A Phase 4, Single-arm, Open-label Clinical Study of Pembrolizumab (MK-3475) to Evaluate the Efficacy and Safety of MK-3475 Plus Carboplatin and Paclitaxel as First-line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (KEYNOTE B10).
Phase: PHASE4
Conditions: Squamous Cell Carcinoma of Head and Neck
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 4, single-arm, open-label clinical study of 
pembrolizumab
(MK-3475) to evaluate the efficacy and safety of 
MK-3475 plus carboplatin and paclitaxel as first-line 
treatment of recurrent/metastatic head and neck 
squamous cell carcinoma
NCT04489888
16 August 2022

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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 4, single-arm, open-label clinical study of pembrolizumab 
(MK-3475) to evaluate the efficacy and safety of MK-3475 plus carboplatin and paclitaxel as 
first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma 
(KEYNOTE-B10).
Protocol Number: B10-03
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as 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
122325
Approval Date: 16 August 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 03
16-AUG-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in 
an entity name change and update to the address. To update the chemotherapy dose 
modification guidance, to update the scan schedule for Second Course Phase, and 
to make minor protocol language clarifications.
Amendment 02
16-AUG-2021
To update imaging language to comply with Health Authority request. This 
includes clarification on the process to be followed after investigator-assessed 
disease progression and adding the definition of lack of clinical stability. To 
incorporate changes in the PCL (02-NOV-2020), which removed the allowance of 
radiation treatment as concomitant treatment during the study treatment phase. To 
make minor protocol language clarifications and to update the chemotherapy dose 
modification guidance. 
Amendment 01
16-JUN-2021
To update the dose modification and toxicity management guidelines for irAEs.
Original Protocol
07-MAY-2020
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
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. To update the chemotherapy dose modification guidance, 
to update the scan schedule for Second Course Phase, and to make minor protocol language clarifications.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
10.1.1 Code of Conduct 
for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name 
change and update to the address.
6.6.2 Dose Modifications 
for Standard Treatment 
Chemotherapy
Updated carboplatin and paclitaxel contraindications, 
precautions, and dose modification guidance.
To align with the current Prescribing 
Information for paclitaxel and carboplatin.
1.3.2 Second Course 
Phase
8.2.1.4 Second Course 
(Retreatment) Tumor 
Scans
Updated the scan schedule during the Second Course 
Phase after Year 1 to every 9 weeks (63 days ±7 
days), and added the option of a less frequent scan
schedule of every 12 weeks after Sponsor 
consultation.
To align second course tumor scan schedule 
with the Initial Treatment Phase, and allow 
option of less frequent scans after Year 1, if 
appropriate, to align with clinical practice 
schedules.
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis: Intervention 
Groups and Duration
In the intervention groups table, updated “Use” for all 
study interventions from “Experimental” to “Test 
Product”. 
To align 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 per the EU CTR.
6.1 Study Intervention(s) 
Administered
Made the following updates to Table 4:
•
Updated “Use” for all study interventions from 
“Experimental” to “Test Product”
•
Updated “NIMP” to “NIMP/AxMP”
•
Deleted drug-specific footnotes
To align with the EU CTR.
To eliminate redundancy, as this information is 
included in Section 8.1.8.
1.1 Synopsis: Duration of 
Participation
Replaced specific reasons for the discontinuation of 
study intervention with “until one of the conditions 
for discontinuation of study intervention is met.”
Replaced specific reasons for the discontinuation of 
imaging with “until any of the conditions for 
discontinuation of imaging are met.”
To maintain consistency with how the study 
intervention and tumor scan discontinuation 
criteria are defined throughout the protocol.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.1 Initial Treatment 
Phase
1.3.2 Second Course 
Phase
Added that information regarding poststudy 
anticancer treatment will be collected if new 
treatment is initiated, and all subsequent anticancer 
therapy given after study intervention discontinuation 
should be recorded in the eCRF in the notes column 
for Subsequent Anticancer Therapy Status.
To clarify when new anticancer therapy is 
given and recorded.
1.3.1 Initial Treatment 
Phase
1.3.2 Second Course 
Phase
Added a cross-reference to Appendix 2 in the notes 
column for hematology, chemistry, thyroid function 
tests, urinalysis, and coagulation factors.
To clarify the individual tests required in each 
laboratory panel.
4.1 Overall Design
Added that central Verification of Progression 
(VOP), or request for iCRO to verify PD, is not 
required.
To clarify that this study does not include 
VOP.
4.1 Overall Design 
8.2.1.2 Tumor Scans 
During the Study
8.2.1.4 Second Course 
(Retreatment) Tumor 
Scans
8.2.1.5 RECIST 1.1 
Assessment of Disease
8.11.4.2 Efficacy 
Follow-up Visits
Updated the list of reasons for discontinuing tumor 
scans/efficacy follow-up in each of these sections to 
align with Section 8.2.1.3.
To maintain consistency with how the tumor 
scan discontinuation criteria are defined 
throughout the protocol.
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Section # and Name
Description of Change 
Brief Rationale 
6.1.2 Second Course
Simplified text describing conditions for Second 
Course retreatment, removed specific conditions of 
treatment during First Course, and clarified that an 
objective response or disease progression that occurs 
during the Second Course for a participant will not be 
counted as an event in the primary efficacy analyses.
To add flexibility, clarity, and consistency to
the requirements for Second Course eligibility.
6.5 Concomitant 
Medications
Restructured section and added clarifications to make 
it clearer which concomitant treatments require 
discontinuation of study intervention before use, and 
which prohibited therapies would not necessarily 
require discontinuation of study intervention or may 
be permitted after Sponsor consultation.
Stated that study intervention must first be 
discontinued if a participant will have oncologic 
surgery or radiation therapy for the disease under 
study.
In the note regarding COVID-19 vaccines, added 
“replication-incompetent” before “adenoviral 
vaccines”.
Minor editorial clarifications to the permitted 
conditions of use for glucocorticoids.
Clarified that the link provided for a list of 
strong/moderate inducers and inhibitors of CYP3A is 
not all-inclusive, and any inducers or inhibitors not 
approved in the US will not appear in the list, and 
that the investigator must review locally approved 
product labels and use best medical judgment.
To clarify which prohibited medications 
warrant the discontinuation of study 
intervention, and which require Sponsor 
consultation.
To clarify that study intervention must be 
discontinued before surgery can be performed 
or radiotherapy can be administered.
To clarify which COVID-19 vaccines are 
permitted.
To clarify the permitted use of steroids.
To ensure that investigators outside the US 
refer to locally approved product labels and 
use best medical judgment for any concomitant 
medications not included in the FDA list.
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Section # and Name
Description of Change 
Brief Rationale 
6.6.1 Immune-Related 
Events and Dose 
Modification (Withhold, 
Treat, Discontinue)
In Table 5, replaced the term “Grade 1 myocarditis” 
with “Asymptomatic cardiac enzyme elevation with 
clinical suspicion of myocarditis (which was 
previously myocarditis Grade 1 using CTCAE 
v4.0).”
To update the pembrolizumab dose 
modification table to include elevated cardiac 
enzymes, suspected myocarditis, instead of 
Grade 1 myocarditis, based on updated 
CTCAE v5.0 toxicity grading.
6.6.2 Dose Modifications 
for Standard Treatment 
Chemotherapy
Added that dose modifications for hematologic AEs 
may also be based on hematology laboratory tests 
performed on or up to 3 days prior to Day 8 for 
paclitaxel 100 mg/m2.
After the statement that chemotherapy may be 
interrupted for a maximum of 6 weeks, clarified that 
this should be calculated from the omitted Day 1 dose 
to the next planned dose and must be within 9 weeks 
of the previously administered Day 1 dose. 
Added that Sponsor consultation is required to 
administer paclitaxel and/or carboplatin study 
intervention after a >6-week dose interruption of 
chemotherapy.
To clarify that dose modifications for 
hematologic AEs must also be followed for 
Day 8 if the participant is receiving paclitaxel 
100 mg/m2.
To clarify that Sponsor consultation to 
continue chemotherapy is required after a 
>6-week dose interruption of paclitaxel and/or 
carboplatin.
7.1 Discontinuation of 
Study Intervention
Added new anticancer therapy to the list of reasons 
for discontinuation of study intervention. 
To maintain consistency with how the study 
intervention discontinuation criteria are 
defined throughout the protocol.
8.1.8.1 Timing of Dose 
Administration
Updated premedication requirements for paclitaxel to 
refer to corticosteroids instead of steroids, and to 
include H2-receptor antagonists.
To align with the current product Prescribing 
Information.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.1 Tumor Imaging and 
Assessment of Disease
In the last paragraph, clarified that Sponsor approval 
is required prior to continuing study intervention
beyond progression, and that any confirmatory 
unscheduled scan following initial documentation of 
disease progression is not required.
Clarification regarding continuation of study 
intervention beyond progression and scan 
requirements.
8.2.1.2 Tumor Scans 
During the Study
Deleted sentence “Note: Response does not typically 
need to be verified in real time by the BICR.”
This study does not require BICR verification 
of progression or any other tumor response (ie, 
CR, PR).
8.2.1.3 End of Treatment 
and Follow-up Tumor 
Scans
Clarified that disease progression as defined by 
RECIST 1.1 will be identified by the investigator. 
Cross-referenced Section 8.2.1.5 for alternative 
options available to the investigator.
To clarify that tumor scans are discontinued 
when disease progression is identified locally 
by the investigator, since there is no VOP in 
this study.
To refer to details of the process to be followed 
after disease progression is established by the 
investigator.
8.2.1.5 RECIST 1.1 
Assessment of Disease
Clarified process to be followed if disease 
progression is established by the investigator.
To clarify scan schedule. 
8.3.4.2 Pregnancy Test
Deleted sentence “Repeated pregnancy test (such as 
monthly testing) may be conducted if required by 
local regulation.”
Added sentence “Pregnancy testing requirements 
during study treatment and in post-treatment are 
described in Appendix 2.”
Repeated pregnancy testing is not optional, but 
is required during study treatment and in 
post-treatment as described in Appendix 2.
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Section # and Name
Description of Change 
Brief Rationale 
8.8 Biomarkers
Changed “Newly Obtained or Archival Tumor Tissue 
Collection” to “Tumor Tissue”.
To reduce ambiguity and eliminate a source of 
confusion. “Tumor tissue” represents all tumor 
collections (archival tissue, newly 
obtained/biopsies, etc.).
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.
To clarify biomarker sample collection.
8.9 Future Biomedical 
Research Sample 
Collection
Deleted list of samples and replaced with “Leftover 
samples listed in Section 8.8”.
To reduce ambiguity and eliminate a source of 
confusion.
8.11.3 Participants 
Discontinued From Study 
Intervention but 
Continuing to Be 
Monitored in the Study
Updated section heading to clarify that the section 
applies for participants who have discontinued from 
study treatment, but are continuing to be monitored in 
the study.
Added that the Discontinuation Visit may either 
occur within 21 days after the last dose of study 
intervention, or approximately 30 days after the last 
dose of study intervention if combined with the 30-
Day Safety Follow Visit, and that study procedures 
for both visits (notably laboratory tests) should be 
performed before initiation of new anticancer 
therapy.
To improve clarity on the information included 
in this section.
To clarify when the Discontinuation Visit 
should be performed and that study procedures 
for the Discontinuation and 30-Day Safety 
Follow-Up Visits should be performed before 
initiation of new anticancer therapy.
8.11.4.3 Survival Follow-
up Contacts
Added that information regarding poststudy 
anticancer treatment will be collected and recorded in 
the eCRF if a new anticancer treatment is initiated.
To align with clarifications made in the 
Schedule of Activities in Sections 1.3.1 and 
1.3.2.
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Section # and Name
Description of Change 
Brief Rationale 
10.2 Appendix 2: Clinical 
Laboratory Tests
Updated the required duration of pregnancy testing 
for WOCBP during post-treatment from at 30 days/4 
weeks after the last dose of study intervention, to 
until 120 days after the last dose of pembrolizumab, 
30 days after the last dose of paclitaxel, and 6 months 
after the last dose of carboplatin.
To ensure that pregnancy testing is continued 
for the time required to eliminate systemic 
exposure after the last dose of study 
interventions, as noted in Section 5.1.
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 ............................................................................................20
1.1
Synopsis.................................................................................................................20
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities...........................................................................................25
1.3.1
Initial Treatment Phase ................................................................................25
1.3.2
Second Course Phase...................................................................................35
2
INTRODUCTION..........................................................................................................39
2.1
Study Rationale....................................................................................................39
2.2
Background ..........................................................................................................41
2.2.1
Pharmaceutical and Therapeutic Background .............................................41
2.2.2
Preclinical and Clinical Studies ...................................................................42
2.2.2.1
Completed Studies with Pembrolizumab in Head and Neck 
Cancer ................................................................................................42
2.2.3
Ongoing Clinical Studies.............................................................................42
2.2.4
Information on Other Study-related Therapy ..............................................45
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................46
4
STUDY DESIGN............................................................................................................48
4.1
Overall Design......................................................................................................48
4.2
Scientific Rationale for Study Design.................................................................49
4.2.1
Rationale for Endpoints ...............................................................................49
4.2.1.1
Efficacy Endpoints.............................................................................49
4.2.1.2
Safety Endpoints................................................................................50
4.2.1.3
Pharmacokinetic Endpoints ...............................................................50
4.2.1.4
Pharmacodynamic Endpoints.............................................................50
4.2.1.5
Planned Exploratory Biomarker Research.........................................50
4.2.1.6
Future Biomedical Research..............................................................52
4.2.2
Rationale for the Use of Comparator/Placebo .............................................52
4.3
Justification for Dose...........................................................................................52
4.3.1
Starting Dose for This Study........................................................................52
4.3.2
Maximum Dose/Exposure for This Study ...................................................53
4.4
Beginning and End of Study Definition .............................................................53
4.4.1
Clinical Criteria for Early Study Termination .............................................53
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5
STUDY POPULATION ................................................................................................53
5.1
Inclusion Criteria.................................................................................................54
5.2
Exclusion Criteria................................................................................................57
5.3
Lifestyle Considerations......................................................................................60
5.3.1
Meals and Dietary Restrictions....................................................................60
5.4
Screen Failures.....................................................................................................60
5.5
Participant Replacement Strategy......................................................................60
6
STUDY INTERVENTION............................................................................................60
6.1
Study Intervention(s) Administered...................................................................60
6.1.1
Treatment .....................................................................................................62
6.1.2
Second Course .............................................................................................62
6.2
Preparation/Handling/Storage/Accountability .................................................63
6.2.1
Dose Preparation..........................................................................................63
6.2.2
Handling, Storage, and Accountability........................................................63
6.3
Measures to Minimize Bias: Randomization and Blinding..............................64
6.3.1
Intervention Assignment..............................................................................64
6.3.2
Stratification.................................................................................................64
6.3.3
Blinding........................................................................................................64
6.4
Study Intervention Compliance..........................................................................64
6.5
Concomitant Therapy..........................................................................................65
6.5.1
