X
Approval of radiotherapy 
plan is required prior to 
randomization. Refer to the 
Radiation Manual and the 
Radiation Therapy Quality 
Assurance Manual for details.
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Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Randomization 
(via IRT)
X
First dose of CCRT and 
pembrolizumab or placebo 
may begin up to 3 days after 
randomization.
Subsequent Anticancer
Treatment
X
X
X
X
X
X
Participants should be 
contacted by telephone to 
monitor new anticancer
treatment if there is no 
corresponding clinic visit.
Survival Status
X
On Sponsor request, 
participants may be contacted 
for survival status at any time 
during the course of the 
study.
Safety Procedures (during treatment visits safety assessments and procedures should be performed prior to treatment administration) 
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
Report all AEs through 
30 days following the last 
dose of study intervention. 
Report SAEs through 90 days 
following the last dose of 
study intervention (or 30 days 
following the last dose if 
participant initiates a new 
anticancer treatment).
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Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
ECOG Performance 
Status
X
X
X
X
Perform within 7 days prior 
to C1D1 of study 
intervention. 
During Cycles 1-5, assess 
ECOG at visits when 
pembrolizumab / placebo is 
being administered.
Complete Physical 
Examination
X
X
Symptom-directed 
Physical Examination
X
X
X
Gynecological 
Examination
X
X
Vital Signs 
(temperature, blood 
pressure, respiratory 
rate, heart rate, weight, 
height [height -
screening only])
X
X
X
X
X
Assess vital signs within 
72 hours prior to cisplatin 
and pembrolizumab/placebo
administration. 
Audiometry
X*
X*
*May be performed at 
screening and during the 
study per local practice as 
clinically indicated. This is 
not a required procedure.
08JCZC

PRODUCT: MK-3475  
33
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
12-lead ECG
X
Additional ECGs may be 
performed as clinically 
indicated.
HIV / HBV / HCV 
Testing
X
Required for eligibility if 
mandated by local health 
authority. 
Refer to Appendix 7 for 
country-specific
requirements.
08JCZC

PRODUCT: MK-3475  
34
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Urine or Serum 
Pregnancy Test 
(WOCBP only)
X
Required within 72 hours
(serum) or 24 hours (urine) of 
C1D1 of study intervention, 
monthly while receiving 
study intervention, and up to 
120 days after the last 
administration of 
pembrolizumab/placebo and 
up to 180 days after the last 
administration of 
chemoradiotherapy.
Home pregnancy tests are 
acceptable when a scheduled 
visit does not occur within 
the month (per local 
regulation), but the site must 
make monthly telephone 
contact with the participant to 
determine the results of the 
pregnancy test. 
See Section 8.3.5.1 for 
details.
08JCZC

PRODUCT: MK-3475  
35
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
PT or INR and 
aPTT / PTT
X
Perform within 7 days prior 
to C1D1 of study 
intervention.
Additional assessments may 
be performed as clinically 
indicated.
Chemistry
X
X
X
X
X
Perform within 7 days prior 
to C1D1 of study 
intervention.
While on CCRT perform 
within 72 hours prior to each 
cisplatin administration. 
Perform within 72 hours prior 
to each pembrolizumab or 
placebo administration.
Perform more frequently as 
clinically indicated.
Note: does not need to be 
performed prior to cisplatin 
and pembrolizumab/placebo 
administration at C1D1.
08JCZC

PRODUCT: MK-3475  
36
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Hematology
X
X
X
X
X
Perform within 7 days prior 
to C1D1 of study 
intervention.
While on CCRT perform 
within 72 hours prior to each 
cisplatin administration.
Perform within 72 hours prior 
to each pembrolizumab or 
placebo administration.
Perform more frequently as 
clinically indicated.
Note: does not need to be 
performed prior to cisplatin 
and pembrolizumab/placebo 
administration at C1D1.
Urinalysis
X
X
X
X
X
Perform within 7 days prior 
to C1D1 of study 
intervention.
Perform within 72 hours prior 
to pembrolizumab or placebo 
administration at C2, C4, and 
every cycle from C6 
onwards.
08JCZC

PRODUCT: MK-3475  
37
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
T3 or FT3 / FT4 / TSH
X
X
X
X
X
Perform during screening, 
and within 72 hours prior to 
pembrolizumab or placebo 
administration at C2, C4, and
every cycle from C6 
onwards.
Study Treatment Administration
Pembrolizumab 
(MK-3475) or placebo
X
X
For pembrolizumab: 200 mg 
by IV Cycles 1-5 followed by 
400 mg by IV Cycles 6-20.
For placebo: normal saline or 
dextrose Cycles 1-20. Note: 
Pembrolizumab/placebo 
should be administered prior 
to cisplatin when possible.
Cisplatin
X
40 mg/m2 by IV weekly. 
Cisplatin must be given on a 
day that EBRT is scheduled 
and prior to that radiation 
treatment.
An optional sixth infusion of 
cisplatin may be administered 
according to local practice.
Refer to Section 6.1 for 
treatment requirements.
08JCZC

PRODUCT: MK-3475  
38
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
External Beam 
Radiotherapy
X
Refer to Section 6.1 for 
treatment requirements.
Brachytherapy
X
Refer to Section 6.1 for 
treatment requirements.
Efficacy Assessments
PET / CT Scan
X
X
Baseline PET/ CT scan to be 
performed within 28 days prior 
to randomization.
A PET/CT scan will be 
performed 12 weeks (±14 days) 
after completing CCRT. 
For participants who are lymph 
node positive at baseline by PET 
only, a PET scan (with CT 
component only as necessary for 
attenuation correction and 
anatomic location) to confirm 
disappearance of the FDG uptake 
in the node(s) is required to 
determine that a complete 
response has occurred. If the 
nodal activity has not resolved, 
another PET scan should be 
performed at later time points, if 
the MRI and/or CT scan still 
shows complete response.
08JCZC

PRODUCT: MK-3475  
39
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
CT – chest
MRI – abdomen & 
pelvis
X
Imaging during treatment is 
performed according to the schedule 
in the ‘Notes’ column
X
X
X
X
Baseline CT/MRI to be 
performed within 28 days 
prior to randomization.
The first postrandomization 
imaging will be performed 
12 weeks (±14 days) after 
completing CCRT and Q12W 
(±14 days) from that point 
forward in years 1-2, Q24W
(±14 days) in year 3, annually 
(±14 days) in year 4 onwards.
Perform again within ±4 
weeks of treatment 
discontinuation unless most 
recent scan was already 
performed within 4 weeks 
prior to discontinuation.
08JCZC

PRODUCT: MK-3475  
40
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Patient-reported Outcomes (perform in the order shown below and prior to performing any study procedures)
EORTC QLQ-C30
EORTC QLQ-CX24
PGI-S
PGI-C*
EQ-5D-5L
X
X
X
X
X
X
Administer PROs prior to 
performing any procedures, 
assessments, and treatment. 
Collect at every cycle that 
pembrolizumab / placebo is 
administered, until treatment 
completion or 
discontinuation. Continue to 
collect in posttreatment
follow-up until disease 
progression; only 1 collection 
is required for each scheduled 
evaluation time point. If 
pembrolizumab/ placebo is 
discontinued prior to the 
completion, continue to 
administer PROs every 
3 weeks until discontinuation 
and then administer 
according to the schedule of 
activities.
* PGI-C is only administered 
at Cycles 4, 7, 8, 10, 11, and 
12.
08JCZC

PRODUCT: MK-3475  
41
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Period
Screen-
ing
Treatment
EOT
Post treatment
Notes
Cycle
Screen-
ing
Cycles 1-5
Cycles 6-20
Discon-
tinuation
Safety 
Follow-
upa
Posttreatment Follow-upb
Survival 
Follow-
up
Q12W
Participant must receive 
5 infusions (ie, Cycles) of 
pembrolizumab or placebo 
Q3W before moving to Q6W 
dosing. The interval between 
Cycle 5 and Cycle 6 is 3 
weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. 
CCRT are administered 
during the Q3W dosing 
regimen. Interruptions of 
cisplatin, EBRT, BT, 
pembrolizumab or placebo 
are allowed according to 
Section 6.4.
Cisplatin (QW) 
plus EBRT 
followed by BT 
plus 
pembrolizumab or 
placebo (Q3W)
Pembrolizumab 
or placebo 
(Q6W)
Years 
1-2
Q12W
Year 3
Q24W
Years
4 +
Annually
Scheduling
–42 
days to 
–1 day
±1 day (cisplatin)
±3 days 
(pembrolizumab or 
placebo)
±3 days
30 days 
after 
last 
dose 
(+7 
days)
±14
days
±14 
days
±14 
days
±14 
days
Blood and Tissue Sample Collection for Biomarker Analyses
Archival or Newly 
Obtained Tissue 
Collection (Required) 
X
Tissue is required at 
screening for all participants.
Newly Obtained Tissue 
Collection (Optional)
During C5 and prior to C6D1 
and at disease progression 
(any cycle) collect additional 
tissue for participants who 
are able to undergo a biopsy
and provide optional tissue 
collection consent.
Blood for Genetic 
Analyses
X
Collect prior to 
administration of study 
treatment at C1D1. Refer to 
Section 8.8 for
additional collection 
information.
Blood for RNA 
Analyses
X
X
X
Collect prior to
administration of study 
treatment at C1D1, C6D1 and
EOT.
Blood for ctDNA 
Analyses
X
X
X
Collect prior administration 
of study treatment at C1D1, 
C2D1, C6D1, C7D1, C8D1,
and at EOT
08JCZC

PRODUCT: MK-3475  
42
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
Abbreviations: AE=adverse event; aPTT / PTT=activated partial thromboplastin time / partial thromboplastin time; BT=brachytherapy; C=Cycle; CCRT=concurrent 
chemoradiotherapy; CT=computed tomography; ctDNA=circulating tumor deoxyribonucleic acid; D=day; EBRT=external beam radiotherapy; ECG=electrocardiograph, 
ECOG=Eastern Cooperative Oncology Group; EQ-5D-5L=EuroQoL 5 Dimension Questionnaire; EORTC QLQ-C30=European Organization for Research & Treatment of Cancer 
Quality of Life Questionnaire global health status; EORTC QLQ-CX24=European Organization for Research & Treatment of Cancer Quality of Life Questionnaire (Symptom 
Score for Cervical Cancer); EOT=end of treatment; FDG=fluorodeoxyglucose; FT3=free T3 thyroid hormone; FT4=free thyroxine; HBV= hepatitis B virus; HCV=hepatitis C 
virus; HIV=human immunodeficiency virus; ID=identity; INR=international normalized ratio; IRT=interactive response technology; IV=intravenous; MRI=magnetic resonance 
imaging; PET=positron emission tomography; PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; PRO=patient-reported outcomes; 
PT=prothrombin time; QW=dosing every week; QW3=dosing every 3 weeks; QW6=dosing every 6 weeks; Q12W=every 12 weeks; Q24W=every 24 weeks; RECIST=Response 
Evaluation in Solid Tumor; RNA=ribonucleic acid; SAE=serious adverse event; T3=T3 thyroid hormone; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing
potential.
a.
If the Discontinuation Visit occurs ≥30 days from last dose of study treatment, a separate Safety Follow-up Visit is not required. 
b.
Participants who discontinue study intervention for reasons other than RECIST 1.1 radiographic disease progression (including those with histopathologic confirmation of 
suspected disease progression) will have posttreatment follow-up imaging for disease status until disease progression is documented radiographically per RECIST 1.1 by the 
investigator, withdrawal of consent, pregnancy, death, or loss to follow-up, whichever comes first.
08JCZC