Rescue Medications and Supportive Care ...................................................68
6.6
Dose Modification (Escalation/Titration/Other)...............................................68
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................69
6.6.2
Dose Modifications for Standard Treatment Chemotherapy.......................75
6.7
Intervention After the End of the Study............................................................81
6.8
Clinical Supplies Disclosure................................................................................81
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................82
7.1
Discontinuation of Study Intervention...............................................................82
7.2
Participant Withdrawal From the Study...........................................................83
7.3
Lost to Follow-up .................................................................................................83
8
STUDY ASSESSMENTS AND PROCEDURES........................................................83
8.1
Administrative and General Procedures ...........................................................84
8.1.1
Informed Consent.........................................................................................84
8.1.1.1
General Informed Consent.................................................................85
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................85
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8.1.2
Inclusion/Exclusion Criteria ........................................................................85
8.1.3
Participant Identification Card.....................................................................85
8.1.4
Medical History ...........................................................................................86
8.1.5
Prior and Concomitant Medications Review...............................................86
8.1.5.1
Prior Medications...............................................................................86
8.1.5.2
Concomitant Medications..................................................................86
8.1.6
Assignment of Screening Number...............................................................86
8.1.7
Assignment of Treatment/Randomization Number.....................................87
8.1.8
Study Intervention Administration ..............................................................87
8.1.8.1
Timing of Dose Administration.........................................................87
8.1.9
Discontinuation and Withdrawal .................................................................88
8.1.9.1
Withdrawal From Future Biomedical Research ................................88
8.1.10
Participant Blinding/Unblinding..................................................................88
8.1.11
Domiciling ...................................................................................................88
8.1.12
Calibration of Equipment.............................................................................88
8.1.13
Tumor Tissue for Biomarker Status.............................................................89
8.2
Efficacy Assessments ...........................................................................................89
8.2.1
Tumor Imaging and Assessment of Disease................................................89
8.2.1.1
Initial Tumor Scans............................................................................90
8.2.1.2
Tumor Scans During the Study..........................................................91
8.2.1.3
End of Treatment and Follow-up Tumor Scans.................................92
8.2.1.4
Second Course (Retreatment) Tumor Scans......................................92
8.2.1.5
RECIST 1.1 Assessment of Disease..................................................93
8.3
Safety Assessments...............................................................................................94
8.3.1
Physical Examinations.................................................................................94
8.3.1.1
Full Physical Examination.................................................................94
8.3.1.2
Directed Physical Examination..........................................................94
8.3.2
Vital Signs....................................................................................................95
8.3.3
Electrocardiograms ......................................................................................95
8.3.4
Clinical Safety Laboratory Assessments .....................................................95
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................96
8.3.4.2
Pregnancy Test...................................................................................96
8.3.5
Performance Assessments............................................................................96
8.3.5.1
Eastern Cooperative Oncology Group Performance Scale................96
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................96
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................97
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......99
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...99
8.4.4
Regulatory Reporting Requirements for SAE .............................................99
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................99
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................100
8.4.7
Events of Clinical Interest..........................................................................100
8.5
Treatment of Overdose......................................................................................100
8.6
Pharmacokinetics...............................................................................................101
8.7
Pharmacodynamics............................................................................................101
8.8
Biomarkers .........................................................................................................101
8.8.1
Planned Genetic Analysis Sample Collection............................................101
8.9
Future Biomedical Research Sample Collection.............................................102
8.10
Medical Resource Utilization and Health Economics.....................................102
8.11
Visit Requirements.............................................................................................102
8.11.1
Screening....................................................................................................102
8.11.2
Treatment Period........................................................................................103
8.11.3
Participants Discontinued From Study Intervention but Continuing to 
Be Monitored in the Study.........................................................................103
8.11.4
Post-treatment Visit ...................................................................................103
8.11.4.1
Safety Follow-up Visit.....................................................................103
8.11.4.2
Efficacy Follow-up Visits................................................................103
8.11.4.3
Survival Follow-up Contacts ...........................................................104
8.11.5
Survival Status ...........................................................................................104
9
STATISTICAL ANALYSIS PLAN ...........................................................................104
9.1
Statistical Analysis Plan Summary...................................................................105
9.2
Responsibility for Analyses/In-house Blinding ...............................................105
9.3
Hypotheses/Estimation ......................................................................................106
9.4
Analysis Endpoints.............................................................................................106
9.4.1
Efficacy Endpoints.....................................................................................106
9.4.2
Safety Endpoints........................................................................................106
9.5
Analysis Populations..........................................................................................106
9.5.1
Efficacy Analysis Population.....................................................................106
9.5.2
Safety Analysis Population........................................................................106
9.6
Statistical Methods.............................................................................................107
9.6.1
Statistical Methods for Efficacy Analyses.................................................107
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9.6.2
Statistical Methods for Safety Analyses ....................................................109
9.6.3
Summaries of Baseline Characteristics and Demographics.......................109
9.7
Interim Analyses ................................................................................................110
9.8
Multiplicity .........................................................................................................110
9.9
Sample Size and Power Calculations ...............................................................110
9.10
Subgroup Analyses.............................................................................................110
9.11
Compliance (Medication Adherence)...............................................................111
9.12
Extent of Exposure.............................................................................................111
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................112
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......112
10.1.1
Code of Conduct for Clinical Trials...........................................................112
10.1.2
Financial Disclosure...................................................................................114
10.1.3
Data Protection...........................................................................................114
10.1.3.1
Confidentiality of Data ....................................................................115
10.1.3.2
Confidentiality of Participant Records.............................................115
10.1.3.3
Confidentiality of IRB/IEC Information..........................................115
10.1.4
Publication Policy......................................................................................115
10.1.5
Compliance with Study Registration and Results Posting Requirements .116
10.1.6
Compliance with Law, Audit, and Debarment ..........................................116
10.1.7
Data Quality Assurance .............................................................................117
10.1.8
Source Documents .....................................................................................118
10.1.9
Study and Site Closure...............................................................................118
10.2
Appendix 2: Clinical Laboratory Tests............................................................119
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................121
10.3.1
Definition of AE ........................................................................................121
10.3.2
Definition of SAE ......................................................................................122
10.3.3
Additional Events Reported in the Same Manner as SAE.........................123
10.3.4
Recording AE and SAE .............................................................................123
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................127
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................129
10.5
Appendix 5: Contraceptive Guidance..............................................................130
10.5.1
Definitions..................................................................................................130
10.5.2
Contraception Requirements......................................................................132
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................133
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10.7
Appendix 7: Country-specific Requirements..................................................138
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................139
10.9
Appendix 9: Abbreviations ...............................................................................140
11
REFERENCES.............................................................................................................143
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LIST OF TABLES
Table 1
Initial Treatment Phase ....................................................................................25
Table 2
Second Course Phase.......................................................................................35
Table 3
Adequate Organ Function Laboratory Values .................................................57
Table 4
Study Interventions..........................................................................................61
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................70
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................74
Table 7
Dose Modification Guidelines for Febrile Neutropenia or Documented 
Infection ...........................................................................................................77
Table 8
Carboplatin Dose Modifications for Drug-related Adverse Events.................78
Table 9
Paclitaxel Dose Modifications for Drug-related Adverse Events....................81
Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................98
Table 11
Censoring Rules for DOR..............................................................................107
Table 12
Censoring Rules for PFS................................................................................108
Table 13
Analysis Strategy for Key Efficacy Variables...............................................109
Table 14
Two-sided 95% CI for ORR with 100 Participants .......................................110
Table 15
Protocol-required Safety Laboratory Assessments........................................120
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LIST OF FIGURES
Figure 1
Initial Treatment Phase ....................................................................................24
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 4, single-arm, open-label clinical study of pembrolizumab 
(MK-3475) to evaluate the efficacy and safety of MK-3475 plus carboplatin and paclitaxel as 
first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma 
(KEYNOTE-B10).
Short Title: MK-3475 Taxane Combo Single-Arm Phase 4
Acronym: KEYNOTE-B10
Hypotheses, Objectives, and Endpoints:
Adult participants with a histologically or cytologically-confirmed R/M HNSCC that is 
considered incurable by local therapies will be enrolled in this study.
Throughout this protocol, the term RECIST 1.1 refers to the adjustment 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 further details.
Primary Objectives
Primary Endpoints
Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel 
with respect to objective response rate (ORR) 
per RECIST 1.1 as assessed by blinded 
independent central review (BICR).
Objective Response: Complete response 
(CR) or Partial response (PR)
Secondary Objectives
Secondary Endpoints
Key Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel 
with respect to duration of response (DOR) 
per RECIST 1.1 as assessed by blinded 
independent central review (BICR).
DOR: For participants who demonstrate 
confirmed CR or PR, DOR is defined as 
the time from first documented evidence of 
CR or PR until disease progression or 
death due to any cause, whichever occurs 
first.
Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel 
with respect to progression-free survival 
(PFS) per RECIST 1.1 as assessed by blinded 
independent central review (BICR).
PFS: The time from first dose to the first 
documented disease progression or death 
due to any cause, whichever occurs first.
Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel 
with respect to overall survival (OS).
OS: The time from first dose to death due 
to any cause.
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Objective: To assess the safety and 
tolerability of study intervention with 
pembrolizumab + carboplatin + paclitaxel.
- AEs.
- Study intervention discontinuation due to 
AEs.
Overall Design:
Study Phase
Phase 4
Primary Purpose
Treatment
Indication
Treatment of participants with R/M HNSCC
Population
Participants with R/M HNSCC who are eligible for 1L 
treatment
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 48 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 100 participants will be treated. All allocated participants who are treated will 
be included in the APaT analysis as described in Section 9.0.
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Intervention Groups and Duration:
Intervention 
Groups
Drug
Dosage Level(s)
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/
Use
Pembrolizumaba
200 mg
Q3W
IV infusion
Day 1 of 
each cycle 
(35 cycles)
Test 
Product
Carboplatin
AUC 5 mg/mL/min
Q3W
IV infusion
Day 1 of 
each cycle 
(6 cycles)
Test 
Product
Paclitaxelb
100 mg/m2
Q1W
IV infusion
Day 1 and 
Day 8 of 
each cycle 
(6 cycles)
Test 
Product
Paclitaxelb
175 mg/m2
Q3W
IV infusion
Day 1 of 
each cycle 
(6 cycles)
Test 
Product
Abbreviations: AUC = area under the curve; IV = intravenous; Q1W = weekly; Q3W = every 
3 weeks.
a Pembrolizumab must be administered prior to chemotherapy.
b Paclitaxel 100 mg/m2 Q1W or paclitaxel 175 mg/m2 Q3W. 
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: KEYTRUDA and MK-3475.
Total 
Number of 
Intervention 
Groups/ 
Arms
1 Arm
Duration of 
Participation
Each participant will participate in the study from the time that the 
participant provides documented informed consent through the final 
protocol-specified contact.
After a screening phase of 28 days, each participant will be assigned to 
receive study intervention until one of the conditions for discontinuation of 
study intervention is met.
Participants who complete study intervention after receiving 35 
administrations of pembrolizumab, and participants who attain a complete 
response and stop study intervention may be eligible for up to 17 additional 
administrations of pembrolizumab (approximately 1 year) upon 
experiencing disease progression.
After the end-of-treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until any of the conditions for discontinuation of imaging are met.
All participants will be followed for overall survival until death, withdrawal 
of consent, or the end of the study.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
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 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Initial Treatment Phase
1L=first-line; AUC=area under the curve; CR=complete response; dx=disease DOR=duration of response; 
ECOG=Eastern Cooperative Oncology Group; FU=Follow-up; HNSCC=head and neck squamous cell 
carcinoma; HPV=Human papillomavirus; OP=oropharynx; ORR=objective response rate; OS=overall survival; 
PD=progressive disease; PD-L1=programmed cell death ligand-1; PFS=progression-free survival; PR=partial 
response; Q1W=weekly; Q3W=every 3 weeks; R/M=recurrent/metastatic SD=stable disease.
a
Participants who complete 35 cycles of pembrolizumab study intervention after achieving SD/PR/CR may 
be eligible to receive an additional 17 cycles of pembrolizumab if disease progression occurs.
b
Paclitaxel, per Investigator’s choice of:

100 mg/m2 Q1W on Day 1 and Day 8 (6 cycles), OR

175 mg/m2 Q3W on Day 1 (6 cycles).
c
Carboplatin AUC 5 mg/mL/min Q3W on Day 1 (6 cycles).
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1.3
Schedule of Activities
The SoAs for the Initial Treatment Phase and the Second Course Phase are provided in Table 1 and Table 2, respectively.
1.3.1
Initial Treatment Phase
Details regarding procedures listed in this table are outlined in Section 8.0.
Table 1
Initial Treatment Phase
Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed Consent
X
If the investigator plans to 
treat beyond disease 
progression, additional 
consent is required.
Informed Consent 
for Future 
Biomedical 
Research
X
This is optional for the 
participant.
Inclusion/Exclusion 
Criteria
X
Participant 
Identification Card
X
Xa
a Add the allocation 
number at the time of 
treatment/ allocation.
Medical History 
X
Includes demographics, 
smoking, alcohol and 
tobacco use.
Prior Treatment for 
HNSCC
X
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Prior/Concomitant 
Medication Reviewa
X
X
X
X
X
X
X
a All prior/concomitant 
medications received 
within 28 d prior to the 
first dose of study 
intervention and up to 
30 d after the last dose 
of study intervention 
should be recorded. All 
concomitant 
medications received 
for SAEs and ECIs
should be recorded.
Contact IRT
X
X
Xa
X
Xa
X
Xa
X
X
When participant provides 
documented informed
consent, contact IRT to 
obtain screening number.
On C1D1, contact IRT to 
obtain allocation number. 
At subsequent visits, 
contact IRT to ensure 
visits are captured in the 
IRT system (for centrally 
sourced study 
intervention).
a Visit D8 only applies to 
participants receiving 
paclitaxel 100 mg/m2
Q1W.
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Assignment of 
Treatment/
Randomization 
(Allocation) 
Number
X
It is strongly preferred that 
participants receive first 
dose of study intervention 
on day of allocation. Study 
intervention should begin 
within 3 d of allocation.
Subsequent 
Anticancer Therapy 
Status
X
X
X
X
Information regarding 
poststudy anticancer 
treatment will be collected 
if new treatment is 
initiated. All subsequent 
anticancer therapy given 
after study intervention
discontinuation should be 
recorded in the eCRF.
Survival Status
X
On Sponsor request, 
participants may be 
contacted for survival 
status at any time during 
the course of the study.
Study Intervention Administration
Pembrolizumab 
X
X
X
X
Pembrolizumab given on 
D1 (up to 35 cycles). 
Pembrolizumab should be 
given first, when given on 
the same day as other 
study intervention.
Paclitaxel Administration (Investigator choice of one of the following doses) Note:  Paclitaxel should be given after pembrolizumab
Paclitaxel
(100 mg/m2
Q1W)
X
X
X
X
X
X
Paclitaxel 100 mg/m2
given on D1 and D8 
(6 cycles) (Dose 
Modification Table 9).
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Paclitaxel 
(175 mg/m2
Q3W)
X
X
X
Paclitaxel 175 mg/m2
given on D1 (6 cycles)
(Dose Modificaton 
Table 9).
Carboplatin
X
X
X
Carboplatin given on D1 
(6 cycles). Carboplatin 
should be given last, when 
given on the same day as 
other study intervention
(Dose Modification 
Table 7 and Table 8).
Efficacy Procedures
Tumor Scans
(head and neck, 
chest, abdomen) and 
RECIST 1.1
Assessment
Note: Scans of the 
brain and pelvis are 
optional (if 
clinically indicated).
X
Xa
Xa
Xa
X
X
BICR confirmation of 
measurable disease is 
required at Screening. 
Timing of tumor scans
will be calculated from the 
date of allocation. 
a Scans are performed at 
Screening, Wk 6 (+ 7 d, 
no earlier than Day 42) 
and every 6 wk (± 7 d) 
during Y1. After Y1, 
scans are performed 
every 9 wk (± 7 d). This 
schedule will be 
maintained regardless of 
treatment delays
(Section 8.2.1.2).
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Safety Procedures
Full Physical 
Examination 
X a
X
a Tumor staging needs to 
be completed per AJCC 
Cancer Staging Manual, 
eighth Edition
[American Joint 
Committee on Cancer 
2018].
Height
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Vital Signs
(temperature, heart 
rate, respiratory 
rate, resting blood 
pressure, and 
weight)
X
X
X
X
X
X
X
X
Xa
X
X
X
a For C5 and C6, Visit D8 
procedures only apply to 
participants receiving 
paclitaxel 100 mg/m2
Q1W.
12-lead ECG 
(Local)
Xa
a Required at Screening 
only. ECG should be 
performed at subsequent 
visits only if clinically 
indicated.
ECOG Performance 
Status
Xa
X
X
X
X
X
X
a Screening ECOG within 
7 d before initiation of 
study intervention. 
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
AE/SAE Review
X
X
X
X
X
X
X
Xa
X
X
X
X
Report AEs occurring 
within 30 d after the last 
dose of study intervention. 
Report SAEs occurring 
within 90 d after the last 
dose of study intervention, 
or 30 d after the last dose 
of study intervention if a 
new anticancer therapy is 
initiated, whichever is 
first.
a For C5 and C6, Visit D8 
procedures only apply to 
participants receiving 
paclitaxel 100 mg/m2
Q1W.
Laboratory Procedures/Assessments (Local Laboratory)
Highly sensitive 
serum or Urine hCG 
Pregnancy Test 
(WOCBP only)
X a
X
X
X
X
X
a WOCBP require a 
negative test within 24 h 
before the first dose of 
study intervention. If a 
urine test cannot be 
confirmed as negative, a 
serum pregnancy test is 
required to be confirmed 
as negative. Serum or 
urine pregnancy tests
will be performed 
during the study per 
Appendix 2.
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
HIV, Hepatitis B, 
and Hepatitis C
X a
a Required at Screening 
only if mandated by 
local health authority.
Hematology
X
X
X
X
X
X
X
Xa
X
X
X
Perform screening 
laboratory tests within 7 d 
prior to the first dose.
After C1, laboratory
samples can be collected 
up to 3 d prior to D1 of 
subsequent cycles.
Refer to Appendix 2.
a For C5 and C6, Visit D8 
procedures only apply to 
participants receiving 
paclitaxel 100 mg/m2
Q1W.
Chemistry
X
X
X
X
X
X
X
Xa
X
X
X
Perform screening 
laboratory tests within 7 d 
prior to the first dose.
After C1, laboratory
samples can be collected 
up to 3 d prior to D1 of 
subsequent cycles.
Refer to Appendix 2.
a For C5 and C6, Visit D8 
procedures only apply to 
participants receiving 
paclitaxel 100 mg/m2
Q1W.
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Thyroid Function 
Tests
(T3 or FT3, T4 or 
FT4, and TSH)
X a
Xa
Xa
Xa
X
a Perform screening 
laboratory tests within 7 
d prior to the first dose,
then at C2 and every 
2 cycles thereafter (C4, 
C6, C8, etc.). After 
Screening, laboratory
samples can be collected 
up to 3 d prior to D1 of 
subsequent cycles. The 
central laboratory may 
be used only if the local 
laboratory cannot 
perform these tests.
Refer to Appendix 2.
Urinalysis
X
X
Xa
Xa
X
Perform screening 
laboratory tests within 7 d 
prior to the first dose. 
Refer to Appendix 2.
a Collect on D1 for first 
6 cycles (when chemo is 
given), and then every 
6 cycles after C6 (C6, 
C12, C18, etc.). After 
Screening, laboratory
samples can be collected 
up to 3 d prior to D1 of 
subsequent cycles.
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Coagulation Factors 
(PT/INR and
aPTT/PTT)
Xa
a Perform screening 
laboratory tests within 
7 d prior to the first 
dose.
Additional testing is to be 
performed as clinically 
indicated for participants 
taking anticoagulants.
Refer to Appendix 2.
HPV status using 
CINtec® p16 
Histology assay 
(oropharynx 
participants only)
X
Historical result may be 
used. If historical p16 
testing result is not 
available or cannot be 
performed locally, a new 
or archival tumor tissue 
sample must be submitted 
to the central laboratory, 
and results must be 
received prior to 
allocation.
Biomarkers (Central Laboratory)
Newly Obtained or 
Archival Tumor 
Tissue Collection
X
New or archival tumor 
tissue sample <5 years of 
age at time of sample 
submission must be 
provided for PD-L1 
biomarker analysis prior to 
allocation (Section 5.1, 
inclusion criterion #7 and 
Section 8.1.13).
Blood for Genetic 
Analysis
X
Collect predose on C1D1.
See Section 8.8. 
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Study Period:
Screening
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit Number/Title:
Screening
C1
C2 to C4
C5 to 
C6
C7 to 
C35
Safety 
FU
Efficacy FU
Survival 
FU
Cycle Day
1
8
15
1
8
15
1
8
1
Scheduling Window 
(days)
-28 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Blood for RNA 
Analysis
X
X
Xa
X
a Collect predose on 
C1D1, C2D1, C5D1 and 
at EOT.
Blood for ctDNA 
Analysis
X
Xa
Xa
Xa
X
Collect predose on C1D1, 
C2D1, C3D1.
a After C3D1 collection, 
the ctDNA samples 
should be collected 
within ±7 d of all 
subsequent scan visits
(actual scan date) and at 
EOT. Collection of 
ctDNA samples is not 
required after EOT.
After Wk 6, scan visits are 
every 6 wk (±7 d) during 
Y1. After Y1, scan visits 
will occur every 9 wk 
(±7 d).
AE=adverse event; aPTT=activated partial thromboplastin time; BICR=blinded independent central review; BP=blood pressure; C=cycle; ctDNA=circulating tumor 
deoxyribonucleic acid; CXDY=Cycle X Day Y; d=day; discon=discontinuation; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; eCRF=electronic case 
report form; EOT=end of treatment; FT3=free triiodothyronine; FT4=free thyroxine; FU=follow-up; hCG=human chorionic gonadotropin; HIV=human immunodeficiency 
virus; HNSCC=head and neck squamous cell carcinoma; HPV=Human papillomavirus; INR=international normalized ratio; IRT=interactive response technology; 
PT=prothrombin time; PTT=partial thromboplastin time; Q1W=weekly; Q6W=every 6 weeks; Q9W=every 9 weeks; Q12W=every 12 weeks; RECIST 1.1=Response 
evaluation criteria in solid tumors; RNA=ribonucleic acid; SAE=serious adverse event; SoA=schedule of activities; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-
stimulating hormone; Wk(s)=weeks; WOCBP=women of childbearing potential; Y1=Year 1; Y2=Year 2.