PRODUCT: MK-3475  
43
PROTOCOL/AMENDMENT NO.: A18-04 / ENGOT-cx11 / GOG-3047
MK-3475-A18-04 FINAL PROTOCOL
08-NOV-2022
2
INTRODUCTION
Cervical cancer is one of the most frequently diagnosed malignancies and causes of cancer 
related death among women [Bray, F., et al 2018]. Worldwide, there are an estimated 
569,847 newly diagnosed cases of cervical cancer and an estimated 311,365 deaths per year 
[Bray, F., et al 2018]. The extent of disease at the time of diagnosis is a significant prognostic 
factor presenting patients with more advanced disease especially in developing countries 
[Pisani, P., et al 1999]. Women with LACC (Stage IB2 to IVA) have higher disease 
recurrence rates than those with earlier stages of disease. 
According to FIGO 2014 staging, Stage IB2 is confined to the cervix with a clinically visible 
mass >4 cm, Stage II invades beyond uterus but not to pelvic wall or to the lower third of the 
vagina, Stage III extends to the pelvic sidewall and/or involves the lower third of the vagina, 
and/or causes hydronephrosis, or a nonfunctioning kidney, while Stage IVA invades the 
mucosa of the bladder or rectum, and extends beyond the true pelvis [Belhadj, H., et al 
2014].
Rate of recurrence worsen by stage, and benefits of SOC treatment are greater with earlier 
versus more advanced stages of disease. The 5-year OS rates for Stage III to IVA versus 
Stage IB2 to IIB were reported as 60% versus 86%, respectively, demonstrating the impact of 
staging on prognosis [Cetina, L., et al 2006]. A meta-analysis from 18 randomized studies 
also provides clear evidence of a larger unmet medical need for patients with Stage III-IVA 
despite standard of care treatment [Chemoradiotherapy for Cervical Cancer Meta-Analysis 
Collaboratio 2008]. Most recently, patients with OS and pelvic control rates at 3 and 5 years 
were reported in a large, multicentral study clearly demonstrating worse control rates and 
survival for Stage III and IVA patients [Sturdza, A., et al 2016].
Nodal involvement has also been an established prognostic factor as shown in several studies 
with the help of MRI or PET [Kim, Y. S., et al 2008]. In a recent study, half of the patients 
developed recurrent disease with PET positive nodes. Similarly, 5 year overall survival rates 
were 48% versus 70%, respectively, showing worse outcomes for patients with nodal 
involvement [Narayan, K., et al 2009]. The 3-year survival rate of negative PALN patients 
was higher than that of positive PALN patients in a recently reported study (89.5±1.5% 
versus 67.0 ± 6.0%, p<0.001). The corresponding positive PALN rates were 8.4%, 11.1%, 
17.2%, and 21.7% for Stage IB1, IB2, IIA1, and IIA2 disease, respectively, which suggested 
that patients with more advanced FIGO stage were more likely to have PALN metastasis. 
Pelvic LN involvement rates also increased from 30.9% at the IB1 stage to 59.4% at the IIA2 
stage [Han, X., et al 2017]. Similarly, patients with positive pelvic LNM have a higher 
recurrence rate and poor survival outcomes compared with pelvic LNM negative ones. 
Patients with more than 2 pelvic nodes have even poorer outcomes than the those who have 2 
or less [Liu, Y., et al 2015].
Standard of care treatment is concurrent chemoradiation followed by brachytherapy [Sturdza, 
A., et al 2016]. Chemoradiation was shown to be superior versus RT alone in a meta-analysis 
from randomized controlled studies in terms of overall survival, event-free survival and 
pelvic control [Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboratio 2008] 
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[Green, J. A., et al 2005] [Chemoradiotherapy for Cervical Cancer Meta-analysis 
Collaboratio 2010]. Chemoradiation showed a reduction in risk of death which translated in 
to a 10% absolute improvement in survival. The survival benefit, however, significantly 
decreased with increasing stage. For Stage IB to IIA, IIB and III to IVA, the 5-year survival
benefit was 10%, 7%, and 3%, respectively (p=0.017). An absolute improvement in PFS was 
higher than the absolute improvement in OS, at 13% and there was no association between 
staging and disease-free interval. Particularly in studies with platinum-based regimens, there 
was a reduction of risk in local recurrence and some trends seen toward a reduction in distant 
metastasis as well [Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboratio 
2008].
Chemotherapy regimen is single agent cisplatin given weekly (40 mg/m2) along with RT for 
5 weeks. Single agent cisplatin administered with RT was shown to have a better tolerability 
with similar efficacy versus cisplatin and fluorouracil given with RT with higher rate of 
completion of chemoradiation, less Grade 3-4 hematologic toxicities and same ORR. The OS 
rate reported at 4 years were also similar in this study [Kim, Y. S., et al 2008]. The number of 
cycles received during treatment seems important for systemic control in high-risk patients 
[Schmid, M. P., et al 2014], even if retrospective data analysis from Gynecologic Oncology 
Group 120 and Gynecologic Oncology Group 165 found no difference in efficacy for 
patients treated with 5 cycles versus 6 cycles of weekly cisplatin [Monk, B. J., et al 2007]. Of 
the note, only 50% to 70% of patients were able to complete 6 cycles of cisplatin without 
dose decreases or delays, mainly due to hematologic toxicities [Monk, B. J., et al 2007] 
[Nugent, E. K., et al 2010] [Keys, H. M., et al 1999] [Lanciano, R., et al 2005]. Another 
study reported inferior survival if less than 5 cycles were administered [Nugent, E. K., et al 
2010].
Radiotherapy is delivered to the pelvis using external beam RT concurrently with cisplatin 
administration. 
Brachytherapy is an absolute requisite component for the curative management of locally 
advanced cervical cancer and cannot be defined “optional” as referred by a recent editorial 
from Tanderup et al [Tanderup, K., et al 2013]. Brachytherapy is mainly administered in an 
effort to maximize the local control, can be intracavitary, using applicators inserted into the 
uterus or vagina, or interstitial, in which needles/catheters are inserted directly into the tumor. 
Brachytherapy should follow EBRT and concomitant chemotherapy to obtain maximal tumor 
regression. It can be delivered with either a low dose rate, pulse dose rate or high dose rate. 
Data highlighting the importance of brachytherapy derived from more than 7000 locally 
advanced cervical cancer patients is available in the SEER database [Han, K., et al 2013].
Overall, the concurrent use of image guided brachytherapy improves pelvic control by 
approximately 10% compared with conventional 2D BT with no evident impact of the use of 
concomitant chemotherapy. The effect was larger in advanced stages. Image guided BT 
combined with chemoradiotherapy led to excellent local control and pelvic control rates with 
limited morbidity in a study called RetroEMBRACE. A total of 731 patients from 12 centers 
who were treated with CCRT followed by image guided brachytherapy were analyzed 
[Sturdza, A., et al 2016].
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Despite these improvements, approximately half of the women with high-risk cervical cancer 
experience a recurrence of their cervical cancer within 2 years. Thus, new treatment 
modalities and paradigms are needed to significantly improve the prognosis for women 
diagnosed with high-risk LACC.
2.1
Study Rationale
Immunotherapy is emerging as a potential strategy to enhance traditional cervical cancer 
treatments. It is considered that pembrolizumab and CCRT will be more beneficial to the 
patient via enhancing immunostimulatory activity of pembrolizumab as a single agent use. 
Cervical cancer is overwhelmingly an HPV-driven cancer, with HPV DNA detected in 90% 
of tumors. Human papillomavirus infection, particularly types 16 and 18, are significantly 
associated with subsequent development of cervical cancer. Recent research on the biology 
of HPV-related cancers supports the strategy of targeting PD-L1 with pembrolizumab 
demonstrating durable responses in such tumors. The expression of high levels of PD-L1 was 
reported in cervical cancer, thus restoring host antitumor immunity might provide a new 
therapeutic strategy. 
Pembrolizumab monotherapy demonstrated durable antitumor activity and manageable safety 
in patients with advanced cervical cancer. At ASCO in 2016, the preliminary results of
KEYNOTE-028 study on cervical cancer patients were presented: 17% objective response 
and OS of 9 months were reported with pembrolizumab single agent in a population of 
24 advanced/recurrent cervical cancer patients pretreated with platinum-based chemotherapy 
(96%), radiotherapy (92%) and bevacizumab (42%), in which 38% of patients received 
pembrolizumab at least as fourth line of chemotherapy [Frenel, J. S., et al 2017]. A 
subsequent Phase 2 study, KEYNOTE-158, enrolled 98 patients with pretreated advanced 
cervical cancer to receive single agent pembrolizumab. The ORR was 13.3%, with 3 patients 
with CR and 10 patients with PR [Chung, H. C., et al 2018]. On the basis of these results 
with pembrolizumab, the US Food and Drug Administration granted accelerated approval of 
pembrolizumab for patients with advanced PD-L1–positive cervical cancer who experienced 
progression during or after chemotherapy [Chung, H. C., et al 2019]. Recently, Hollebecque 
et al presented at ASCO 2017 the results of a Phase 1/2 study evaluating nivolumab 240 mg 
every 2 weeks in vulvar, vaginal and cervical tumors. Cervical cancer patients experienced 
promising clinical activity with good toxicity profile (ORR 26.3%; PFS 5.5 months) 
[Hollebecque, A., et al 2017].
Currently, there are limited data on the use anti-PD-1 or anti-PD-L1 in the LACC setting in 
combination with chemoradiotherapy. However, preclinical and preliminary clinical 
observations provide a strong rationale for testing RT and cisplatin as potentiators of immune 
checkpoint inhibitors. Radiotherapy used at therapeutic doses, as well as some cytotoxic 
agents induce immunogenic cell death and the release of tumor antigens that can effectively 
prime antigen presenting cells [Formenti, S. C. 2009] [Reits, E. A., et al 2006]. Radiotherapy 
and chemotherapy act on the microenvironment to decrease its immunosuppressive 
properties by inducing the release of cytokines and chemokines that have the ability to attract 
T-cells [Golden, E. B. 2015]. Radiotherapy has both systemic and local effects on the
immune system which in combination with immunotherapy may lead to maximizing 
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antitumor responses [Grassberger, C., et al 2019]. In addition, RT may augment the TILs
numbers and broaden their T-cell receptor repertoire of cytotoxic effectors cells [Derer, A., et 
al 2015] [Esposito, A., et al 2015]. Radiotherapy also increases the expression of PD-L1 on 
tumor cells, which can also explain part of the synergism [Deng, L., et al 2014]. Radiation 
therapy in combination with immunotherapy is being evaluated as an attractive option across 
gynecologic cancers [Lee, L. 2019]. In addition to immunomodulation, the abscopal effects 
in gynecologic and other cancers are also suggested to contribute to efficacy of the 
combination treatment. 
Preclinical models have demonstrated synergy between RT and PD-1 blockade treatments 
[Zeng, J., et al 2013] and several clinical studies combining RT with immunotherapy are 
underway in multiple tumor types [Daly, M. E., et al 2015]. Mayedev et al reported at ASCO 
2017 the safety, tolerability, and efficacy of a Gynecologic Oncology Group Phase 1 study 
evaluating sequential ipilimumab in combination with definitive CCRT in node-positive 
cervical cancer [Mayadev, J., et al 2017]. The data suggest that immunotherapy has potential 
activity (secondary endpoint 1-year disease-free survival was 74%) and a good toxicity 
profile: most common adverse events were Grade 1-2 diarrhea, rash and endocrinopathies. 
Incidence of Grade 3 toxicity was 16%, all of which resolved. With a median follow-up of 12 
months, there were no major late toxicities reported, and a 1-year disease-free survival of 
74%. 
Antonia SJ et al recently reported the results of a Phase 3 study on durvalumab after CCRT 
in locally advanced lung cancer (PACIFIC study): 713 patients with Stage III lung cancer at 
completion of CCRT were randomly assigned to receive durvalumab (at a dose of 10 mg per 
kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months
[Antonia, S. J., et al 2017]. The median PFS was 16.8 months with durvalumab versus 5.6 
months with placebo (stratified HR 0.52; p<0.001); the response rate was higher with 
durvalumab than with placebo (28.4% versus 16.0%; p<0.001), and the median duration of 
response was longer (72.8% versus 46.8% of the patients had an ongoing response at 18 
months); the median time to death or distant metastasis was longer with durvalumab than 
with placebo (23.2 months versus 14.6 months; p<0.001). Of note, safety was similar 
between the groups. 
Chemoradiotherapy appears to modulate tumor microenvironment favorably for 
immuno-oncology as shown in the PACIFIC study. Progression-free survival was 
significantly longer with durvalumab than with placebo. The secondary endpoints also 
favored durvalumab, and safety was similar between the groups [Antonia, S. J., et al 2017]. 
The addition of pembrolizumab (Keytruda®) to a CCRT regimen yielded CR rates of 85% in 
patients with HPV-positive advanced squamous cell carcinoma of the head and neck. These 
findings from a Phase 1b study were presented at the 2018 Society for Immunotherapy of 
Cancer Annual Meeting. The study enrolled patients with HPV-positive and HPV-negative 
tumors, with 34 and 23 patients, respectively, evaluable for the interim analysis. All patients 
were eligible for definitive CCRT and were not surgical candidates. The HPV-positive cohort 
had at least 70% of cells staining positive for P16. The regimen’s backbone was cisplatin at 
40 mg/m2 given weekly for 6 planned doses, radiation therapy at 2 Gy once daily for a total 
of 70 Gy, plus pembrolizumab at 200 mg every Q3W for 8 planned doses. Patients first 
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received pembrolizumab 1 week before chemoradiation, and this treatment was followed by 
2 doses during chemoradiation and 5 doses afterward. Weekly cisplatin was chosen because 
it is potentially less myelosuppressive than some other regimens and avoids the need for 
dexamethasone, which may dampen the immune response. The primary endpoint was overall 
CR at Day 150. Two patients discontinued treatment due to immune-related adverse events, 
both of which resolved. Most adverse events were in line with previous experience with this 
regimen. The chemotherapy and RT regimens were able to be administered as planned, with 
no major delays in treatment. The addition of pembrolizumab did not impact the safety of 
standard chemoradiotherapy. Full radiation dose was achieved for the vast majority of 
patients with the intended chemotherapy dose [Frontline Medical Communications Inc. 
2018].
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the IB.
2.2.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (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 
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immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following 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 high-risk LACC.
2.2.2
Preclinical and Clinical Studies
Accumulating evidence shows a correlation between TILs in cancer tissue and favorable 
prognosis in various malignancies [Lavoue, V., et al 2013]. In particular, the presence of 
CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to 
correlate with improved prognosis and long-term survival in many solid tumors.
The ligands PD-L1 and PD-L2 are commonly up-regulated in many different human tumors 
with PD-L1 being the predominant PD-1 ligand on solid tumors. High expression levels of 
PD-L1 have been shown in cervical cancer and PD-1/PD-L1 inhibitors might be a novel 
choice to improve the clinical outcomes of these patients [Liu, Y., et al 2019]. Importantly, 
many studies have described the correlation of PD-L1 with invasiveness, metastasis, and 
poor prognosis. When PD-1 receptor binds with its ligand (PD-L1/B7-H1), T-cell inhibition 
and down regulation of T-cell responses occur. This allows tumors to directly halt antitumor 
T-cell activity, also known as adaptive resistance. Blocking PD-1 or PD-L1 via a mAb 
empowers the T-cell response. To date, different mAbs against PD-1 and PD-L1 have been 
evaluated showing effectiveness and low toxicities in different cancer types, including 
melanoma, nonsmall-cell lung cancer, renal-cell carcinoma, bladder cancer, and Hodgkin’s 
lymphoma.
Preclinical evidence seems to suggest that immunotherapy may have a potential therapeutic 
impact in cervical cancer and represent a promising therapeutic tool for the future [Menderes, 
G., et al 2016].
Preclinical models have demonstrated synergy between RT and PD-1 blockade treatments 
[Zeng, J., et al 2013]. Radiation therapy is thought to have immunostimulatory effects by 
enhancing cancer antigen presentation. Because both modalities work through immune-
mediated mechanisms, combination therapy has the potential to augment immune activation 
by PD-1 checkpoint inhibitors [Formenti, S. C. 2009].
2.2.3
Ongoing Clinical Studies
There is an ongoing randomized Phase 2 study of chemoradiation and pembrolizumab in
88 participants with LACC to compare concurrent versus sequential use of pembrolizumab in 
combination with CCRT. The primary objective of the study is to assess the safety and 
immune response to pembrolizumab given either sequentially or with CCRT. The study 
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design also focuses on the effect of treatment on immune response pathways and specific 
immune markers (ClinicalTrials.gov Identifier: NCT02635360). 
As of AUG 2019, 60 patients (of a planned total of 88) had started treatment; 52 had 
completed treatment. Overall, there were 22 Grade 3 and 11 Grade 4 treatment-related 
adverse events, the most common of which was lymphopenia (Arm 1: n=8; Arm 2: n=12). 
Two patients experienced the adverse event of special interest of diarrhea. Most patients 
completed 6 cisplatin treatments (100% in Arm 1; 82% in Arm 2). 83% of patients completed 
3 infusions of pembrolizumab. All but 2 patients completed radiation (2 patients in Arm 2 
withdrew from the study). As of AUG 2019, the safety and feasibility of the combination of 
pembrolizumab and pelvic CRT has been demonstrated and no major differences in safety 
were evident by arm. The safety stopping bounds were not crossed and the study is 
continuing with accrual [Duska, L. R., et al 2020].
Most recently a randomized, Phase 3, global, multicenter, double-blind, placebo-controlled
study was initiated to compare the efficacy and safety of durvalumab + CCRT versus CRT 
alone as treatment for women with high-risk LACC (CALLA; ClinicalTrials.gov Identifier: 
NCT03830866). Results based on 770 randomized patients (N=385 per arm) with median 
follow-up of ~18.5 months (data cut-off 20-JAN-2022) did not show a statistically significant 
improvement in PFS for durvalumab + CCRT versus placebo + CRT (HR: 0.84; 95% CI: 
0.65, 1.08; p=0.174), with 2-year PFS rates of 65.9% and 62.1%, respectively. There was no 
detriment to OS (HR: 0.78; 95% CI: 0.55, 1.10; nominal p=0.156), although data were 
immature (17% maturity) and not formally tested. OS rates were not reported. Grade 3/4 AEs 
occurred in 51.7% and 51.0% of patients in the durvalumab + CCRT and placebo + CRT 
arms, respectively; 12.5% and 9.6% of patients discontinued treatment due to AEs possibly 
related to study drug [Monk, B. J. 2022].
There are also other ongoing Phase 1/2 studies with atezolizumab, dostarlimab (TSR-042)
and nivolumab in combination with CCRT mainly focusing on high-risk LACC patients.
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.
Given the high rate of relapse following chemoradiation, new treatment modalities and 
paradigms are needed to significantly improve the prognosis of women diagnosed with 
high-risk LACC. Immunotherapy is emerging as a potential strategy to enhance traditional 
cervical cancer treatments. Pembrolizumab and CCRT may be more beneficial to the patient 
via enhancing immunostimulatory activity of pembrolizumab as a single agent use. The 
current data discussed above suggests that the chemotherapy and radiotherapy regimens may 
be administered as planned, with no major delays in treatment when given in combination 
with pembrolizumab. Full radiation dose is expected to be achieved for the vast majority of 