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1.3.2
Second Course Phase
Further details on Second Course (Retreatment) Phase are outlined in Section 6.1.2 and 8.2.1.4. Second Course retreatment 
participants may receive up to 17 cycles (approximately 1 year) of pembrolizumab study intervention.
Table 2
Second Course Phase
Study Period:
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit / Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
Safety 
Follow-up
Second Course 
Efficacy FU
Survival 
FU
Cycle Day
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Administrative Procedures
Informed Consent
X
Reconsent is required at the time of 
progression if study intervention will 
continue and/or restart.
Second Course 
Inclusion/Exclusion 
Criteria
X
Contact IRT
X
X
X
X
X
X
X
On C1D1, contact IRT to register the 
participant in Second Course. At 
subsequent visits, contact IRT to ensure 
visits are captured in the IRT system.
Prior/Concomitant 
Medication Reviewa
X
X
X
X
X
X
X
X
a All prior/concomitant medications 
received within 28 d prior to the first 
dose of second course study 
intervention and up to 30 d after the last 
dose of study intervention should be 
recorded. All concomitant medications 
received for SAEs and ECIs should be 
recorded.
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Study Period:
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit / Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
Safety 
Follow-up
Second Course 
Efficacy FU
Survival 
FU
Cycle Day
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Subsequent Anticancer
Therapy Status
X
X
X
X
Information regarding poststudy 
anticancer treatment will be collected if 
new treatment is initiated. All subsequent 
anticancer therapy given after study 
intervention discontinuation should be 
recorded in the eCRF.
Survival Status
X
On Sponsor request, participants may be 
contacted for survival status at any time 
during the course of the study.
Study Intervention Administration
Pembrolizumab 
Administration
IV Q3W
X
X
X
X
X
X
Efficacy Procedures
Tumor Scans
(head and neck, chest, 
abdomen) and RECIST 
1.1 Assessment
Note: Scans of the 
brain and pelvis are 
optional (if clinically 
indicated).
Xa
X
X
X
X
X
a Baseline scan is the CT or MRI 
showing PD. Baseline tumor scans must
be performed within 28 d before C1. 
First on-study scan at Wk 6 (+ 7 d, no 
earlier than 42 d after Cycle 1 Day 1 of 
Second Course), every 6 wk (± 7 d) 
during Y1, and every 9 wk (± 7 d)
thereafter (a 12-weekly scan schedule 
may be implemented after Y1 following
consultation with the Sponsor). This 
schedule will be followed regardless of 
delays in study intervention (see 
Section 8.2.1.4). 
Safety Procedures
Full Physical 
Examination 
X
X
Directed Physical 
Examination
X
X
X
X
X
X
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Study Period:
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit / Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
Safety 
Follow-up
Second Course 
Efficacy FU
Survival 
FU
Cycle Day
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Vital Signs 
(temperature, heart 
rate, respiratory rate, 
resting blood pressure, 
and weight)
X
X
X
X
X
X
X
X
12-lead ECG 
X a
a Perform within 7 d prior to first dose in 
C1. ECG should be performed at 
subsequent visits only if clinically 
indicated.
ECOG Performance 
Status
X a
X
X
X
X
X
X
X
a Perform within 7 d prior to first dose in 
C1.
AE/SAE Review
X
X
X
X
X
X
X
X
X
Report AEs occurring within 30 d after 
the last dose of study intervention. 
Report SAEs occurring within 90 d after 
the last dose of study intervention, or 
30 d after the last dose of study 
intervention if a new anticancer therapy 
is initiated, whichever is first.
Laboratory Procedures/Assessments (Local Laboratory)
Highly sensitive serum
or urine hCG 
pregnancy test 
(WOCBP only)
X a
a Obtain a urine pregnancy test within 
72 h before the first dose for WOCBP 
participants.
If a urine pregnancy test cannot be 
confirmed as negative, a serum 
pregnancy test is required.
Additional urine/serum testing may be 
performed if clinically warranted, and/or 
as defined by local regulations.
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Study Period:
Intervention (21-Day Cycles)
End of 
Treatment
Post-treatment Visits
Notes
Visit / Cycle Number
C1
C2
C3
C4
C5
C6 to 
C17
Safety 
Follow-up
Second Course 
Efficacy FU
Survival 
FU
Cycle Day
1
1
1
1
1
1
Scheduling Window 
(days)
+3
±3
±3
±3
±3
±3
At time of 
treatment 
discon
30d after 
last dose 
(+7d)
Q6W (Y1) or
Q9W (Y2+)
(± 7d)
Q12W
(± 14d)
Hematology
X a
X
X
X
X
X
X
X
a
Perform within 7 d prior to first dose 
in C1 to confirm Second Course 
eligibility. After Cycle 1, laboratory
samples can be collected up to 3 d 
prior to the scheduled visit.
Refer to Appendix 2.
Chemistry
X a
X
X
X
X
X
X
X
a
Perform within 7 d prior to first dose 
in C1 to confirm Second Course 
eligibility. After C1, laboratory
samples can be collected up to 3 d 
prior to the scheduled visit.
Refer to Appendix 2.
Thyroid Function Tests
(T3 or FT3, T4 or FT4, 
TSH)
X a
X
X
X a
X
a
Perform within 7 d prior to first dose 
in C1, then every 2 cycles thereafter 
(C3, C5, C7, etc.). After Cycle 1, 
laboratory samples can be collected up 
to 3 d prior to the scheduled visit. 
Refer to Appendix 2.
Urinalysis
Xa
a Perform within 7 d prior to first dose 
in C1 to confirm Second Course 
eligibility. Additional testing to be 
conducted as clinically indicated. 
Refer to Appendix 2.
Coagulation Factors 
(PT/INR and
aPTT/PTT)
Xa
a Perform within 7 d prior to first dose 
in C1. Additional testing to be 
conducted as clinically indicated for 
participants taking anticoagulants.
Refer to Appendix 2.
AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; CT=computed tomography; CXDY=Cycle X Day Y; d = day; discon = discontinuation; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; EOT = end of treatment; FT3=free triiodothyronine; FT4= free thyroxine; FU=follow-up; hCG=human chorionic gonadotropin; INR=international normalized 
ratio; IRT=interactive response technology; IV=intravenous; MRI=magnetic resonance imaging; PD=progressive disease; PT=prothrombin time; PTT=partial thromboplastin time; Q9W=every 9 weeks; 
Q12W=every 12 weeks; RECIST 1.1=Response evaluation criteria in solid tumors; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; Wk(s)=Weeks; 
WOCBP=women of childbearing potential.
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2
INTRODUCTION
Pembrolizumab, in combination with carboplatin and paclitaxel, rather than 5-FU, is being 
investigated for participants eligible for 1L treatment of R/M HNSCC in this open-label 
Phase 4 study.
2.1
Study Rationale
Head and neck cancers describe an anatomically heterogeneous group of cancers that arise 
most often from the oral cavity, the oropharynx, hypopharynx, and the larynx [Dorsey, K. 
2013]. More than 90% of head and neck cancers are squamous cell carcinomas, originating 
from the epithelium of the mucosal lining of the upper aerodigestive tract [Gupta, B., et al 
2016]. Head and neck cancers are the ninth most common malignancy in the world, with 
high mortality rates in developing countries (age-standardized mortality rates of 7.9 and 2.2 
per 100,000 in males and females, respectively) [Gupta, B., et al 2016].
More than 90% of patients with HNSCC initially present with disease confined to the head 
and neck mucosa and/or to the regional cervical lymph nodes [Machiels, J. P. 2011]. Surgery 
and radiation therapy are markedly effective for patients with Stage I and II disease. 
However, despite intensive multimodal treatment, approximately 50% of patients with 
locally advanced Stage III or Stage IV HNSCC recur initially with locoregional disease. 
However, a significant proportion of these patients ultimately have incurable disease 
recurrence requiring palliative systemic treatment. The prognosis for patients with R/M 
HNSCC is dismal and OS is less than 1 year [Argiris, A., et al 2017].
Patients with R/M HNSCC present a therapeutic challenge. Historically, first-line treatment 
has generally included the combination of either cetuximab or docetaxel with a platinum-
based chemotherapy with or without 5-FU, as shown with the OS advantage of the 
EXTREME regimen. More recently, the KEYNOTE-048 study showed an OS advantage 
compared with the EXTREME regimen and has replaced it as the new standard of care. 
KEYNOTE-048, an ongoing Phase 3, open-label study to compare the efficacy and safety of
pembrolizumab as monotherapy or in combination with chemotherapy (platinum plus 5-FU) 
in first-line treatment versus the standard EXTREME chemotherapy regimen (cetuximab in 
combination with platinum plus 5-FU) is provided in Section 2.2.3. In the population of all 
participants regardless of PD-L1 expression status, there was a clinically meaningful 
difference in OS when comparing pembrolizumab plus chemotherapy with standard 
treatment. The pembrolizumab plus chemotherapy group had a longer DOR than the 
EXTREME regimen and the safety profile was comparable. There was a clinically 
meaningful difference in OS when comparing pembrolizumab monotherapy group with 
standard treatment for participants whose tumors expressed PD-L1 (CPS ≥1). The 
pembrolizumab monotherapy group had more responders who achieved a CR and a more 
durable DOR. The safety profile for pembrolizumab monotherapy was favorable. Based on 
this data, pembrolizumab is now approved in the US and EU as monotherapy and in 
combination with chemotherapy for 1L R/M HNSCC treatment.
Patients who are asymptomatic usually are treated with monotherapy to balance the side-
effects associated with combination regimens. Options for first-line single-agent treatment 
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include platinum, 5-FU, paclitaxel, docetaxel, methotrexate, cetuximab, gemcitabine, or 
capecitabine [National Comprehensive Cancer Network 2018]. 
The available evidence from several exploratory and preclinical studies on the interaction 
between taxanes and platinum agents is of high interest and suggests that inhibition of 
microtubule assembly by taxanes [Abal, M., et al 2003] and the formation of DNA adducts 
by platinum agents together lead to apoptosis of the tumor cell. [Siddik, Z. H. 2003] [Chao, 
S. Y., et al 2011]. Adding anti-PD-1 to this combination may further potentiate tumor cell 
death by increasing T-cell mediated immune response.
The idea of combining paclitaxel and anti-PD-1 has been shown in a recent in vitro study. In 
this study, paclitaxel increased MMP-13 expression in R/M HNSCC cells and suggested that 
paclitaxel is a strong candidate for use in combination with anti-PD-1 therapy. MMP-13 may 
play a critical role in the shedding/cleavage of PD-L1 and therefore this may be an important 
factor of combining paclitaxel with anti-PD-1 [Hira-Miyazawa, M., et al 2018].
Based on the preclinical rationale and emerging clinical data, treatment guidelines also note 
the use of taxanes combination with platinum as an alternative treatment option.
Taxanes can help expand the treatment options available in the first line, where they can 
replace 5-FU in the both Pembrolizumab + Platinum + 5-FU regimen per KEYNOTE-048 
and EXTREME regimen, as well as in second- or later-line settings and in settings where 
cisplatin/carboplatin treatment is unsuitable [Iglesias Docampo, L. C., et al 2018].
The combination of taxanes with checkpoint inhibitors is currently being evaluated, such as 
in the single-arm, Phase 1/2 PemDoc II study of pembrolizumab plus docetaxel [National 
Library of Medicine 2020]. Furthermore, the following studies are investigating the efficacy 
and safety of combining taxanes with platinum and cetuximab [National Library of Medicine 
2020] [National Library of Medicine 2020] [National Library of Medicine 2020] [National 
Library of Medicine 2020] [Guigay, J., et al 2019].
Based on the KEYNOTE-048 results, pembrolizumab became the first-line treatment of R/M 
HNSCC for the majority of patients. Taxanes can help expand the available treatment options 
in the ﬁrst line, where they can be used instead of 5-FU. Encouraging early results from 
preclinical and small clinical studies on the combination of taxanes suggest that taxanes can 
have additive immunogenic eﬀects with other immuno-oncology based anticancer therapies. 
The combination of taxanes with checkpoint inhibitors is also currently being evaluated in 
Phase 1/2 studies. Therefore, there is a strong biological and mechanistic rationale behind 
combining pembrolizumab with a platinum and a taxane agent when treating patients with 
R/M SCCHN. In this proposed study, carboplatin was selected over cisplatin as the platinum 
agent due to the potentially less toxic side effect profile. Based on KEYNOTE-048 
approvals, carboplatin and cisplatin were shown to be effective platinum agents for patients 
with R/M HNSCC [Burtness, B., et al 2019]. In addition, the 2020 NCCN HNSCC 
guidelines [National Comprehensive Cancer Network 2020], state that either cisplatin or 
carboplatin can be used as 1L R/M HNSCC systemic therapy component and the guidelines 
do not favor one platinum agent to another in this situation. Such combination regimens can 
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take advantage of adding pembrolizumab to further potentiate antitumor activity of platinum 
and taxane combination, as shown in preclinical and early clinical studies. 
The intended population of this Phase 4 study represents patients with a high unmet medical 
need considering such patients with incurable disease and combination therapy of 
pembrolizumab with taxanes may provide additional 1L treatment options for R/M HNSCC 
patients, where they can replace 5-FU in the pembrolizumab + chemotherapy regimen per 
KEYNOTE-048 study.
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
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].
PD-1 and its family members are type I transmembrane glycoproteins containing an IgV–
type domain responsible for ligand binding and a cytoplasmic tail responsible for the binding 
of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-
based switch motif. 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 
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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 R/M HNSCC.
2.2.2
Preclinical and Clinical Studies
2.2.2.1
Completed Studies with Pembrolizumab in Head and Neck Cancer
Refer to the pembrolizumab IB for preclinical and clinical study data for pembrolizumab [IB 
Edition 18 2020].
2.2.3
Ongoing Clinical Studies
There is an expansive ongoing research program of clinical studies evaluating 
pembrolizumab in patients with a number of hematological and solid malignancies, including 
HNSCC. The clinical program for HNSCC consists of the completed and ongoing studies for 
recurrent/metastatic disease: KEYNOTE-012, KEYNOTE-055, KEYNOTE-040, 
KEYNOTE-048, LEAP-009, LEAP-010, as well as this study, KEYNOTE-B10.
Completed/Active Clinical Studies of Pembrolizumab in HNSCC
KEYNOTE-012
KEYNOTE-012 is a Phase 1B multicohort study of MK-3475 in participants with advanced 
solid tumors, including 2 cohorts of participants with R/M HNSCC.
Efficacy was evaluated for a subgroup of 174 participants with recurrent and/or metastatic 
HNSCC who progressed on or after treatment with platinum containing chemotherapy and 
cetuximab (n=110) or platinum containing chemotherapy without previous cetuximab 
(n=64). Participants received 10 mg/kg pembrolizumab Q2W (n=53) or 200 mg Q3W 
(n=121).
The major efficacy outcome measures were ORR and DOR; secondary outcome measures 
included PFS and OS. Outcome measures were assessed by BICR using RECIST 1.1. 
Efficacy results for the 2 subgroups of participants (previously treated with platinum 
containing chemotherapy with cetuximab versus without cetuximab) were ORR of 14% 
compared with 20% and similar DOR ≥6 months of 86% and 85%.
The ORR and DOR were similar, irrespective of dosage regimen (10 mg/kg Q2W or 200 mg 
Q3W) or HPV tumor status. For the combined population (n=174) who progressed after 
platinum based chemotherapy regardless of cetuximab, the ORR was 16% (95% CI: 11, 22) 
with a complete response rate of 5%.
The results of KEYNOTE-012, supported by the results of KEYNOTE-055, demonstrate 
consistent and clinically meaningful activity of pembrolizumab 200 mg Q3W in heavily 
pretreated participants with HNSCC. The clinically meaningful response rate, coupled with 
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the durability of response, demonstrates the benefit of pembrolizumab in the treatment of 
platinum-progressed HNSCC [IB Edition 18 2020].
KEYNOTE-055
KEYNOTE-055 is a Phase 2, nonrandomized, single cohort study of pembrolizumab 
(200 mg Q3W) monotherapy in a heavily pretreated population of patients with 
recurrent/metastatic HNSCC who have progressed on prior platinum and cetuximab therapy. 
Results from 171 participants treated with pembrolizumab were presented by Bauml et al 
[Bauml, J., et al 2017]. When confirmed responses were evaluated, the ORR was 16% (CR, 
n=1; PR, n=27; 95% CI: 11% to 23%) with a median DOR of 8 months (range, 2+ to 12+ 
months); the stable disease rate was 19% (n=33; 95% CI: 14% to 26%). Response rates were 
slightly higher in participants that were PD-L1 positive; 18% of participants with CPS ≥1% 
PD-L1 expression responded to pembrolizumab compared with 12% of participants with 
CPS <1% expression. Nonetheless, PD-L1–negative participants responded to 
pembrolizumab at a rate that is clinically meaningful; 6- and 12-month PFS and OS rates 
were relatively similar between PD-L1–negative and PD-L1–positive participants. The 
results presented by Bauml et al [Bauml, J., et al 2017], confirm findings from KEYNOTE-
012 in the recurrent/metastatic HNSCC population; pembrolizumab monotherapy (200 mg 
Q3W) demonstrates consistent and clinically meaningful activity in heavily pretreated 
participants with HNSCC.
KEYNOTE-040
KEYNOTE-040 is an ongoing Phase 3, randomized, active-controlled, open-label study of
pembrolizumab versus the choice of 3 different SOC therapies in participants with R/M
HNSCC. Four hundred and ninety-five participants with R/M HNSCC were randomized 1:1
to receive pembrolizumab 200 mg Q3W or the investigator’s choice of one of the following
therapies chosen prior to randomization: single-agent methotrexate, single-agent docetaxel, 
or single-agent cetuximab. Randomization was stratified by ECOG performance status (0 vs. 
1), HPV status (oropharynx – p16 positive vs. oropharynx – p16 negative or
larynx/hypopharynx/oral cavity HNSCC), and PD-L1 status (strong positive or not; strong
positive was defined as TPS ≥50% PD-L1 testing by IHC). The primary objective of the
study was to evaluate OS in participants with R/M HNSCC treated with pembrolizumab
compared with SOC treatment. Enrollment is closed, but participants are ongoing in the 
study.
The efficacy and safety data from the final analysis were reported, and at the time of the final
analysis, 181 (73%) of 247 patients in the pembrolizumab group and 207 (83%) of 248 
patients in the SOC group had died. The median OS in the ITT population was 8.4 months 
(95% CI 6.4-9.4) with pembrolizumab and 6.9 months (5.9-8.0) with SOC (HR = 0.8, 0.65-
0.98; nominal p=0.0161). In the ITT population, the median DOR was 18.4 months in the 
pembrolizumab group compared with only 5 months for SOC [Cohen, E. E. W., et al 2019].
For participants with a PD-L1 CPS≥1 tumor score, the HR for OS was 0.74 (95% CI 0.58-
0.93; nominal p= 0.0049), with a median survival of 8.7 months (95% CI 6.9-11.4) for
pembrolizumab versus 7.1 months (5.7-8.3) with SOC. In participants whose tumor had 