patients with the intended chemotherapy dose providing an acceptable safety profile.
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Throughout this protocol, the term RECIST 1.1 refers to the modification of RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1 for additional details. When tumor growth is suspected on imaging or by 
physical examination, an optional biopsy for confirmation of suspected disease progression is 
allowed at investigator discretion. Throughout the protocol, the term “histopathologic 
confirmation” is used when referencing a biopsy that confirms suspected disease progression 
either from a new lesion or a pre-existing lesion showing growth.
This study will enroll female participants, at least 18 years of age, with high-risk locally 
advanced cervical cancer and will include the following objectives and endpoints:
Objectives
Endpoints
Primary
To compare concurrent chemoradiotherapy
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to progression-free survival per RECIST 1.1 
as assessed by investigator or by 
histopathologic confirmation of suspected 
disease progression (in the absence of 
radiographic disease progression per 
RECIST 1.1) as assessed by investigator
Hypothesis (H1): concurrent 
chemoradiotherapy plus pembrolizumab is 
superior to concurrent chemoradiotherapy
plus placebo with respect to progression-free 
survival per RECIST 1.1 by investigator or 
by histopathologic confirmation as indicated
Progression-free survival: The time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
To compare concurrent chemoradiotherapy
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to overall survival 
Hypothesis (H2): concurrent 
chemoradiotherapy plus pembrolizumab is 
superior to concurrent chemoradiotherapy 
plus placebo with respect to overall survival
Overall survival: The time from 
randomization to death due to any cause
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Objectives
Endpoints
Secondary
To compare concurrent chemoradiotherapy
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to progression-free survival per RECIST 1.1 
as assessed by blinded independent central 
review (BICR)
Progression-free survival: The time from 
randomization to the first documented 
disease progression or death due to any 
cause, whichever occurs first
To compare concurrent chemoradiotherapy
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to progression-free survival at 2 years per 
RECIST 1.1 as assessed by investigator or
by histopathologic confirmation of suspected 
disease progression (in the absence of 
radiographic disease progression per 
RECIST 1.1)
Progression-free survival at 2 years: The 
proportion of participants that are 
progression-free survival event-free at 
2 years 
To compare concurrent chemoradiotherapy
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to progression-free survival at 2 years per 
RECIST 1.1 as assessed by blinded 
independent central review
Progression-free survival at 2 years: The 
proportion of participants that are 
progression-free survival event-free at
2 years
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to overall survival at 3 years
Overall survival at 3 years: The proportion 
of participants that are overall survival 
event-free at 3 years
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to complete response rate at 12 weeks after 
completion of concurrent chemoradiotherapy 
per RECIST 1.1 as assessed by investigator 
in all randomly assigned participants with 
measurable disease at study entry
Complete response rate at 12 weeks after 
completion of concurrent 
chemoradiotherapy 
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Objectives
Endpoints
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to objective response rate per RECIST 1.1 as 
assessed by investigator in all randomly 
assigned participants with measurable 
disease at study entry
Objective response: complete response or 
partial response 
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to complete response rate at 12 weeks after 
completion of concurrent chemoradiotherapy 
per RECIST 1.1 as assessed by blinded 
independent central review in all randomly 
assigned participants with measurable 
disease at study entry
Complete response rate at 12 weeks after 
completion of concurrent 
chemoradiotherapy 
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to objective response rate per RECIST 1.1 as 
assessed by blinded independent central 
review in all randomly assigned participants 
with measurable disease at study entry
Objective response: complete response or 
partial response 
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to overall survival and progression-free 
survival per RECIST 1.1 as assessed by 
investigator or by histopathologic 
confirmation of suspected disease 
progression (in the absence of radiographic 
disease progression per RECIST 1.1), by 
PD-L1 status (by combined positivity score)
Overall survival
Progression-free survival
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to overall survival and progression-free 
survival per RECIST 1.1 as assessed by 
blinded independent central review, by 
PD-L1 status (by combined positivity score)
Overall survival
Progression-free survival
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Objectives
Endpoints
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to progression-free survival after next-line 
treatment (progression-free survival 2) 
following discontinuation of study treatment 
administration as determined by the 
investigator according to the local standard 
of clinical practice
Progression-free survival 2: The time from 
the date of randomization until disease 
progression on next-line treatment or death 
due to any cause, whichever occurs first
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to change from baseline score in global 
quality of life and physical function using the 
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C30) global 
health status/Quality of Life scale and 
Physical Function subscale
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire EORTC QLQ-C30 Global 
Score and Physical Function subscale
To compare concurrent chemoradiotherapy 
plus pembrolizumab with concurrent 
chemoradiotherapy plus placebo with respect 
to change from baseline score in symptom 
experience using the European Organization 
for Research and Treatment of Cancer 
Quality of Life Questionnaire (Symptom 
Score for Cervical Cancer) the EORTC 
QLQ-CX24 symptom specific scale (11 
items)
The European Organization for Research 
and Treatment of Cancer Quality of Life 
Questionnaire (Symptom Score for 
Cervical Cancer) EORTC QLQ-CX24 
symptom specific scale
To evaluate the safety and tolerability of 
pembrolizumab in combination with 
concurrent chemoradiotherapy 
Adverse events 
Study treatment discontinuation due to 
adverse events
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Objectives
Endpoints
Tertiary/Exploratory
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Objectives
Endpoints
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, Phase 3, placebo-controlled, multisite, double-blind study of 
chemoradiotherapy with or without pembrolizumab in participants with high-risk LACC. 
Approximately 980 participants will be enrolled in the global portion of the study. After 
enrollment of the global portion of the study is complete, the study may remain open to 
enrollment in China alone until the target number of participants in China has been enrolled 
to meet local regulatory requirements. An extension portion of the study will be identical to 
the global study, (eg, inclusion and exclusion criteria, study endpoints, primary and 
secondary objectives, study procedures, and statistical analyses).
Eligible participants with high-risk LACC FIGO 2014 Stage IB2-IIB (with node-positive
disease) or Stage III-IVA (either node-positive or node-negative disease) will be randomly 
assigned in a 1:1 ratio to one of the following treatment arms:
1) Concurrent chemoradiotherapy in combination with pembrolizumab (200 mg Q3W 
for 5 infusions) followed by pembrolizumab alone (400 mg Q6W for 15 infusions) or
2) Concurrent chemoradiotherapy in combination with placebo (Q3W for 5 infusions) 
followed by placebo alone (Q6W for 15 infusions). 
Standard of care CCRT is given during the Q3W dosing period of pembrolizumab (Arm 1) or 
placebo (Arm 2) and includes the following:
1) Cisplatin, 5 infusions given IV QW at 40 mg/m2 (an optional, sixth infusion of 
cisplatin may be administered according to local practice) plus
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2) EBRT over 40 days, followed by 
3) Brachytherapy 
Note: brachytherapy should follow the completion of EBRT, and the overall treatment time
of EBRT and brachytherapy together should not exceed 50 days (with an extension to a 
maximum of 56 days for unforeseen delays). The minimum acceptable radiation is 80 Gy for 
volume-directed and 75 Gy for point-directed. Please refer to the Radiation Manual for 
further guidance.
Geographic variance in total radiation dose administered, number of fractions and 
methodology of application may be permitted after consultation with the Sponsor.
The SOC will be at least 3D conformal planning.
To limit overall treatment time, efficient organization of the whole multimodal treatment is 
required. This includes use of SIB in participants with lymph node involvement, minimizing 
treatment interruptions as much as possible and by planning the timing of brachytherapy 
carefully.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3 (Table 1). Details of each 
procedure are provided in Section 8.
There will be 2 formal interim analyses. The first interim analysis will be conducted when 
approximately 237 PFS events are observed. The second interim analysis will be conducted 
when approximately 304 PFS events are observed. A final analysis will be conducted when 
approximately 240 OS events are observed.
Results of the interim and final analyses will be reviewed by the external DMC, who will 
make recommendations to the Sponsor to continue, modify, or end the study according to the 
plan described in Section 9.
4.2
Scientific Rationale for Study Design
MK-3475 A18/ENGOT-CX11/GOG3047 is a randomized, Phase 3, double-blind study of 
chemoradiotherapy with or without pembrolizumab for the treatment of high-risk, locally 
advanced cervical cancer. 
The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus 
concurrent chemoradiotherapy compared with placebo plus concurrent chemoradiotherapy in 
participants with locally advanced cervical cancer.
The primary hypotheses are that pembrolizumab plus concurrent chemoradiotherapy is 
superior to placebo plus concurrent chemoradiotherapy with respect to progression-free 
survival and overall survival.
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High-risk LACC is a population with larger unmet medical need. Approximately half of the 
women treated with SOC chemoradiotherapy experience a recurrence of their cervical cancer 
within 2 years. Thus, new treatment modalities and paradigms are needed to significantly 
improve the prognosis for women diagnosed with high-risk LACC. It is considered that 
pembrolizumab and CCRT will be more beneficial to the patient via enhancing 
immunostimulatory activity of pembrolizumab. Pembrolizumab monotherapy demonstrated 
durable antitumor activity and manageable safety in patients with advanced cervical cancer 
and received accelerated approval in patients with advanced PD-L1–positive cervical cancer 
who experienced progression during or after chemotherapy. Preclinical and preliminary 
clinical observations from other tumor types provide a strong rationale for testing RT and 
cisplatin as potentiators of immune checkpoint inhibitors.
Study and scientific rationale are further described in Section 2.1.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Progression-free survival and OS are primary endpoints. 
This study will use PFS based on RECIST 1.1 criteria as assessed by investigator and 
histopathologic confirmation of suspected disease progression (in the absence of radiographic 
disease progression per RECIST 1.1) as the primary endpoint. Locally advanced cervical 
cancer is a setting where disease progression is highly informed by clinical judgment, 
including histopathologic confirmation of disease progression with biopsy. PFS by BICR 
may introduce bias because of informative censoring, which results from having to censor 
unconfirmed investigator determined progressions. If BICR cannot confirm the locally 
determined progression, then these cases would be censored at the time of local progression 
for the BICR analysis of PFS. PFS by investigator is anticipated to result in fewer events 
censored from PFS analysis compared with BICR and, therefore, to preserve available power 
for PFS analysis. Investigator is therefore considered a more appropriate primary endpoint in 
this disease setting. For these reasons, the primary endpoint is PFS by investigator and PFS 
by BICR is now a secondary endpoint. Progression-free survival is an acceptable measure of 
clinical benefit for a late stage study that demonstrates superiority of a new antineoplastic 
therapy, especially if the magnitude of the effect is large and the therapy has an acceptable 
risk/benefit profile. The use of PFS per RECIST 1.1 is typically considered acceptable by 
regulatory authorities in a double-blinded randomized controlled study. 
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
Secondary efficacy endpoints include PFS based on RECIST 1.1 criteria CR at 12 weeks and 
ORR as assessed by investigator and BICR.
Complete response at 12 weeks and ORR, as assessed by both investigator and BICR per 
RECIST 1.1 criteria, are commonly accepted endpoints by both regulatory authorities and the 
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oncology community to assess response and the durability of these responses to oncology 
treatments.
RECIST 1.1
RECIST 1.1 will be used by the investigator and BICR when assessing images for efficacy 
measures and by the local site when determining eligibility (Section 8.2.1.5) [NA 2008]. 
Although traditional RECIST 1.1 references a maximum of 5 target lesions in total and 2 per 
organ, this protocol has implemented a modification to RECIST 1.1 to allow a maximum of 
10 target lesions in total and 5 per organ.
Analyses by PD-L1 Status:
As a secondary endpoint, OS and PFS by PD-L1 status (by CPS) will be compared. 
Progression-free survival assessment by the investigator will include RECIST 1.1 or
histopathologic confirmation of suspected disease progression (in the absence of radiographic 
disease progression per RECIST 1.1). Cervical cancer is overwhelmingly an HPV-driven 
cancer, resulting in high levels of PD-L1 expression [Liu, Y., et al 2019]. The baseline PD-
L1 scores may increase significantly due to radiotherapy and chemotherapy, since it has been 
demonstrated that both regimens may increase immunogenicity significantly. Although the 
CPS score in untreated cases is unknown, we may expect high prevalence given that this is 
an HPV-driven cancer [Liu, Y., et al 2019]. In addition, PD-L1 status at baseline (all 
participants), after CRT and at progression (for participants with available biopsies) will be 
evaluated. The PD-L1 status will be tested in “real-time” and will provide CPS information 
early in study. This may help deconvolute between different CPS scores and aid in
potentially deciding which cutoff may be used for further analyses. Statistical analysis will be 
performed to assess the efficacy by PD-L1 status.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Patient-reported Outcomes
As part of the analyses for this study, participants will provide information regarding their
HRQoL via the following assessment tools: European Organisation for Research and 
Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-C24X, PGI-S, PGI-C and EQ-5D-
5L questionnaires. Patient-reported outcomes (PROs) are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
4.2.1.3.1
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific, health-related, QoL instrument, 
which contains 30 items and measures 5 functional dimensions (physical, role, emotional, 
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cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items 
(dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a 
global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 is a 
psychometrically and clinically validated instrument appropriate for assessing QoL in 
oncology studies [Aaronson, N. K., et al 1993]. 
4.2.1.3.2
EORTC QLQ-CX24
The EORTC QLQ-CX24 is a disease-specific questionnaire developed and validated to
address measurements specific to cervical cancer. It is one of multiple disease-specific
modules developed by the EORTC QLG (Quality of Life Group) designed for use in clinical
studies, to be administered in addition to the EORTC QLQ-C30 to assess disease-specific
treatment measurements. The 24-items are classified into 3 multi-item scales, 11 items with 
symptom experience domain, 3 items with body image domain, and 4 items with sexual/ 
vaginal functioning domain. The other domains of the questionnaire are single item scales, 
including lymphedema, peripheral neuropathy, menopausal symptom, sexual worry, sexual 
activity, and sexual enjoyment.
4.2.1.3.3
Patient Global Impression of Severity and Patient Global Impression of 
Change
Considering minimally important difference thresholds indicating clinically significant 
changes or differences for the EORTC QLQ-C30 global health status/QoL scale, EORTC 
QLQ-C30 Physical Function subscale and EORTC QLQ-CX24 symptom specific scale in 
women with LACC have not yet been established, the PGI-S and the PGI-C questionnaires 
will be used to validate clinically meaningful thresholds for severity and change of global 
health status, physical function and cervical cancer symptoms, and sexual domains from the 
EORTC QLQ-C30 and EORTC QLQ-CX24 questionnaires in the study population. 
The PGI-S is a standard single item questionnaire for assessing the severity of disease-related 
symptoms. The response options of the PGI-S are as follows: none, mild, moderate and 
severe.
The PGI-C is a single item questionnaire for assessing the change in disease-related 
symptoms compared with the start of treatment. The response options of the PGI-C are as 
follows: much better, a little better, no change, a little worse and much worse.
4.2.1.3.4
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. and de 
Charro, F. 2001]. The 5 health state dimensions in the EQ-5D-5L include the following: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-
5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant 
rates his or her general state of health at the time of the assessment. This instrument has been 
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used extensively in cancer studies and published results from these studies support its 
validity and reliability [Pickard, A. S., et al 2007]. 
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
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4.2.2
Rationale for the Use of Comparator/Placebo
The current SOC in this patient population is chemoradiotherapy followed by regular 
imaging surveillance for progression/recurrence of disease. In this study, SOC 
chemoradiotherapy will be administered with pembrolizumab (200 mg Q3W for 5 infusions 
followed by 400 mg Q6W for 15 infusions) or placebo. A placebo control is necessary to 
minimize confounding factors, such as the more frequent office visits and physical exams 
required for administration of pembrolizumab, as well as control for knowledge of treatment 
effects on participant reported outcome data.
4.3
Justification of Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W for 5 infusions followed 
by 400 mg Q6W for a maximum of 15 infusions. The first Q6W infusion (Cycle 6) will be 
administered 3 weeks from the last 3QW infusion (Cycle 5). The current approved dosing 
regimens of pembrolizumab for IV administration are 200 mg Q3W and 400 mg Q6W for 
adults.
The Q3W dosing will be administered to align with the CCRT regimen. Participants will 
switch to a Q6W regimen once CCRT is completed. The Q6W regimen is expected to 
increase the compliance in a participant population that would not otherwise be receiving 
SOC after completion of CCRT.
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.
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400 mg Q6W
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is 
currently approved [Lala, M., et al 2018]. Specifically, the dosing regimen of 400 mg Q6W 
for pembrolizumab is considered adequate based on modeling and simulation analyses, given 
the following rationale: 

Pharmacokinetic (PK) simulations demonstrating that in terms of pembrolizumab 
exposures: 
o
Average concentration over the dosing interval (Cavg) (or AUC) at 400 mg Q6W 
is similar to that at the approved 200 mg Q3W dose, thus bridging efficacy 
between dosing regimens. 
o
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of 
those achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients. 
o
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the 
highest clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile 
for 400 mg Q6W should be comparable to the established safety profile of 
pembrolizumab.

Exposure-response for pembrolizumab has been demonstrated to be flat across 
indications, and OS predictions in melanoma and NSCLC demonstrate that efficacy at 
400 mg Q6W is expected to be similar to that at 200 mg or 2 mg/kg Q3W, given the 
similar exposures; thus, 400 mg Q6W is expected to be efficacious across indications.
4.3.1
Maximum Dose/Exposure for This Study 
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W for 
5 infusions followed by 400 mg Q6W for 15 infusions. 
The maximum dose of CCRT is cisplatin, 5 infusions given IV QW at 40 mg/m2 (an optional, 
sixth infusion of cisplatin may be administered according to local practice), plus EBRT over 
40 days, followed by brachytherapy. The minimum acceptable radiation dosing for this 
protocol is 80 Gy for volume-directed and 75 Gy for point-directed. Refer to the Radiation 
Manual for further guidance.
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 (Section 7.3). 
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For purposes of analysis and reporting, the overall study ends when the Sponsor receives the 
last laboratory test result or at the time of final contact with the last participant, whichever 
comes last. 
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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 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 as described in Appendix 10.1.10.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 10.1.1), this study includes
participants of varying age, race, ethnicity, and sex. The collection and use of these 
demographic data will follow all local laws and participant confidentiality guidelines while 
supporting the study of the disease, its related factors, and the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has high-risk LACC (a or b below):
a.
FIGO 2014 Stage IB2-IIB (with node-positive disease) – must meet criteria below 
for positive pelvic lymph node OR para-aortic lymph node involvement up to the 
L1 cephalad body level.

Pelvic lymph node involvement as assessed by one of the following criteria:
o
Histopathologic, biopsy-proven pelvic node involvement (high-risk 
LACC patient with locally evaluable disease is eligible if removal of 
positive lymph node[s] is documented), or
o
2 or more positive pelvic nodes by MRI or CT (≥1.5 cm shortest 
dimension), or
o
2 or more positive pelvic nodes by PET / CT with SUV (max) ≥2.5 
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
Para-aortic lymph node involvement as assessed by one of the following
criteria:
o
Histopathologic, biopsy-proven para-aortic node involvement
(high-risk LACC patient with locally evaluable disease is eligible if 
removal of positive lymph node[s] is documented), or
o
1 or more positive para-aortic nodes by MRI or CT (≥1.5 cm shortest 
dimension), or 
o
1 or more positive para-aortic nodes by PET / CT with SUV (max)
≥2.5 
b. FIGO 2014 Stages III-IVA (either node-positive or node-negative disease)
Refer to Appendix 9 for further details of FIGO 2014 staging for cervical cancer.
2. Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or 
adenosquamous carcinoma of the cervix.
3. Has not previously received any definitive surgical, radiation, or systemic therapy for 
cervical cancer, including investigational agents, and is immunotherapy-naïve. Note: 
Previous surgical procedure for localized cervical tumor is allowed.
4. Has an ECOG performance status of 0 or 1 within 7 days prior to the first dose of study 
intervention.
Demographics
5. Is female, at least 18 years of age at the time of documented informed consent.
Female Participants
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:

Is not a WOCBP
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least 120 days after the last dose of pembrolizumab or placebo and 180 days 
following the end of chemoradiotherapy 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 investigator should evaluate the potential for contraceptive method failure 
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(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.

A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 72 hours (serum) or 24 hours (urine) 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 
located in Section 8.3.5.1. Refer to Appendix 7 for country-specific requirements.

Abstains from breastfeeding during the study intervention period and for at least 120 
days after the last dose of pembrolizumab or placebo and 180 days following the end 
of chemoradiotherapy.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
7. The participant (or legally acceptable representative if applicable) has provided
documented informed consent for the study. The participant may also provide consent for 
future biomedical research. However, the participant may participate in the main study 
without participating in future biomedical research. Refer to Appendix 7 for country-
specific requirements.
Additional Categories
8. Has radiographically evaluable disease, either measurable or nonmeasurable per 
RECIST 1.1, as assessed by the local site investigator/radiology.

As per inclusion criterion #1, for Stage IB2-IIB (FIGO 2014) disease, if nodal 
involvement is assessed by CT or MRI, the participant must have measurable 
disease (≥1.5 cm in shortest dimension) per RECIST 1.1.

High-risk LACC patient with radiographically locally evaluable disease is eligible
if removal of positive lymph node(s) is documented.
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9. Has provided a tissue sample from a core, incisional, or excisional biopsy of a tumor to 
the central vendor prior to randomization. Formalin-fixed, paraffin-embedded tissue 
blocks are preferred to slides (details pertaining to tumor tissue submission can be found 
in the Laboratory Manual).
10. Has adequate organ function as defined in the following table (Table 2). Specimens must 
be collected within 7 days prior to the start of study intervention.
Table 2
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
Measured or calculatedb creatinine clearance
OR
GFR
≥50 mL/min
OR
GFR ≥50 mL/min/1.73m2
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
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
a Criteria must be met without erythropoietin dependency within last 2 weeks; administration of packed 
RBCs is allowed prior to randomization.
b Creatinine 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.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has histological subtypes other than those allowed per inclusion criterion 2 (eg, sarcoma, 
small cell carcinoma with neuroendocrine differentiation, nonepithelial cancer). 
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2. Has FIGO 2014 Stage IVB disease. Evidence of metastatic disease per RECIST 1.1 
including lymph nodes above the L1 cephalad body or in the inguinal region. Participants
with inguinal lymph node involvement should be discussed with Sponsor and may 
potentially be eligible after confirmation of the Sponsor with participant’s disease details.
3. Has undergone a previous hysterectomy defined as removal of the entire uterus or will 
have a hysterectomy as part of their initial cervical cancer therapy. NOTE: Women who 
have had a partial/subtotal hysterectomy for reasons other than cervical cancer are 
eligible to participate in the study. Note: Radiologically-evaluable local disease such as 
cervix tumor will meet the eligibility criteria for assessable disease in the absence of 
measurable/evaluable metastatic disease.
4. Has bilateral hydronephrosis, unless at least one side has been stented or resolved by 
positioning of nephrostomy or considered mild and not clinically significant in the 
opinion of the investigator.
5. Has anatomy or tumor geometry or any other reason or contraindication that cannot be 
treated with intracavitary brachytherapy or a combination of intracavitary and interstitial 
brachytherapy.
Prior/Concomitant Therapy
6. Has received a live vaccine within 30 days prior to the first dose of study intervention. 
Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed. Refer to Appendix 7 for country-specific requirements.
Refer to Section 6.5 for information on COVID-19 vaccines.
7. Has received treatment with systemic immunostimulatory agents, colony stimulating 
factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-lives 
of the drug, whichever is shorter, prior to Cycle 1, Day 1. 
Prior/Concurrent Clinical Study Experience
8. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
9. Has received prior systemic anticancer therapy including investigational agents within 
4 weeks prior to randomization.
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10. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to randomization.
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
11. Has any contraindication to the use of cisplatin.
12. 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.
13. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have 
undergone potentially curative therapy are not excluded.
14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
15. 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.
16. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
17. Has an active infection requiring systemic therapy.
18. Has a known history of HIV infection.
Note: No testing for HIV is required unless mandated by local health authority. Refer to 
Appendix 7 for country-specific requirements.
19. 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. Refer to Appendix 7 for country-specific requirements.
20. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that may increase the risk associated with study participation or study 
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intervention administration or may interfere with the interpretation of study results, and 
in the judgment of the investigator or Sponsor, would make the participant inappropriate 
for entry into this study.
21. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
22. Has had an allogenic tissue/solid organ transplant.
23. Evidence of metastatic disease per RECIST 1.1 including lymph nodes above the L1 
cephalad body, in the inguinal region. Participants with inguinal lymph node involvement
should be discussed with Sponsor and may potentially be eligible after confirmation of 
the Sponsor with participant’s disease details. 
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an
AE such as diarrhea, nausea, or vomiting.
5.4
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. 
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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 will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 3.
Country-specific differences are noted in Appendix 7.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Form-
ulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experimental
Pembrolizumab 
(MK-3475)
Drug
Solution 
for 
Infusion
25 mg/mL
200 mg for 
5 infusions 
followed by 
400 mg for 
15 infusions
IV 
Infusion
Q3W (200 mg) 
for 5 infusions 
followed by 
Q6W (400 mg) 
for 15 infusions 
Test 
Product
IMP
Central
Arm 1
Experimental
Cisplatin
Drug
Solution 
for 
Infusion
Variable
40 mg/m2
IV 
Infusion
Weekly for 
5 infusions 
(an optional, 
sixth infusion 
may be 
administered 
according to 
local practice)
Background 
Treatment
NIMP/
AxMP
Local or 
central
Arm 1
Experimental
Radiation 
(EBRT)
Radiation
N/A
Refer to 
Radiation 
Manual for 
further 
guidance 
Refer to 
Radiation 
Manual for 
further 
guidance
External
40 days
Background 
Treatment
NIMP/
AxMP
Local
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Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Form-
ulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experimental
Radiation 
(Brachytherapy)
Radiation
N/A
Refer to 
Radiation 
Manual for 
further 
guidance
Refer to 
Radiation 
Manual for 
further 
guidance
Internal
Total treatment 
duration should 
not exceed 
50 days (with an 
extension to a 
maximum of 
56 days for 
unforeseen 
delays) with 
radiotherapy 
including 
brachytherapy. 
Brachytherapy 
sessions should 
be performed 
immediately 
after EBRT 
sessions
Background 
Treatment
NIMP/
AxMP
Local
Arm 2
Placebo 
Comparator
Placebo
Drug
Solution 
for 
Infusion
Normal 
Saline or 
dextrose
0 mg
IV 
Infusion
Q3W for 
5 infusions, 
followed by 
Q6W for 15 
infusions
Placebo
IMP
Local
Arm 2
Placebo 
Comparator
Cisplatin
Drug
Solution 
for 
Infusion
Variable
40 mg/m2
IV 
Infusion
Weekly for 
5 infusions
(an optional, 
sixth infusion 
may be 
administered 
according to 
local practice)
Background 
Treatment
NIMP/
AxMP
Local or 
central
Arm 2
Placebo 
Comparator
Radiation 
(EBRT)
Radiation
N/A
Refer to 
Radiation 
Manual for 
further 
guidance
Refer to 
Radiation 
Manual for 
further 
guidance
External
40 days
Background 
Treatment
NIMP/
AxMP
Local
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Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Form-
ulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Placebo 
Comparator
Radiation 
(Brachytherapy)
Radiation
N/A
Refer to 
Radiation 
Manual for 
further 
guidance
Refer to 
Radiation 
Manual for 
further 
guidance
Internal
Total treatment 
duration should 
not exceed 
50 days (with an 
extension to a 
maximum of 
56 days for 
unforeseen 
delays) with 
radiotherapy 
including 
brachytherapy. 
Brachytherapy 
sessions should 
be performed 
immediately 
after EBRT
Background 
Treatment
NIMP/
AxMP
Local
AxMP=Auxiliary Medicinal Product; EBRT=external beam radiotherapy; IMP=investigational medicinal product; IV=intravenous; N/A=not applicable; 
NIMP=Non-Investigational Medicinal Product; Q3W=dosing every 3 weeks; Q6W=dosing every 6 weeks
Geographic variance in total radiation dose administered, number of fractions and methodology of application may be permitted after consultation with the Sponsor.
Participants must receive 5 infusions of pembrolizumab 200 mg or placebo at Q3W before moving to pembrolizumab 400 mg or placebo Q6W dosing. Chemoradiotherapy and 
brachytherapy are administered during the Q3W dosing regimen. Interruptions of cisplatin, EBRT, brachytherapy, pembrolizumab or placebo are allowed according to Section 
6.4.
Administration of EBRT must be completed within 40 days from start to finish. Total radiation treatment (EBRT and brachytherapy) should not exceed 50 days (with an 
extension to a maximum of 56 days for unforeseen delays).
See Appendix 7 for country-specific requirements for concurrent chemoradiotherapy.
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product/Auxiliary Medicinal Product (NIMP/AxMP) is based on guidance issued by the 
European Commission. Regional and/or Country differences of the definition of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed. Refer to 
Appendix 7 for country-specific requirements.
In this protocol, placebo for pembrolizumab is diluent alone (normal saline and/or dextrose); diluent is used for blinding purposes and does not contain active ingredients.
The unit dose strength for cisplatin may vary depending on market availability.
The maximum dosage for radiation depends on the methodology used. The minimum acceptable radiation dosing for this protocol is 80 Gy for volume-directed and 75 Gy for 
point-directed. Please refer to the Radiation Manual for additional details such as nodal boost dosing requirements.
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All study interventions will be administered on an outpatient basis. Refer to Appendix 7 for 
country-specific requirements.
All products indicated in Table 3 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention. Refer to 
Appendix 7 for country-specific requirements for concurrent chemoradiotherapy.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Cisplatin will be prepared and administered as per the approved product label(s).  
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 CCRT + 
pembrolizumab or CCRT + placebo, respectively.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Planned type of EBRT: IMRT or VMAT versus non-IMRT and non-VMAT
2. Stage at screening of cervical cancer: FIGO 2014 Stage IB2-IIB (node-positive 
disease) versus FIGO 2014 Stage III-IVA (node-negative or node-positive disease)
3. Planned total radiotherapy dose (EBRT + brachytherapy dose) of <70 Gy (EQ2D) 
versus ≥70 Gy (EQ2D)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used.  The participant, the 
investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention 
administration or clinical evaluation of the participants are unaware of the intervention 
assignments.
6.4
Study Intervention Compliance
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.
6.4.1
Pembrolizumab or Placebo
The first infusion of pembrolizumab or placebo combined with chemoradiotherapy may 
begin up to 3 days after randomization.
The standard dosing window for pembrolizumab or placebo is 21 days (± 3 days) during 
Q3W dosing and 42 days (± 3 days) during Q6W dosing.
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Interruptions from the protocol-specified treatment plan for more than 3 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Participants must receive 5 infusions of pembrolizumab or placebo Q3W before moving to 
Q6W dosing. The interval between Cycle 5 and Cycle 6 is 3 weeks ±3 days. Q6W dosing 
starts from Cycle 6 onwards. Chemoradiotherapy and brachytherapy are administered during 
the Q3W dosing regimen. Pembrolizumab or placebo infusions should be continued during 
cisplatin or radiotherapy delay. Note: On treatment days where both pembrolizumab/placebo 
and cisplatin are administered, it is preferable for pembrolizumab/placebo to be administered 
prior to cisplatin. However, cisplatin may be administered prior to pembrolizumab/placebo 
per local standard practice.
6.4.2
Chemoradiotherapy
The standard treatment includes cisplatin, EBRT, and brachytherapy. The overall 
chemoradiotherapy treatment (including both EBRT and brachytherapy) should be 
administered within 50 days (with an extension to a maximum of 56 days for unforeseen 
delays). Summation of EBRT and brachytherapy doses will be performed by calculation of a 
biologically equieffective dose in 2 Gy per fraction using the linear-quadratic model with 
a/b= 10 Gy for tumor effects and a/b= 3 Gy for late normal tissue damage. The repair half 
time is assumed to be 1.5 h. The D90 for the high-risk CTV should be higher than 85 Gy. An 
extension due to toxicity-related interruptions may be permitted with Sponsor consultation.
Further monitoring/assessments should be performed in accordance with the local label 
and/or local practice for cisplatin and radiotherapy.
6.4.2.1
Concurrent Chemotherapy
Cisplatin should only be given weekly (± 1-day window) on a day that EBRT is scheduled 
and must be given prior to radiation treatment on that day. If due to interruptions and dosing 
delays cisplatin administration continues beyond EBRT, cisplatin should not be administered 
on a day when brachytherapy is also administered. All participants should receive 5 infusions 
of cisplatin regardless of the radiation fractionation schedule planned. Refer to Appendix 7 
for country-specific requirements.
Note: an optional, sixth infusion of cisplatin may be administered according to local practice.
Cisplatin should not be administered during an EBRT therapy delay.
For weekly cisplatin dosing, interruptions of more than 3 days between infusions, for 
non-drug-related or administrative reasons, require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
Cisplatin dose interruption due to treatment-related toxicity are allowed as per local standard. 
Dose reductions are also allowed as follows: the cisplatin standard dose of 40 mg/m2 may be 
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reduced to 30 mg/m2. If the participant cannot tolerate 30 mg/m2, no further dose reductions 
are allowed. A 70-mg dose cap of cisplatin may be applied in accordance with local practice.
Refer to Section 6.6 (Dose Modification) and Section 6.6.3 (Cisplatin Dose Modifications) 
for additional information on dose modifications due to toxicity.
When applicable, participants should receive premedication and supportive care measures to 
prevent hypersensitivity reactions and minimize toxicity, according to the local label and/or 
per local practice. Sites should follow local standard of care for hydration prior to cisplatin 
administration.
6.4.2.2
External Beam Radiotherapy
Pelvic EBRT is an integral part of the overall treatment strategy with the primary aim of 
obtaining regional and nodal control.
It is currently delivered with different techniques: 3D conformal EBRT, IMRT, or VMAT
over 40 days. Daily image guidance is mandatory with couch correction according to bony 
structures if IMRT or VMAT is used. The definition of primary tumor targets is CT- and 
MRI-based. An individualized ITV-T is recommended based on participant anatomy and 
target motion. Nodal target (CTV-E) is defined according to risk of nodal spread and 
involved nodes or parametria are boosted, when possible, using SIB to reach a minimum 
radiation dosing of 80 Gy for volume-directed and 75 Gy for point-directed [Landberg, T., et 
al 1993] [Landberg, T., et al 1999]. Refer to the Radiation Manual for further guidance.
The main advantage of IMRT is the ability to deliver a high dose of radiation to tumor tissue 
while restricting dose exposure of adjacent noncancerous tissues. The overall volume 
irradiated to 43 Gy during EBRT is known to be associated with acute and late morbidity 
[Stanic, S. 2013] [Sondergaard, J., et al 2014] [Letschert, J. G. J., et al 1994]. By reducing the 
volume of normal tissues irradiated, IMRT reduces the risk of acute [Naik, A., et al 2016] 
[Gandhi, A. K., et al 2013] and late [Mundt, A. J., et al 2002] [Chopra, S., et al 2015]
morbidity [Kloop, A. H., et al 2016], including urinary and bowel morbidity. Furthermore, 
image guided radiotherapy allows tight treatment margins to be applied which has signiﬁcant 
potential to reduce the overall volume irradiated with EBRT.
VMAT is a complex IMRT technique. In the process of irradiation, it can adjust the beam 
intensity from different beam directions by way of altering the dose rate and gantry rotation 
speed. VMAT allows to reduce treatment time, thus improving performance. It integrates the 
advantages of speed and dose distribution of rotational therapy and dynamic IMRT [Holt, A., 
et al 2011]. According to a recently reported study, VMAT plans showed superior dose 
coverage of the PTV, better protection of the rectum and bladder in dosimetry, and 
significantly reduced monitor units and treatment time compared with f-IMRT. Clinical 
results were similar for both plans[Guo, M., et al 2018].
In the EMBRACE I study, the utilization of IMRT and 3D CCRT was 27% and 73%, 
respectively. Therefore, stratification according to IMRT or VMAT versus non-IMRT and 
non-VMAT are considered since it is important to account for potential differences in safety 
and efficacy outcomes depending on EBRT technique [Potter, R., et al 2018].
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Radiotherapy will not be omitted or delayed for cisplatin-related toxicities unless the 
investigator considers the participant too ill to be treated. Participants who fail to recover 
from toxicities within 21 days will not receive further protocol-directed therapy without 
Sponsor consultation.
Midline block (central shielding) maybe applied if required per local practice.
Geographic variance in total radiation dose administered, number of fractions and 
methodology of application may be permitted after consultation with the Sponsor.
6.4.2.3
Brachytherapy
Brachytherapy should follow EBRT and concomitant chemotherapy to obtain maximal tumor 
regression.
Intercalation of brachytherapy and EBRT is not allowed.
Please refer to the Radiation Manual for further guidance on dosing.
To achieve adequate target coverage and to reduce the dose to the organs at risk, 
brachytherapy could be only intracavitary or a combination of intracavitary and interstitial.
Recommendations for target and organ-at-risk contouring are outlined in the ICRU/GEC 
ESTRO report 89 [SAGE Publications 2016].
Geographic variance in total radiation dose administered, number of fractions and 
methodology of application may be permitted after consultation with the Sponsor.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
Participants are prohibited from receiving the following concomitant therapy or vaccination 
during the treatment period:

Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Radiosensitizers other than protocol-specified cisplatin
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
Investigational agents other than pembrolizumab

Radiation therapy not specified in this protocol
Note: Palliative radiation to symptomatic lesions may be allowed following Sponsor 
consultation after assessment of disease progression has been determined.

Use of nephrotoxic or ototoxic medications concurrently with cisplatin administration.

Live vaccines within 30 days prior to the first dose of study intervention and up to 
30 days following the last dose of study intervention. Examples of live vaccines include, 
but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow 
fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not allowed. Refer to Appendix 7 for 
country-specific requirements.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.

Systemic glucocorticoids except when used for the following purposes:
o
To modulate symptoms of an AE that is suspected to be related to study intervention
o
For the prevention of emesis
o
To premedicate for IV contrast allergies
o
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
o
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent

Other glucocorticoid use except when used for the following purposes:
o
For topical use or ocular use
o
Intraarticular joint use
o
For inhalation in the management of asthma or COPD
Note: The use of systemic steroids to treat AEs related to study interventions (including 
pembrolizumab/placebo, cisplatin, and RT), as well as prophylaxis/premedication, and use of 
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physiologic doses to treat AEs not related to study intervention is allowed without Sponsor 
consultation. However, if systemic steroids are needed at a higher dose than physiologic dose 
to treat any other AE not related to any of the study interventions, Sponsor consultation is 
required.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from study 
intervention.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 42 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs as defined in Section 8.4, as well as recorded 
regardless of whether associated with an SAE or ECI. 
Cytokines (eg, G-CSF, GM-CSF, or recombinant erythropoietin) should not be administered 
within 4 weeks before randomization, but may be administered during the treatment period 
per local practice.
6.5.1
Rescue Medications and Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.1, Table 4. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab 
or placebo, the investigator does not need to follow the treatment guidance. Refer to Table 4
in Section 6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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6.6
Dose Modification (Escalation/Titration/Other)
Dose modifications in response to treatment-related adverse events are permitted to keep the 
participant on study medication, when appropriate. Details on the modifications for each 
study intervention are provided in the sections below. In general:

Whenever treatment is withheld, toxicity should resolve to Grade 0 or 1 or to baseline (if 
condition was present at baseline) and

Study drugs, cisplatin and radiation may be held together or separately at the 
investigator’s discretion to determine which drug is the source for a given toxicity and to 
interrupt pembrolizumab/placebo or adjust the dosage of cisplatin / radiation therapies 
accordingly. If study drugs are withheld for hematological toxicity, radiation therapy may 
be continued at the investigator’s discretion to minimize treatment delays.
Refer to Appendix 7 for country-specific requirements.
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab 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 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, 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. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
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Table 4
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 
(which was 
previously 
myocarditis 
Grade 1 using 
CTCAE v4.0).
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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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
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the 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/Placebo
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/placebo
associated infusion reaction are provided in Table 5.
Table 5
Pembrolizumab/Placebo Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical 
therapy may include but is not limited 
to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the 
original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the participant should be 
premedicated for the next scheduled 
dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be permanently 
discontinued from further study drug 
treatment
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not limited 
to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically stable 
in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study drug 
treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab/Placebo
Pembrolizumab/placebo may be interrupted for situations other than treatment-related AEs 
such as medical / surgical events or logistical reasons not related to study therapy. 
Participants should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should 
be documented in the participant's study record.
6.6.2
Radiation Dose Modifications
Radiation treatment may be delayed up to 21 days due to toxicity. A delay of longer than 
21 days will require consultation with the Sponsor, to determine if the participant will 
continue study intervention and/or study. Additionally, the start of brachytherapy can be 
delayed up to 14 days from completion of EBRT, if needed. All radiation treatments must be 
delivered within a total of 50 days (with an extension to a maximum of 56 days for 
unforeseen delays); therefore, treatment breaks should be kept to a minimum. The reason for 
interruptions in radiation therapy must be recorded in the eCRF. 
If EBRT treatment is delayed, then cisplatin dose should be delayed until EBRT treatment is 
resumed. 
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6.6.3
Cisplatin Dose Modifications
Toxicity due to cisplatin administration may be managed by symptomatic treatment, dose 
interruptions and adjustment of cisplatin dose. Recommended dose reductions are provided 
below. The cisplatin dose should only be reduced once to 30 mg/m2, and future dosing 
should continue at the reduced dose. If the reduced dose is not tolerated, the participant may 
continue in the study without cisplatin (may continue to receive pembrolizumab or placebo
and RT). Interruptions in cisplatin for longer than one week due to toxicity requires 
consultation with the Sponsor for appropriate management of the patient.
External radiation should continue while cisplatin is withheld, unless the investigator 
considers the patient too ill to be treated.
Gastrointestinal Adverse Effects
a.
For nausea and vomiting, anti-emetics should be used prophylactically.
b. For Grade 4 nausea and vomiting, reduce cisplatin to 30 mg/m2.
Renal/Genitourinary Adverse Effects
a.
If GFR <50 mL/min [Gault, M. H., et al 1992], hold cisplatin therapy. If creatinine 
does not recover after a one-week delay, discontinue cisplatin for remainder of 
regimen.
b. Selective renal tubular defects are sometimes observed:
i. Hypocalcemia with hypomagnesemia and hypokalemia are common and 
potentially severe.
ii. Replacement of magnesium, calcium and potassium are usually effective.
iii. Severe tubular effects, although rare, may require chronic replacement therapy.
iv. Diagnostic tests for alternative mechanisms of hypocalcemia (eg, GI or 
metabolic) should be considered.
Neurologic Adverse Effects
a.
Grade 1 - no change
b. Grade 2 - reduce cisplatin to 30 mg/m2
c.
Grade 3 to 4 - hold cisplatin and reduce cisplatin to 30 mg/m2 after recovery to 
≤Grade 2
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Hematologic Adverse Effects
a.
Cisplatin should be withheld from participants with an ANC less than 1,000 or 
platelet count less than 50,000. Therapy should be delayed week-by-week until these 
levels are exceeded. Any interruption in cisplatin for longer than one week due to 
toxicity requires a dose reduction of one level.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity for the duration of 
the study. The emergency unblinding call center should only be used in cases of emergency 
(see Section 8.1.10). In the event that the emergency unblinding call center is not available 
for a given site in this study, the central electronic intervention randomization system (IRT) 
should be used to unblind participants and to unmask study intervention identity. The 
Sponsor will not provide random code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
participants who received placebo in the image of the Sponsor’s product to provide the 
following advice:
“You have participated in a study conducted by the Sponsor. This letter is to advise you that 
you were among those who received a look-alike product. You did not receive the active 
drug as manufactured by MSD.”
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.10.3.
Participants may discontinue study intervention at any time for any reason or be dropped 
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 
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investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
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

The participant interrupts study intervention administration with pembrolizumab/placebo 
for more than 12 consecutive weeks due to AE(s). Any prolonged interruption of study 
intervention beyond the permitted periods, for irAE management or other allowed dose 
interruptions, as noted in Section 6.6.1 require Sponsor consultation before restarting 
treatment

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

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

Radiographic disease progression outlined in Section 8.2.1 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond radiographic disease progression).

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
Note: If only local treatment is performed for an occurrence of another malignancy, the 
participant may continue on study treatment upon Sponsor consultation and approval

Completion of 20 infusions of pembrolizumab or placebo (5 infusions Q3W [concurrent 
with chemoradiotherapy] and another 15 infusions Q6W)
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits. 
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Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, 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 signing of ICF may be utilized for screening or 
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baseline purposes provided the procedures meet 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.

Information regarding the amount of blood collected from each participant over the 
duration of the study can be found in the Laboratory Manual.

Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
8.1.1.1
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.
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If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the 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.
8.1.1.3
Consent for Optional Collection of Tumor Samples
An optional tissue sample may be collected and submitted to a central laboratory for study 
investigational purposes for participants who are able to undergo a biopsy and provide 
optional tissue collection consent. The investigator or medically qualified designee will 
explain this optional part of the study that includes collecting fresh tumor biopsy samples 
during Cycle 5 and before Cycle 6, Day 1 and at disease progression and submitting the 
tissue sample for analysis. Study consent is not required when a tissue sample is performed 
for histopathologic confirmation if the tissue sample is not submitted to the central laboratory 
for study-specific investigational purposes.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available. 
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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. The investigator will enter 
any prior cancer other than high-risk LACC as a medical history condition.
Details regarding the diagnosis of high-risk LACC 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).
8.1.4.1
Cervical Cancer History
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s cervical cancer history. This history may include but is not limited to FIGO 
stage, location of tumor burden at baseline, histology, and potential prior treatment for early 
stage disease that may have been treated prior to diagnosis with high-risk LACC.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 42 days before starting study intervention. 
Enter all treatments for a prior cancer other than high-risk LACC even if taken more than 
42 days prior to start of study medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
within 42 days prior to the first dose of study intervention and up to 30 days after the last 
dose of study intervention. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs as defined in Section 8.4.
8.1.5.3
Subsequent Anticancer Therapy
Details of subsequent therapies for cancer (including surgical procedure and radiation) after 
discontinuation of study intervention will be collected. These details include but are not 
limited to treatment start and stop dates, reason for treatment, response to treatment, dates of 
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progression after the completion of subsequent treatment, and reason for discontinuation 
from treatment. Reasons for starting subsequent anticancer therapies including access to 
other PD-1/PD-L1 inhibitors or investigational drugs will be collected.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain their original screening number 
assigned at the initial screening visit.
8.1.7
Assignment of Randomization Number
All eligible participants will be randomly allocated and will receive a randomization number. 
The randomization number identifies the participant for all procedures occurring after 
treatment randomization. Once a randomization number is assigned to a participant, it can 
never be re-assigned to another participant.
A single participant cannot be assigned more than 1 randomization number.
8.1.8
Study Intervention Administration
Administration of study intervention will be monitored by the investigator and/or study staff. 
Study intervention should be administered after all assessments have been completed. Study 
intervention should be administered in this order: pembrolizumab/placebo first, followed by 
cisplatin and then radiotherapy. Variation to the order of administration for
pembrolizumab/placebo and cisplatin is permitted according to local practice—however 
cisplatin must be administered prior to radiotherapy (refer to Appendix 7 for country-specific 
requirements). Study intervention should begin within 3 days of and as close as possible to 
the date on which the participant is randomized.
8.1.8.1
Timing of Dose Administration
Pembrolizumab or Placebo
Pembrolizumab will be administered as a dose of 200 mg Q3W (Cycles 1-5) and 400 mg 
Q6W (Cycles 6-20) using a 30-minute IV 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). 
The Pharmacy Manual contains specific instructions for pembrolizumab/placebo
reconstitution, preparation of the infusion fluid, and administration of infusion solution.
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Cisplatin
Cisplatin should be administered weekly (± 1 day) on a day that EBRT is scheduled and prior 
to radiation treatment on that day. Cisplatin will be prepared and administered according to 
local practices.
Radiotherapy
External Beam Radiotherapy
Pelvic EBRT is an integral part of the overall treatment strategy with the primary aim of 
obtaining regional and nodal control.
It is currently delivered with different techniques: 3D conformal EBRT, IMRT, or VMAT, 
over 40 days. Daily image guidance is mandatory with couch correction according to bony 
structures if IMRT or VMAT is used. The definition of primary tumor targets is CT and 
MRI-based. An individualized ITV-T is recommended based on participant anatomy and 
target motion. Nodal Target (CTV-E) is defined according to risk of nodal spread and 
involved nodes or parametria are boosted, even possible, using SIB to reach the minimum 
acceptable radiation of 80 Gy for volume-directed and 75 Gy for point-directed. Refer to the 
Radiation Manual for further guidance.
Radiotherapy will not be omitted or delayed for cisplatin-related toxicities unless the 
investigator considers the participant too ill to be treated. Participants who fail to recover 
from toxicities within 21 days will not receive further protocol-directed therapy without 
Sponsor consultation. Refer to Radiation Manual for further guidance.
Geographic variance in total radiation dose administered, number of fractions and 
methodology of application may be permitted after consultation with the Sponsor.
Details of the required equipment and treatment planning for radiotherapy can be found in
the Radiation Manual. The radiotherapy plan must be submitted to QARC during screening. 
Approval of plan will be provided following QARC receipt of all required data for the rapid 
review. Approval of plan is required prior to randomization. The maximum dosage for 
radiation depends on the methodology used. The minimum acceptable radiation dosing for 
this protocol is 80 Gy for volume-directed and 75 Gy for point-directed. Additional detail on 
radiation requirements can be found in the Radiation Manual and Radiation Therapy Quality 
Assurance Manual (eg, radiotherapy plan submission requirements, nodal boost dosing 
requirements, etc.).
Brachytherapy
Brachytherapy should follow EBRT and concomitant chemotherapy to obtain maximal tumor 
regression. Intercalation of brachytherapy and EBRT is not allowed.
Refer to the Radiation Manual for further guidance.
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To achieve adequate target coverage and to reduce the dose to the organs at risk, 
brachytherapy should be intracavitary or a combination of intracavitary and interstitial. 
Recommendations for target and organ-at-risk contouring are outlined in the ICRU/GEC
ESTRO report 89.
Geographic variance in total radiation dose administered, number of fractions and 
methodology of application may be permitted after consultation with the Sponsor.
Details of the required equipment and treatment planning for radiotherapy can be found in
the Radiation Manual. Digital treatment plans for brachytherapy administration for each 
participant must be submitted to QARC within 2 weeks, or sooner if requested by the 
Sponsor, of brachytherapy completion. Additional detail on the radiotherapy plan submission 
requirements can be found in the Radiation Therapy Quality Assurance Manual.  
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to 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 8.10.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End of Treatment / Discontinuation Visit at the time of 
withdrawal. Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
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8.1.10
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study intervention, the reason thereof, etc., 
in the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, and site personnel, may be 
unblinded so that the appropriate follow-up medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
8.1.10.1
Nonemergency Unblinding
Nonemergency unblinding to study intervention (pembrolizumab / placebo) administration 
may occur on an individual participant basis and only after consultation with the Sponsor 
under the following circumstances:

Disease progression or recurrence with discontinuation of study intervention and the 
participant is being considered for alternate treatment that necessitates knowledge of 
prior treatment on the study.
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
Adverse event necessitates discontinuation from treatment and unblinding is required for 
appropriate clinical management of complications.
Note: in some instances, unblinding to study treatment may be needed for appropriate clinical 
management of the complications but may not necessitate discontinuation of study treatment. 
The Sponsor’s Clinical Director must be consulted to review individual requests for 
unblinding using the Sponsor Consultation Form with reasons to unblind and decision to 
remain on study treatment clearly documented.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.12
Tumor Tissue for Biomarker Analyses
Participation in this study will be dependent on participants supplying tumor tissue prior to 
randomization to the central vendor. Submission of either formalin-fixed paraffin-embedded
tumor blocks or unstained slides is acceptable; however, formalin-fixed paraffin-embedded
tumor block is preferable. Details about collection and submission of tumor tissue samples 
are contained in the Laboratory Manual.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease 
Efficacy will be assessed based on imaging evaluation of changes in tumor burden over time.
The process for image collection and transmission to the iCRO can be found in the SIM.
For the abdomen and pelvis, tumor imaging is strongly preferred to be acquired by 
contrast-enhanced MRI. Imaging of the chest should be performed by contrast-enhanced CT.
If the preferred imaging modality cannot be performed, please refer to the SIM for alternate 
options. 
An MRI is the strongly preferred modality for imaging the brain when clinically indicated to 
rule out brain metastases at baseline or as clinically indicated during the study. 
Bone scans are required for participants with new bone pain, to rule out bone metastases at 
baseline or as clinically indicated during the study. Any supplemental imaging performed to 
support a positive or negative bone scan, such as plain X-rays that may be acquired for 
correlation, should be submitted to the iCRO.
The same imaging technique should be used in each participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and to 
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improve the accuracy of the response assessment based on imaging. Note: for the purposes of 
assessing tumor imaging, the term “investigator” refers to the local investigator at the site 
and/or the radiological reviewer at the site or at an offsite facility.
In addition, images (including via other modalities) that are obtained at an unscheduled time 
point to determine disease progression, as well as imaging obtained for other reasons, but 
which demonstrate radiologic progression, should also be submitted to the central imaging 
vendor.
8.2.1.1
Initial Tumor Imaging
The screening images must be submitted to the iCRO for retrospective review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization and can be assessed by the iCRO.
A contrast-enhanced PET/CT scan and baseline chest CT and MRI of the abdomen/pelvis are 
to be performed within 28 days prior to randomization. If the participant has had both a 
PET/CT scan (with the CT component of diagnostic quality) and an MRI of the pelvis and 
abdomen, then a separate CT of the chest is not required.
Participant eligibility will be determined using local assessment (investigator assessment).
8.2.1.2
Tumor Imaging During the Study
The first scheduled postrandomization imaging assessment required are a contrast-enhanced 
PET/CT scan as well as a chest CT and MRI of abdomen/pelvis that should be performed at 
12 weeks (± 14 days) after the completion of CCRT. 
Subsequent tumor imaging should be performed every 12 weeks (Q12W ± 14 days)
thereafter from the completion of CCRT during Years 1 and 2, every 24 weeks (Q24W
± 14 days) in Year 3, and once per year (± 14 days) in Year 4 onwards. Years are calculated 
from the date of randomization. Unscheduled imaging due to new clinical symptoms can 
occur at any time, including prior to the post-CCRT Week 12 assessment, to identify either 
new metastatic/regional disease or recurrence of locally treated disease. Timing of tumor 
imaging should follow calendar days and should not be adjusted for delays in cycle starts. 
(Note: the date imaging is performed is the date of assessment, not the date the images are 
reviewed.) For participants who are lymph node positive at baseline by PET only, a PET scan
(with CT scan only as necessary for attenuation correction and anatomic localization) to 
confirm disappearance of the FDG uptake in the node(s) is required to determine that a
complete response has occurred. If the nodal activity has not resolved, another PET scan 
should be performed at selected later time points (with the interval to be based on the 
investigator’s clinical judgment), until the nodal uptake is seen to have resolved, if the MRI 
and/or CT scan still shows complete response. Imaging should continue to be performed until
radiographic disease progression is documented per RECIST 1.1 by the investigator, 
withdrawal of consent, pregnancy, loss to follow-up, or death, whichever occurs first.
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Treatment beyond documented disease progression may be permitted at the discretion of the 
investigator after consultation with the Sponsor and receiving appropriate documented
informed consent. Sponsor consultation should be sought after each subsequent imaging 
evaluations and where the investigator may continue treatment. Participants who continue 
treatment beyond disease progression must continue tumor assessments as described in the 
SoA (Section 1.3). Investigator assessments are to be documented on the eCRF, and all scans 
are to be submitted to the iCRO. Further progression and discontinuation of study 
intervention are to be determined by the investigator.
Supplemental imaging must be submitted to the central imaging vendor if it shows evidence 
of disease progression or recurrence.
8.2.1.3
Optional Biopsy for Confirmation of Disease Progression
When tumor growth is suspected on imaging or by physical examination, an optional biopsy 
for confirmation of suspected disease progression is allowed at investigator discretion.
Throughout the protocol, the term “histopathologic confirmation” is used when referencing a 
biopsy that confirms suspected disease progression either from a new lesion or a pre-existing 
lesion showing growth. A redacted copy of the local pathology assessment may be requested 
by the Sponsor, if acceptable per local regulations.
8.2.1.4
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
radiographic disease progression, this is the final required tumor imaging.
For participants who discontinue study intervention without documented radiographic 
disease progression, every effort should be made to continue monitoring disease status by 
tumor imaging using the same imaging schedule used while on treatment calculated from the 
date of CCRT (see Section 8.2.1.2) until radiographic disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by the investigator 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. 
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8.2.2
Patient-reported Outcomes
The questionnaires will be administered by trained site personnel and completed 
electronically by participants in the following order: 
1) EORTC QLQ-C30
2) EORTC QLQ-CX24
3) PGI-S
4) PGI-C
5) EQ-5D-5L
The questionnaires should be administered according to the schedule in the SoA.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants prior to drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISSMODE form 
must be completed to capture the reason the assessment was not performed.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period (consistent with local requirements) as per institutional standard. Height 
and weight will also be measured and recorded. Clinically significant abnormal findings 
should be recorded as medical history. After the first dose of study intervention, new 
clinically significant abnormal findings should be recorded as AEs. The time points for full 
physical examinations are described in the SoA (Section 1.3).
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination, the investigator or qualified 
designee will perform a symptom-directed physical examination (consistent with local 
requirements) per institutional standard as clinically indicated prior to study intervention 
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administration. New clinically significant abnormal findings should be recorded as AEs. The 
time points for directed physical examinations are described in the SoA (Section 1.3).
8.3.1.3
Gynecological Examination
The investigator or qualified designee will perform a gynecological examination during the 
screening period (consistent with local requirements) as per institutional standard. Clinically 
significant abnormal findings should be recorded as medical history. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
The time points for gynecological exams are described in the SoA (Section 1.3).
8.3.2
Vital Signs
The investigator or qualified designee will measure vital signs at the time points specified in 
the SoA (Section 1.3) and will include temperature, systolic and diastolic blood pressure, 
heart rate, and respiratory rate.
8.3.3
Audiometry
Consistent with local requirements, an audiometry test may be performed and reviewed by an 
investigator or medically qualified designee, as outlined in the SoA (Section 1.3).
8.3.4
Electrocardiograms
A 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA (Section 1.3). Additional 
ECGs may be performed during the study as clinically indicated.
8.3.5
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.

If laboratory values from nonprotocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 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.
The specific laboratory procedures/assessments to be performed in this study are provided 
below. The amount of blood to be drawn/collected over the course of the study can be found 
in the Laboratory Manual. Refer to the SoA (Section 1.3) for the timing of laboratory 
assessments.
8.3.5.1
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 up to 120 days after the last dose of pembrolizumab or placebo and up to 
180 days after the last dose of Chemoradiotherapy

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 patient’s participation in the study

Home pregnancy tests are acceptable when a scheduled visit does not occur within 
the month (per local regulation), but the site must make monthly telephone contact 
with the participant to determine the results of the pregnancy test. The results of the 
test must be recorded in the participant’s eCRF.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status at screening to determine 
eligibility and at subsequent time points 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.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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 120 days after the last dose of pembrolizumab or placebo and 
180 days following the end of chemotherapy, 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 the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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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 6.
Table 6
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:
Nonserious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days 
of learning of 
event
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.
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. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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.
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The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that on review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs 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. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3X the upper limit of normal and an elevated total bilirubin laboratory
value that is greater than or equal to 2X the upper limit of normal and, at the same time, 
an alkaline phosphatase laboratory value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent). 
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times and ≥2.5 times the indicated doses [200 mg and 400 mg, respectively]).
No specific information is available on the treatment of overdose of pembrolizumab. 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
Pharmacodynamic parameters will not be evaluated in this study.
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8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
The planned genetic analysis sample should be obtained pre-dose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instruction for planned genetic analysis samples will be provided in the 
operations/laboratory manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:

Leftover samples listed in Section 8.8
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.10.1
Screening
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing 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 42 days prior to the 
first dose of study intervention except for the following:

Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. An exception is hepatitis or HIV testing which may be performed up to 
28 days prior to the first dose of study intervention.

Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.

For WOCBP, a urine or serum pregnancy test will be performed within 72 hours (serum) 
or 24 hours (urine) prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).

Newly obtained tumor tissue from a core, incisional, or excisional biopsy performed prior 
to screening can be used. 