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PD-L1 TPS ≥50% expression, the HR for death was 0.53 (95% CI 0.35-0.81; nominal 
p=0.0014), and median OS was 11.6 months (95% CI 8.3-19.5) compared with 6.6 months 
(4.8-9.2) for pembrolizumab and SOC, respectively.
Fewer patients treated with pembrolizumab than with SOC had treatment-related AEs (63% 
vs. 84%), as well as higher toxicity AEs (Grade ≥3 treatment-related AEs 13% vs. 36%).
KEYNOTE-048
KEYNOTE-048 is an ongoing Phase 3, randomized, active-controlled, open-label study of
pembrolizumab, or pembrolizumab plus platinum plus 5-FU chemotherapies versus platinum
plus 5-FU plus cetuximab (EXTREME regimen) in participants with 1L R/M HNSCC. A
total of 882 participants with 1L R/M HNSCC were randomized worldwide 1:1:1 between
the 3 arms of the study to examine the efficacy and safety of pembrolizumab (n= 301
participants), or pembrolizumab plus chemotherapy (n= 281 participants) versus SOC with
cetuximab and chemotherapy (n= 300 participants) [Burtness, B., et al 2018] [CSR 
P048V01MK3475 2018]. The primary endpoints of the study are PFS per RECIST 1.1 as 
assessed by BICR, and OS [CSR P048V01MK3475 2018].
Data from the second interim analysis for KEYNOTE-048 were presented at the 2018 ESMO
Congress [Burtness, B., et al 2018]. The cutoff date for this final PFS/interim OS analysis
was 13-JUN-2018, with a minimum follow-up of approximately 17 months. For OS,
pembrolizumab monotherapy was superior to the EXTREME regimen in participants with a
CPS ≥20, HR = 0.61 (95% CI 0.45-0.83, p=0.0007), and yielded a median OS that was
longer with pembrolizumab (14.9 months) than the EXTREME regimen (10.7 months).
Statistical significance was also achieved for pembrolizumab monotherapy in participants
whose tumors had PD-L1 expression of CPS ≥1 with HR = 0.78 (95% CI 0.64-0.96,
p=0.0086) and a median OS of 12.3 months versus 10.3 months in participants receiving the
EXTREME regimen [Burtness, B., et al 2018].
Confirmed ORR for pembrolizumab versus EXTREME was 23% versus 36% for CPS ≥20
with a more durable DOR of 20.9 versus 4.2 months, and 19% versus 35% for CPS ≥1 with a
median DOR of 20.9 versus 4.5 months for CPS ≥1 [Burtness, B., et al 2018].
Pembrolizumab monotherapy had a more favorable toxicity profile compared with the
EXTREME regimen with few treatment-related AEs (58.3% vs. 96.9%), fewer treatment-
related Grade 3 to 5 AEs (16.7% vs. 69.0%), and fewer treatment-related AEs that led to
treatment discontinuation (4.7% vs. 19.9%) [CSR P048V01MK3475 2018].
Data cutoff of the final analysis was 25-FEB-2019 (approximately 25 months after the last
participant was randomized) [CSR P048 2020]. In participants whose tumors had PD-L1
expression, OS results further confirmed the statistically and clinically meaningful results
observed at the second interim analysis, with an OS HR = 0.74 [95% CI: 0.61, 0.90] for CPS
≥1 and HR = 0.58 [95% CI: 0.44, 0.78] for CPS ≥20 [CSR P048 2020]. In the population of 
all participants, there was a clinically meaningful difference in OS when comparing
pembrolizumab plus chemotherapy with standard treatment. The pembrolizumab 
monotherapy group had more responders who achieved a CR and a more durable DOR (22.6 
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vs. 4.5 months) [Rischin, D., et al 2019]. The safety results at the final analysis were similar 
to those observed at the second interim analysis.
At the second interim analysis, pembrolizumab + chemotherapy significantly improved OS in
the total population (HR = 0.77 [95% CI 0.63-0.93]; p=0.00335 [CSR P048V01MK3475 
2018]. Additionally, the safety profiles for pembrolizumab + chemotherapy and the
EXTREME regimen were comparable (95.3% vs. 96.9% treatment-related AEs; 71.0% vs
69.0% treatment-related Grade 3 to 5 AEs; and 22.8% vs 19.9% treatment-related AEs that
led to treatment discontinuation) [CSR P048V01MK3475 2018].
At the final analysis, pembrolizumab + chemotherapy OS results (HR = 0.72 [95% CI: 0.60
0.87] [CSR P048 2020]), further confirmed the statistically significant and clinically 
meaningful OS observed at the second interim analysis. In the population of participants who 
tumors express PD-L1, OS was statistically significant and clinically meaningful in PD-L1 
CPS ≥1 (HR = 0.65 [95% CI: 0.53, 0.80], p=0.00002) and in CPS ≥20 (HR = 0.60 [95% CI: 
0.45, 0.82], p=0.00044) [CSR P048 2020]. Furthermore, in participants whose tumors had 
PD-L1 expression, ORR and median time to response were similar, but the pembrolizumab +
chemotherapy group had more durable DOR of 6.7 versus 4.3 months for CPS ≥1 and 7.1
versus 4.2 months for CPS ≥20 [Rischin, D., et al 2019]. The safety results at the final
analysis were similar to those observed at the second interim analysis.
In summary, for 1L R/M HNSCC, pembrolizumab monotherapy significantly improved OS
over the EXTREME regimen in both the CPS ≥20 and CPS ≥1 populations. Responses to
pembrolizumab were durable with a more favorable toxicity profile compared with the
EXTREME regimen. Pembrolizumab plus chemotherapy improved OS in the total
population and in participants whose tumors had PD-1 expression, with a comparable safety
profile. Therefore, pembrolizumab-based treatment may be considered a new 1L standard of
care for R/M HNSCC.
2.2.4
Information on Other Study-related Therapy
A variety of chemotherapies are used for patients with 1L R/M HNSCC. Early studies 
showed small survival benefits after treatment with cisplatin or methotrexate or 
chemotherapy combinations. In next 2 decades, following this early report from the 
Liverpool consortium, cisplatin, carboplatin, methotrexate, paclitaxel, 5-FU, and their 
various combinations have been evaluated in several Phase 3 studies [Liverpool Head and 
Neck Oncology Group 1990] [Forastiere, A. A., et al 2001] [Forastiere, A. A., et al 1992] 
[Gibson, M. K., et al 2005] [Jacobs, C., et al 1992] [Schornagel, J. H., et al 1995].
The proposed choice of the taxane, paclitaxel, as single-agent SOC chemotherapy is based on 
the 2020 HNSCC NCCN guidelines [National Comprehensive Cancer Network 2020]
recognizing these agents as appropriate treatment options in the first-line setting, input from 
key opinion leaders, and prior precedence in 1L registration trials. In consideration of 
institutional preferences and per NCCN recommendations, paclitaxel will be offered in 2
different doses and dosing schedule: 100 mg/m2 Q1W and 175 mg/m2 Q3W in this study.
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Paclitaxel has been shown in several clinical trials to show clinical efficacy for the treatment 
of R/M HNSCC. The majority of these studies are in mixed populations of 1L and 2L R/M 
HNSCC. In the BERIL-1 study, paclitaxel plus buparlisib was compared versus paclitaxel 
plus placebo for participants with second line R/M HNSCC. Approximately 78 participants 
with second line R/M HNSCC were enrolled in this study and received paclitaxel 80 mg/m2
weekly. ORR was observed to be 14% for the paclitaxel plus placebo arm. For this treatment 
arm, median OS was 6.5 months (5.3-8.8) and median PFS was 3.5 months (2.2-3.7).
Furthermore, there are number of studies investigating the efficacy and safety of taxane plus
platinum regimens in 1L R/M HNSCC setting [National Library of Medicine 2020] [National 
Library of Medicine 2020] [National Library of Medicine 2020] [National Library of 
Medicine 2020] [Guigay, J., et al 2019]. 
The combination of taxanes with checkpoint inhibitors is also currently being evaluated, such 
as in the single-arm, Phase 1/2 PemDoc II study of pembrolizumab plus docetaxel [National 
Library of Medicine 2020].
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.
With the results of the KEYNOTE-048 clinical study demonstrating survival benefit with 
pembrolizumab for 1L R/M HNSCC, and considering that the intended population of this 
Phase 4 study represent patients with a high unmet medical need and incurable disease,
combination therapy of pembrolizumab with carboplatin and taxanes may provide additional 
1L treatment options for R/M HNSCC patients, where they can replace 5-FU in the 
pembrolizumab + chemotherapy regimen per KEYNOTE-048 study.
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
Adult participants with a histologically or cytologically-confirmed R/M HNSCC that is 
considered incurable by local therapies will be enrolled in this study.
Throughout this protocol, the term RECIST 1.1 refers to the adjustment 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 further details.
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Objectives
Endpoints
Primary
Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel
with respect to objective response rate (ORR) 
per RECIST 1.1 as assessed by blinded 
independent central review (BICR).
Objective Response: Complete response 
(CR) or Partial response (PR)
Secondary
Key Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel
with respect to duration of response (DOR) 
per RECIST 1.1 as assessed by blinded 
independent central review (BICR).
DOR: For participants who demonstrate 
confirmed CR or PR, DOR is defined as 
the time from first documented evidence 
of CR or PR until disease progression or 
death due to any cause, whichever occurs 
first.
Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel
with respect to progression-free survival 
(PFS) per RECIST 1.1 as assessed by blinded 
independent central review (BICR).
PFS: The time from first dose to the first 
documented disease progression or death 
due to any cause, whichever occurs first.
Objective: To evaluate the efficacy of 
pembrolizumab + carboplatin + paclitaxel
with respect to overall survival (OS).
OS: The time from first dose to death due 
to any cause.
Objective: To assess the safety and 
tolerability of study intervention with 
pembrolizumab + carboplatin + paclitaxel.