Approval of radiotherapy plan is required prior to randomization.
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.
8.10.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 6.4 and Section 8.
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study  
When a participant discontinues study intervention during the treatment period, procedures 
for discontinuation will be performed.
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional safety follow-up procedures should be performed. Visit requirements are 
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outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.10.4
Posttreatment Visits
8.10.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted 30 days (+ 7 days) after the last 
dose of study intervention or before the initiation of a new anticancer treatment, whichever 
comes first.
8.10.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention will begin the Efficacy Follow-up Phase and should be 
assessed every 12 weeks for the first 2 years, every 24 weeks during the third year, and 
annually thereafter to monitor disease status. Efficacy Follow-up visits should align with the 
posttreatment imaging visit schedule (see Section 8.2.1.2). For participants who discontinue 
study intervention for reasons other than radiographic disease progression (including those 
with histopathologic confirmation of suspected disease progression) will have posttreatment 
follow-up imaging for disease status until disease progression is documented 
radiographically per RECIST 1.1 by the investigator, or until withdrawal of consent, 
pregnancy, death, or loss to follow-up, whichever comes first. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated. Participants 
who completed all efficacy assessments and/or will not have further efficacy assessments due 
to documented disease progression per RECIST 1.1 must enter the Survival Follow-up Phase.
8.10.4.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up Phase, the first survival follow-up contact will be scheduled 
12 weeks after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is 
last).

For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
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8.10.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an eDMC 
review, interim and/or final analysis. Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status (excluding participants that have a 
previously recorded death event in the collection tool). 
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes 
to exploratory or other nonconfirmatory analyses made after the protocol has been finalized, 
but prior to the unblinding/final database lock, will be documented in a sSAP and referenced 
in the CSR for the study. A separate biomarker analysis plan will be provided. Posthoc 
exploratory analyses will be clearly identified in the CSR. The PRO analysis plan will also be 
included in the sSAP.
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 through 9.12.
Study Design
Overview
A Randomized Phase 3, Double-Blind Study of Chemoradiotherapy 
With or Without Pembrolizumab for the Treatment of High-risk, 
Locally Advanced Cervical Cancer
Treatment
Assignment
Approximately 980 participants will be randomized in a 1:1 ratio 
between 2 treatment arms: 
Arm 1: CCRT + pembrolizumab
Arm 2: CCRT + placebo
Stratification factors are as follows:
1. Planned type of EBRT: IMRT or VMAT versus non-IMRT and 
non-VMAT
2.
Stage at screening of cervical cancer FIGO 2014 Stage IB2-IIB 
(node-positive disease) versus FIGO 2014 Stage III-IVA (node-
negative or node-positive disease)
3.
Planned total radiotherapy dose (EBRT + brachytherapy dose) of 
<70 Gy versus ≥70 Gy (EQ2D)
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Analysis
Populations
Efficacy: ITT
The analysis population for ORR consists of all randomly assigned 
participants with measurable disease.
Safety: APaT
Primary
Endpoints

PFS as assessed by investigator or by histopathologic confirmation
of suspected disease progression as assessed by investigator

OS
Secondary 
Endpoints

PFS assessed by BICR

PFS at 2 years per RECIST 1.1 as assessed by Investigator or by
histopathologic confirmation of suspected disease progression (in 
the absence of radiographic disease progression per RECIST 1.1)

PFS at 2 years per RECIST 1.1 as assessed by BICR 

OS at 3 years

CR rate at 12 weeks after CCRT per RECIST 1.1 as assessed by 
Investigator and BICR, respectively, in all randomly assigned 
participants with measurable disease

ORR per RECIST 1.1 as assessed by Investigator and BICR, 
respectively, in all randomly assigned participants with measurable 
disease

PFS per RECIST 1.1 as assessed by Investigator or by 
histopathologic confirmation of suspected disease progression (in 
the absence of radiographic disease progression per RECIST 1.1)
by PD-L1 status (by CPS)

PFS per RECIST 1.1 as assessed by BICR by PD-L1 status (by 
CPS) 

OS by PD-L1 status (by CPS)

PFS2: The time from randomization to subsequent disease 
progression after initiation of new anticancer therapy, or death from 
any cause, whichever occurs first

Patient-reported quality of life by EORTC QLQ-C30 global score 
and physical function subscale, and EORTC QLQ-CX24 symptom 
specific subscale

Safety and tolerability of the 2 treatment arms
Statistical
Methods for
Key Efficacy
Analyses
The primary hypotheses will be evaluated by comparing the treatment 
groups with respect to PFS and OS using a stratified log-rank test. The
hazard ratio will be estimated using a stratified Cox regression model.
Progression-free survival at 2 years and OS at 3 years will be estimated 
using the Kaplan-Meier method.
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Statistical
Methods for
Key Safety
Analyses
The analysis of safety results will follow a tiered approach. The tiers 
differ with respect to the analyses that will be performed. There are no 
events of interest that warrant elevation to Tier 1 events in this study. 
Tier 2 parameters will be assessed via point estimates with 95% CIs 
provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters. The 95% CIs 
for the between-treatment differences in percentages will be provided 
using the Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
Interim
Analyses
Two IAs and 1 final analysis are planned in this study. Comparisons 
between 2 treatment arms will be conducted at the IAs and final 
analysis. Results of the IAs will be reviewed by an external data 
monitoring committee. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multiplicity
The overall Type I error rate over the multiple endpoints will be 
strongly controlled at 2.5% (1-sided) with initially 2.5% allocated to 
test PFS superiority. No initial alpha is allocated to the OS hypothesis.
The graphical approach of Maurer and Bretz [Maurer, W. and Bretz, F. 
2013] will be applied to reallocate alpha among the hypotheses of PFS 
and OS. In particular, OS can be tested hierarchically following the 
successful outcome of PFS. Lan-DeMets O’Brien-Fleming group 
sequential methods will be used to allocate alpha among the interim and 
final analyses for the PFS and OS endpoints. 
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Sample Size and
Power
The planned sample size is approximately 980 participants with 
490 participants in each arm.
 
The PFS hypothesis testing is designed for one-sided α = 0.025 and 
power of 95% to detect an HR of 0.660 
 
304 events between the 2 arms at the 
 final 
analyses. The OS hypothesis testing is designed for one-sided α = 0.025 
and power of 86% to detect an HR of 0.671 with 
 
240 events between the 2 arms at the 
 
final analyses.
9.2
Responsibility for Analyses/In-house Blinding 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study will be conducted as a double-blind study with in-house blinding procedures. The 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data has been declared final and 
complete. 
The Sponsor will generate the randomized allocation schedule for study treatment 
assignment for this protocol and the randomization will be implemented in IRT.
Blinding issues related to the planned interim analyses are described in Section 9.7.
9.3
Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints 
Efficacy, safety and PRO endpoints that will be evaluated for within- and/or 
between-treatment differences are listed below. Other endpoints will be described in the 
sSAP.
9.4.1
Primary
PFS INV: The time from randomization to the first documented disease progression per 
RECIST 1.1 as assessed by investigator or per histopathologic confirmation of disease 
progression (in the absence of radiographic disease progression per RECIST 1.1), or death 
due to any cause, whichever occurs first. 
OS: The time from randomization to death due to any cause.
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9.4.2
Secondary
PFS BICR: The time from randomization to the first documented disease progression per 
RECIST 1.1 as assessed by BICR, or death due to any cause, whichever occurs first. 
PFS INV at 2 years: The proportion of participants that are PFS event-free at 2 years per 
RECIST 1.1 as assessed by investigator or by histopathologic confirmation of suspected 
disease progression (in the absence of radiographic disease progression per RECIST 1.1).
PFS BICR at 2 years: The proportion of participants that are PFS event-free at 2 years per 
RECIST 1.1 as assessed by BICR.
OS at 3 years: The proportion of participants that are OS event-free at 3 years.
CR rate at 12 weeks after completion of concurrent chemoradiotherapy: The proportion of 
participants that achieve CR at 12 weeks after CCRT per RECIST 1.1 as assessed by 
investigator and BICR, respectively.
ORR: The proportion of participants in the analysis population who have an OR, defined as a 
complete response (CR) or a partial response (PR) per RECIST 1.1 as assessed by 
investigator and BICR, respectively.
PFS INV by PD-L1: The time from randomization to the first documented disease 
progression per RECIST 1.1 as assessed by investigator or by histopathologic confirmation 
of suspected disease progression, by PD-L1 status (by combined positivity score).
PFS BICR by PD-L1: The progression-free survival per RECIST 1.1 as assessed by BICR, or 
death due to any cause, whichever occurs first, by PD-L1 status (by combined positivity 
score).
OS by PD-L1: The time from randomization to death due to any cause, by PD-L1 status (by 
combined positivity score).
PFS2: The time from randomization to subsequent disease progression after initiation of new 
anticancer therapy, or death from any cause, whichever occurs first. If progression after next-
line therapy cannot be measured, a PFS2 event is defined as end or discontinuation of next-
line treatment or death from any cause, whichever occurs first. 
PROs: Endpoints will be assessed by EORTC QLQ-C30 global score and physical function 
subscale, and EORTC QLQ-CX24 symptoms specific scale. Details will be provided in the 
sSAP.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events, laboratory values and vital signs.
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9.5
Analysis Populations 
9.5.1
Efficacy Analysis Population
The ITT population will serve as the population for the primary efficacy analyses. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment group to which they are randomized.
The analysis population for ORR consists of all randomly assigned participants with 
measurable disease.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized/allocated participants who received at least 1 dose of 
study treatment. Participants will be included in the treatment group corresponding to the 
study treatment they actually received for the analysis of safety data using the APaT 
population. This will be the treatment group to which they are randomized except for 
participants who take incorrect study treatment for the entire treatment period; such 
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participants will be included in the treatment group corresponding to the study treatment 
actually received.
At least 1 laboratory, vital sign, or ECG measurement obtained subsequent to at least 1 dose 
of study treatment is required for inclusion in the analysis of the respective safety parameter.
To assess change from baseline, a baseline measurement is also required.
Details on the approach to handling safety analyses are provided in Section 9.6.2.
9.5.3
Patient-reported Outcome Analysis Population
The PRO analyses are based on the PRO full analysis set population, defined as participants 
who have at least 1 PRO assessment available and have received at least 1 dose of study 
medication.
9.6
Statistical Methods 
9.6.1
Statistical Methods for Efficacy Analyses
Statistical testing and inference for safety analyses are described in Section 9.6.2. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type I 
error control strategy are described in Section 9.8. Nominal p-values will be computed for 
other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity.
9.6.1.1
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, the HR) between the treatment 
arms. The HR and its 95% CI from the stratified Cox model with Efron’s method of tie 
handling and with a single treatment covariate will be reported.
 
 
 
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9.6.1.2
Overall Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factors defined in Section 6.3.2). A stratified Cox proportional hazard model 
with Efron’s method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. 
 
 
 
9.6.1.3
Progression-free Survival at 2 Years
Progression-free survival at 2 years and 95% CI will be estimated using Kaplan-Meier 
method. The approach for testing on difference in outcome at a fixed point in time will be 
used for comparison of the PFS rate at 2 years between 2 treatment groups [Klein, J. P. 
2003]. The difference in PFS rate at 2 years, its 95% confidence interval and nominal p-value
will be reported. 
9.6.1.4
Overall Survival at 3 Years
Overall survival at 3 years and 95% CI will be estimated using Kaplan-Meier method. The 
approach for testing on difference in outcome at a fixed point in time will be used for 
comparison of the OS rate at 3 years between 2 treatment groups [Klein, J. P. 2003]. The 
difference in OS rate at 3 years, its 95% confidence interval and nominal p-value will be 
reported. 
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9.6.1.5
Objective Response Rate
Stratified Miettinen and Nurminen’s method will be used for comparison of the objective
response rate (ORR) between 2 treatment groups [Miettinen, O. and Nurminen, M. 1985].
The difference in ORR and its 95% confidence interval from the stratified Miettinen and
Nurminen’s method with strata weighting by sample size will be reported. The stratification
factors used for randomization (See Section 6.3.2) will be applied to the analysis.
9.6.1.6
Duration of Response
For participants with measurable at baseline who demonstrate CR or PR, DOR is defined as 
the time from first documented evidence of CR or PR until disease progression or death due 
to any cause, whichever occurs first. Censoring rules for DOR are summarized in Table 8.
DOR will be assessed using RECIST 1.1 by investigator and BICR, respectively. For each
DOR analysis, a corresponding summary of the censoring reasons for responding participant 
will also be provided.
 
 
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 9.
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Table 9
Efficacy Analysis Methods for Key Efficacy Endpoints
Endpoint/ 
Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
PFS per   
RECIST 1.1 by 
investigator or 
by 
histopathologic 
confirmation
Testing: Stratified log-rank 
test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored according to rules in Table 7
OS
Testing: Stratified log-rank 
test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known alive date
Secondary Analyses:
PFS per 
RECIST 1.1 by 
BICR 
Testing: Stratified log-rank 
test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored according to rules in Table 7
Abbreviations: BICR=blinded independent central review; ITT=intention-to-treat; OS=overall survival; 
PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in Solid Tumors version 1.1.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 10). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory 
values, vital signs, and ECG parameters are either prespecified as “Tier 1” endpoints or will 
be classified as belonging to “Tier 2” or “Tier 3” based on the observed proportions of 
participants with an event.
Tier 1 Events
Safety parameters that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance. Adverse events of special interest that 
are immune-mediated or potentially immune-mediated are well documented and will be 
evaluated separately; however, these events have been characterized consistently throughout 
the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. Additionally, there are no 
known AEs associated with participants with treatment for which determination of a p-value 
is expected to impact the safety assessment. Therefore, there are no Tier 1 events in this 
study.
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events (via the Miettinen and Nurminen method)
[Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 5% participants in any treatment group exhibit the 
event; all other AEs and predefined limits of change will belong to Tier 3. The threshold of at 
least 5% participants was chosen for Tier 2 events because the population enrolled in this 
study is in critical condition and usually experiences various AEs of similar types regardless 
of treatment; events reported less frequently than 5% participants would obscure the 
assessment of the overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. In addition, Grade 3 to 5 AEs (≥5% participants in 1 of the 
treatment groups) and SAEs (≥2% participants in 1 of the treatment groups) will be 
considered Tier 2 endpoints. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not as a formal method for assessing the statistical significance of the between-group 
differences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3-5 AE, a drug-related 
Grade 3-5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures 
For continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format.
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Table 10
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Grade 3 to 5 AE (incidence ≥5% of participants in one 
of the treatment groups)
X
X
Serious AE (incidence ≥5% of participants in one of 
the treatment groups)
X
X
AEs (incidence ≥5% of participants in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Grade 3 to 5 AE
X
Any Serious AE 
X
Any Drug-related AE
X
Any Serious and Drug-related AE
X
Any Grade 3 to 5 and Drug-related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <5% of participants 
in all of the treatment groups)
X
Change from Baseline Results (laboratory toxicity 
shift, vital signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class.
9.6.3
Statistical Methods for PRO Analyses
To evaluate the treatment effect on the HRQoL outcomes at prespecified time points, a 
constrained longitudinal data analysis model will be applied, with the PRO score as the 
response variable, and the treatment by time interaction and stratification factors as 
covariates. Least square mean (LSmean) change from baseline will be summarized. 
Group-wise comparisons will be performed and the model-based LSmean score will be 
provided by treatment group and study visit.
Details of other PRO analyses will be described in the sSAP.
9.6.4
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of participants randomized, and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age) and 
baseline characteristics will be summarized by treatment either by descriptive statistics or 
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categorical tables. The reasons for exclusion from the ITT population (if any) will be 
summarized.
9.7
Interim Analyses 
An eDMC will serve as the primary reviewer of the results of the interim analyses of the 
study and will make recommendations for discontinuation of the study or protocol 
modifications to an Executive Oversight Committee of the Sponsor. 
 