AEs.

Study intervention discontinuation due 
to AEs.
Tertiary/Exploratory
Objective: To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers that 
may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab + 
carboplatin + paclitaxel and other treatments.
Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue.
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Objectives
Endpoints
Objective: To investigate the relationship 
between treatment and PD-L1 as assessed per 
CPS≥1, CPS≥20, CPS≥50 and TPS≥50%, 
using tumor tissue samples.
Objective Response
4
STUDY DESIGN
4.1
Overall Design
This is a nonrandomized, single-arm, multisite, open-label study of intravenous 
pembrolizumab (also known as MK-3475) combined with carboplatin and paclitaxel in 
participants with R/M HNSCC who have not previously received systemic therapy in the 
R/M setting (1L intervention). This Phase 4 study will be conducted in participants who have 
measurable disease per RECIST 1.1 as assessed by BICR, an ECOG performance status of 0 
or 1, and have a tumor that is considered incurable by local therapies.
Approximately 100 participants will be allocated to receive pembrolizumab combined with 
carboplatin and paclitaxel. The study design is shown in Figure 1.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
Participation in this study will be dependent on supplying tumor tissue for PD-L1 testing and 
p16 IHC testing (if HPV status is not already known). The specimen will be evaluated at a 
central laboratory facility for expression status of PD-L1 in a retrospective manner. In 
addition, participation will be dependent on confirmation of measurable disease by BICR at 
baseline.
After allocation, participants will be evaluated with tumor scans to assess response to study 
intervention every 6 weeks from allocation through Year 1, and every 9 weeks after Year 1.
All scans obtained during the study will be submitted to the iCRO for BICR, which will 
assess the scans using RECIST 1.1 (Section 4.2.1.1) for determination of ORR, DOR, and 
PFS. Central Verification of Progression (VOP), or request for iCRO to verify PD, is not 
required.
AE monitoring will be ongoing throughout the study. AEs will be graded in severity 
according to the guidelines outlined in the NCI CTCAE v5.0.
Participants will receive combined treatment with pembrolizumab, carboplatin, and the 
investigator’s choice of paclitaxel dose (paclitaxel 100 mg/m2 Q1W or paclitaxel 175 mg/m2
Q3W) for 6 cycles or until a discontinuation criterion is met. Treatment with pembrolizumab 
will continue for up to 35 cycles, or until a discontinuation criterion (Section 7.1) is met.
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Participants who meet the criteria outlined in Section 6.1.2 may be considered for Second 
Course treatment with up to 17 cycles of pembrolizumab. Carboplatin and paclitaxel will not 
be given in the Second Course (Retreatment) Phase.
After the end of treatment, each participant will be followed for a minimum of 30 days for 
AE monitoring. SAEs will be collected for up to 90 days after the end of treatment or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever 
is earlier. Participants will have post-treatment follow-up for disease status until initiating 
new anticancer treatment, experiencing disease progression, pregnancy, death, withdrawing 
consent, or becoming lost to follow-up.
Survival follow-up will begin following PD or the start of new anticancer treatment, 
whichever occurs first. On Sponsor request, participants may be contacted for survival status 
at any time during the study.
4.2
Scientific Rationale for Study Design
If the safety profile is acceptable and this combination improves ORR, this study could 
support the combination of pembrolizumab with carboplatin and paclitaxel and provide 
additional treatment options for participants with 1L R/M HNSCC.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use ORR as the sole primary endpoint, and DOR, OS, and PFS as secondary 
endpoints. OS has been recognized as the gold standard for demonstration of superiority of a 
new antineoplastic therapy in randomized clinical trials. ORR, DOR and PFS are based on 
RECIST 1.1 criteria as assessed by BICR. ORR, DOR and PFS are acceptable measures of 
clinical benefit for a late stage study that demonstrates superiority of a new antineoplastic 
therapy, especially if the magnitude of the effect is large and the therapy has an acceptable 
risk/benefit profile. The use of BICR and RECIST 1.1 to assess ORR, DOR and PFS is 
typically considered acceptable by regulatory authorities. Scans will be submitted to an iCRO 
and read by independent central review. The final determination of radiologic progression for 
treatment decisions will be based on the local site investigator/radiology assessment, rather 
than central assessment of progression.
RECIST 1.1
RECIST 1.1 will be used when assessing images for efficacy measures. Although the original
RECIST 1.1 publication recommends a maximum of 5 target lesions in total and 2 per organ, 
this protocol has implemented an adjustment to RECIST 1.1 to allow a maximum of 10 target 
lesions in total and 5 per organ, if a larger number of target lesions is needed to adequately 
represent the tumor burden. Refer to Section 8.2.1.5 for additional detail.
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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
Pharmacokinetic Endpoints
No PK endpoints are planned for this study.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.1.5
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.  Finally, MSI may be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
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conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a 
response in tumors that likely reflects an inflamed/immune phenotype. Specific immune-
related gene sets (ie, those capturing interferon-gamma transcriptional pathways) may be 
evaluated and new signatures may be identified. Individual genes related to the immune 
system may also be evaluated (eg, IL-10). MicroRNA profiling may also be pursued as well 
as exosomal profiling.
Proteomics and IHC using blood and/or tumor
Tumor and/or blood samples from this study may undergo proteomic analyses (eg, PD-L1 
IHC). PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate 
with response to pembrolizumab in patients with NSCLC, and an IVD device has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this 
association may also be true in additional cancer types (ie, triple negative breast cancer, head 
and neck, and gastric). Additional tumor or blood-derived proteins may also correlate with 
response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses 
using a variety of platforms that could include but are not limited to immunoassays and 
liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
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4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable.
4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to 
IB, Section 5.2.2)