 
 
 
 
 
Treatment-level results from the interim analysis will be provided to the eDMC by the 
external unblinded statistician. Prior to final study unblinding, the external unblinded 
statistician will not be involved in any discussions regarding modifications to the protocol, 
statistical methods, identification of protocol deviations, or data validation efforts after the 
interim analyses.
9.7.1
Safety Interim Analyses
The eDMC will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the eDMC charter.
9.7.2
Efficacy Interim Analyses
Two interim analyses are planned in addition to the final analysis for this study. 
 
 
 
 
 
 
 
 
 
 
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9.8
Multiplicity 
The study uses the graphical method of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] to 
control multiplicity for multiple hypotheses, as well as interim analyses. 
 
 
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9.8.1
Efficacy Analyses
9.8.1.1
Progression-free Survival
The study initially allocates one-sided α = 0.025 to test PFS between 2 treatment arms. 
 
 
 
 
 
 
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9.8.1.2
Overall Survival
The OS hypothesis will be tested at α = 0.025 (only if the null hypotheses for PFS is 
rejected).
 
 
 
 
9.8.2
Safety Analyses
The eDMC has responsibility for assessment of overall risk:benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of 
efficacy data to assess the overall risk:benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned efficacy interim analysis. 
However, to account for any multiplicity concerns raised by the eDMC review of unplanned 
efficacy data when prompted by safety concerns, a sensitivity analysis for OS adopting a 
conservative multiplicity adjustment will be prespecified in the sSAP.
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9.9
Sample Size and Power Calculations 
This study is well powered for both primary endpoints. Approximately 980 participants will 
be randomized in a 1:1 ratio between 2 treatment arms. 
The PFS hypothesis testing is designed for one-sided α = 0.025 and power of 95% to detect 
an HR of 0.660 with 
 304 events between the 2 arms at the 
 
 final analyses.
The OS hypothesis testing is designed for one-sided α = 0.025 (only if the null hypothesis for 
PFS is rejected) and power of 86% to detect an HR of 0.671 with 
 
 240 events between the 2 arms at the 
 and final analyses.
9.10
Subgroup Analyses 
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9.11
Compliance (Medication Adherence) 
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure 
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on Extent of Exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for 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 regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.2
Scientific Advisory Committee
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team ; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
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10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP 
(eg, International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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.
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10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
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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 14 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 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 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN or ureaa
Potassium
AST/ SGOT
Total bilirubin (and direct bilirubin, if 
total bilirubin is elevated above ULN)
Albumin
Carbon dioxide (CO2
or bicarbonate)b
Chloride
Phosphorous
Creatinine or 
creatinine clearancec
Sodium
ALT/ SGPT
Total Protein
Glucose (fasting or 
nonfasting)
Thyroid-stimulating 
hormone (TSH)d
Calcium
Triiodothyronine 
(T3)d
Alkaline 
phosphatase
Free thyroxine 
(FT4)d
Lactate dehydrogenase
Magnesium
Coagulation 
(to establish 
eligibility)
PT/INR
aPTT/PTT
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterasee by dipstick or 
laboratory analysis
Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
Serum or urine pregnancy test or hCG (qualitative or quantitative) (WOCBP only – as per Schedule of 
Activities)
Serology (HIV antibody, HBV, and HCV) per local requirements
T3 or FT3, FT4, and TSH
NOTES: 
Abbreviations: ALT=alanine aminotransferase; aPTT/PTT=activated partial thromboplastin time / partial thromboplastin time; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; FT3=free thyroid hormone; 
FT4=free thyroxine; HBV=hepatitis B virus; hCG=human chorionic gonadotropin; HCV=hepatitis C virus, HIV=human 
immunodeficiency virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; PT/INR=prothrombin time / 
international normalized ratio; RBC=red blood cell; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic 
transaminase; T3=thyroid hormone or FT3; TSH=thyroid-stimulating hormone; ULN=upper limit of normal; WBC=white blood cell; 
WOCBP=women of childbearing potential.
a.
Blood urea nitrogen is preferred; if not available, urea may be tested.
b.
Performed only if considered local standard of care.
c.
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
d.
Free T3 is acceptable where T3 cannot be determined. There may be instances when sites are unable to obtain the thyroid function 
testing results prior to scheduled dosing. Review of thyroid function test results after dosing is acceptable.
e.
Leukocyte testing can be performed when leukocyte esterase is not possible.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired 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 includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c. Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE.) A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f. Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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)
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
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 
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.
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-
Grade 5: Death related to AE.
Assessment of causality

Did the study intervention cause the AE?

The determination of the likelihood that the study intervention 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 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention(s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
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◦
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) study 
intervention(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 STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION 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 study intervention 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 their best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence 
of the AE onset relative to the administration of the study intervention is 
reasonable. The AE is more likely explained by the study intervention than by 
another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the 
AE onset relative to administration of the study intervention is not reasonable 
OR the AE is more likely explained by another cause than the study 
intervention. (Also entered for a participant with overdose without an associated 
AE.)

The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.

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 
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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 their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.

For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 

New or updated information will be recorded in the CRF. 

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
- Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
- 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.
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
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up 
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.

Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use 
one of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

IUSc,d

Nonhormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to the hormonal contraception.
d
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 participant 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 gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of 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 main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data 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
Laboratory Testing
Pregnancy Testing
While the protocol allows for more frequent pregnancy testing per the discretion of the 
investigator, sites should also check with their local health authority to inquire if 
country-specific guidance regarding the frequency of pregnancy testing is required.
HIV Status
While the protocol does not require specific testing for HIV at screening, it does require 
testing if required by the local health authority. Sites should check with their local health 
authority to inquire if country-specific guidance regarding mandatory HIV testing at 
screening is required. This can also be performed per the discretion of the investigator, if 
desired.
Hepatitis B/C Status
While the protocol does not require specific testing for hepatitis B/C at screening, it does 
require testing if required by the local health authority. Sites should check with their local 
health authority to inquire if country-specific guidance regarding mandatory hepatitis B/C 
testing at screening is required. This can also be performed per the discretion of the 
investigator, if desired.
10.7.2
Country-specific Requirements
10.7.2.1
Germany
Laboratory Testing
HIV testing and hepatitis B/C screening are required evaluations for study entry and need to 
be performed to evaluate eligibility. This testing can be performed at any time during the 
screening period.
Radiotherapy
The IMRT/VMAT radiation techniques are to be the radiation technique of choice.
Legally Acceptable Representative
In order for a participant to be eligible to participate in Germany, they must be capable of 
providing documented informed consent; therefore, all references to a participant’s “legally
acceptable representative” in the protocol are not applicable for participants in Germany.
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10.7.2.2
France
Pembrolizumab Dose Modification Guidelines
Pembrolizumab or placebo should be permanently discontinued in participants with a 
diagnosis of Stevens-Johnson Syndrome and toxic epidermal necrolysis.
Laboratory Testing
Hepatitis B/C screening are required evaluations for study entry and need to be performed to 
evaluate eligibility. This testing can be performed at any time during the screening period.
10.7.2.3
Japan
Sites in Japan may follow local guidelines as specified in the Japan Radiation Manual.
Concurrent Radiotherapy
It is permissible in Japan to administer cisplatin after EBRT if part of standard of care 
procedures.
Study Intervention(s) Administered
The classification of IMP and NIMP in Section 6.1 is based upon guidance issued by the 
European Commission and applies to countries in the EEA. Diluent placebo (normal saline 
and/or dextrose) for this study is not considered as IMP in Japan. Cisplatin used in this study 
is categorized as “test product(s)” in Japan.
10.7.2.4
Czech Republic
Laboratory Testing
HIV testing, and hepatitis B/C screening are required evaluations for study entry and need to 
be performed to evaluate eligibility. This testing can be performed at any time during the 
screening period.
Section 6.5 Concomitant Therapy
In addition to all restrictions or concomitant medications listed in Section 6.5, specific 
concomitant therapies or vaccinations noted below are prohibited during the study:

Live vaccines must not be administered within 30 days prior to the first dose of study 
intervention, while participating in the study, and for 90 days after the last dose of study 
intervention.
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10.7.2.5
Norway
Laboratory Testing
Home pregnancy tests are acceptable, but the site must contact the participant through 
telephone monthly to determine the results of the pregnancy test. The results of the test must 
be recorded in the participant’s eCRF.
10.7.2.6
United Kingdom
Concomitant Therapy
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):

Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
10.7.2.7
China
Section 8.8 Biomarkers
Biomarker sample collection for participants enrolled in China will be dependent on approval 
by the Human Genetic Resources Administration of China (HGRAC). FBR will not be 
conducted in China.
Section 6.1 Study Intervention(s) Administered
The dose formulation for cisplatin used in this study may be powder for infusion or injection 
solution in China.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression 
Not applicable.
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10.9
Appendix 9: Federation of Gynecology and Obstetrics Staging for Cancer of the 
Cervix Uteri
Stage
Description
I
The carcinoma is strictly confined to the cervix (extension to the uterine corpus should be 
disregarded).
   IA
Invasive cancer identified only microscopically. (All gross lesions even with superficial invasion
are Stage IB cancers.) Invasion is limited to measured stromal invasion with a maximum depth 
of 5 mma and no wider than 7 mm.
          
IA1
Measured invasion of stroma ≤3 mm in depth and ≤7 mm width.
          
IA2
Measured invasion of stroma >3 mm and <5 mm in depth and ≤7 mm width.
   IB
Clinical lesions confined to the cervix, or preclinical lesions greater than Stage IA.
          
IB1
Clinical lesions no greater than 4 cm in size.
          
IB2
Clinical lesions >4 cm in size.
II
The carcinoma extends beyond the uterus but has not extended onto the pelvic wall or to the 
lower third of vagina.
   IIA
Involvement of up to the upper 2/3 of the vagina. No obvious parametrial involvement.
         
IIA1
Clinically visible lesion ≤4 cm.
         
IIA2
Clinically visible lesion >4 cm.
   IIB
Obvious parametrial involvement but not onto the pelvic sidewall.
III
The carcinoma has extended onto the pelvic sidewall. On rectal examination, there is no cancer 
free space between the tumor and pelvic sidewall. The tumor involves the lower third of the 
vagina. All cases of hydronephrosis or nonfunctioning kidney should be included unless they are 
known to be due to other causes.
   IIIA
Involvement of the lower vagina but no extension onto pelvic sidewall.
   IIIB
Extension onto the pelvic sidewall, or hydronephrosis/nonfunctioning kidney.
IV
The carcinoma has extended beyond the true pelvis or has clinically involved the mucosa of the 
bladder and/or rectum.
   IVA
Spread to adjacent pelvic organs.
   IVB
Spread to distant organs.
a
The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface of 
glandular, from which it originates. Vascular space invasion should not alter the staging.
Adapted from the Federation of Gynecology and Obstetrics Guidelines 2014 [Belhadj, H., et al 2014].
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ADL
Activities of daily living 
AE
Adverse event 
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APaT
All-Participants-as-Treated
aPTT 
Activated partial thromboplastin time 
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
AUC
Area under the curve
BCG
Bacillus Calmette–Guérin
BICR
Blinded independent central review
BT
Brachytherapy
C
Cycle
Cavg
Average concentration over the dosing interval
Cmax
Maximum concentration
Cmin
Minimum concentration 
CCRT
Concurrent chemoradiotherapy
CD28
Cluster of differentiation 28
CD3ζ
Cluster of differentiation 3 zeta
CI
Confidence interval
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CPS
Combined positive score
CR
Complete response
CrCl
Creatinine clearance
CRF
Case Report Form 
CRT
Chemoradiotherapy
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
CTV
Clinical target volume
D
Day
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid 
DOR
Duration of response
EBRT
External beam radiotherapy
ECG
Electrocardiogram 
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data collection 
EEA
European Economic Area
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
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Abbreviation
Expanded Term
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire global health status
EORTC QLQ-CX24
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire (Symptom Score for Cervical Cancer)
ePROs
Electronic patient-reported outcomes
EQ-2D
Total equieffective dose
EQ-5D-5L
EuroQoL 5 Dimension Questionnaire
ESD
Early stage development
EU CTR
European Union Clinical Trials Regulation
FA
Final analysis
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDG
fluorodeoxyglucose
FIGO
International Federation of Gynecologists and Obstetricians
FSH
Follicle-stimulating hormone 
FSR
First site ready
GCP
Good Clinical Practice 
GFR
Glomerular filtration rate
GI
Gastrointestinal
Gy
Gray
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related quality of life
HRT
Hormone replacement therapy
IA
Interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
Imaging Contract Research Organization
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgG4
Immunoglobulin G4
IgV
Immunoglobulin-variable
IHC
Immunohistochemistry
IMP
investigational medicinal product
IMRT
Intensity modulated radiotherapy
IND
Investigational New Drug 
INR
International normalized ratio
INV
investigator
irAE
Immune-related AE
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
Interactive response technology
ITT
Intent-to-treat
IV
Intravenous
IVD
In vitro diagnostic
LACC
Locally advanced cervical cancer
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Abbreviation
Expanded Term
LAM
Lactational amenorrhea method
LN
Lymph node
LNM
Lymph node metastasis
LSD
Late stage development
mAb
Monoclonal antibody
MRI
Magnetic resonance imaging
mRNA
Messenger RNA
MSI
Microsatellite instability
NCI
National Cancer Institute
NSAE
Nonserious adverse events
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Nonsmall-cell lung cancer
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PALN
Para-aortic lymph nodes
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death 1 ligand 1
PD-L2
Programmed cell death 1 ligand 2
PET
Positron emission tomography 
PFS
Progression-free survival
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PIN
Personal identification number
PK
Pharmacokinetic
PKCθ
Protein kinase C-theta
po
Orally
POS
Probability of success
PR
Partial response
PRO
Patient-reported outcome
PT
Prothrombin time
PTT
Partial thromboplastin time
QW
Once per week
Q2W
Every 2 weeks
Q3W
Every 3 weeks
Q12W
Every 12 weeks
Q24W
Every 24 weeks
QARC
Quality Assurance Review Center
QoL
Quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RT
Radiotherapy
SAC
Scientific Advisory Committee
SAE
Serious adverse event 
SEER
Surveillance, Epidemiology, and End Results
SIB
Simultaneous integrated boosts
SIM
Site imaging manual
SoA
Schedule of activities
SOC
Standard of care
sSAP
Supplemental Statistical Analysis Plan
SUSAR
Suspected unexpected serious adverse reaction
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Abbreviation
Expanded Term
SUV
Standard uptake value
T1DM
Type 1 diabetes mellitus
TEA
Treatment eligibility assessment
TILs
Tumor-infiltrating lymphocytes
US
United States 
VAS
Visual Analog Scale
VMAT
Volumetric arc techniques 
WOCBP
Woman/women of childbearing potential 
ZAP70
Zeta-chain-associated protein kinase
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