Population PK analysis showing that both fixed dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.3.1
Starting Dose for This Study
All participants will receive:

Pembrolizumab 200 mg IV Q3W. Pembrolizumab dose reductions are not permitted.
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
Carboplatin AUC 5 mg/mL/min IV Q3W. 

Paclitaxel 100 mg/m2 IV Q1W or paclitaxel 175 mg/m2 Q3W per investigator’s 
choice.
Dose reductions of carboplatin or paclitaxel are permitted per protocol guidelines (see 
Section 6.6.2).
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W for 
approximately 2 years (35 cycles). Participants meeting criteria for Second Course treatment 
with pembrolizumab (Section 6.1.2) may receive an additional 200 mg IV Q3W for 
approximately 1 year (17 cycles).
The maximum dose/exposure of carboplatin allowed in this study is AUC 5 mg/mL/min 
Q3W for 6 cycles. The maximum dose/exposure of the investigator’s choice of paclitaxel is
paclitaxel 100 mg/m2 Q1W on Day 1 and Day 8 (6 cycles) or paclitaxel 175 mg/m2 Q3W on 
Day 1 (6 cycles).
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 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.
Male or female participants with R/M HNSCC that is not suitable for curative treatment with 
local therapies who are at least 18 years of age will be enrolled in this study.
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Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has histologically or cytologically-confirmed diagnosis of R/M HNSCC that is 
considered incurable by local therapies.

Has not had prior systemic therapy administered in the recurrent or metastatic setting. 
Systemic therapy, which was completed more than 6 months prior to providing 
documented informed consent for this study, if given as part of multimodal treatment 
for locally advanced disease, is allowed.

Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx.

Does not have a primary tumor site of nasopharynx (any histology).

Does not have an unknown primary tumor.

Has M1 or Stage IVC disease (presence of distant metastases) if newly-diagnosed 
with HNSCC.
Demographics
2. Is male or female, and at least 18 years of age, at the time of providing documented
informed consent.
Male Participants
3. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 95 days after carboplatin/paclitaxel.

Refrain from donating sperm

PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.

OR

Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
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
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.

Male participants must also agree to use male condom when engaging in any activity 
that allows for passage of ejaculate to another person of any sex.
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies. If the contraception requirements 
in the local label for any of the study interventions are more stringent than the requirements 
above, the local label requirements are to be followed.
Please note that 95 days after carboplatin/paclitaxel is stopped, if the participant is on 
pembrolizumab only, no male contraception measures are needed.
Female Participants
4. 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 post pembrolizumab or 30 days post paclitaxel, or 6 months post 
carboplatin whichever occurs last, 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 
(ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention.

A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours before the first dose of study 
intervention.

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 Appendix 2.
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
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions are
more stringent than the requirements above, the local label requirements are to be 
followed.
Informed Consent
5. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
Additional Categories
6. Has measurable disease per RECIST 1.1 as assessed by BICR. 
Note: Lesions situated in a previously irradiated area are considered measurable if 
progression has been shown in such lesions.
7. Has provided tumor tissue for PD-L1 biomarker analysis from a core or excisional biopsy 
(FNA is not adequate) of a tumor lesion not previously irradiated. Repeat samples may be 
required if adequate tissue is not provided. FFPE tissue blocks are preferred to slides. A 
newly obtained biopsy (within 90 days prior to start of study treatment) is strongly 
preferred, but an archival sample is acceptable.
Note: Details pertaining to tumor tissue submission can be found in the procedures 
manual or laboratory manual.
8. Participants with oropharyngeal cancer must have results from testing of HPV status 
defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point. If 
HPV status was previously tested using this method, no additional testing is required.
Note: If local p16 IHC testing results are not available or cannot be assessed using this 
method, a tumor tissue sample must be submitted for p16 IHC testing at the designated 
central laboratory, and results must be received prior to allocation.
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV 
testing by p16 IHC, as by convention these tumor locations are assumed to be HPV-
negative.
9. Has an ECOG performance status of 0 or 1 assessed within 7 days before initiation of 
study intervention.
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10. Has adequate organ function as defined in the following table (Table 3). Specimens must 
be collected within 7 days prior to the start of study intervention.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)c
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
aCriteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
bCreatinine clearance (CrCl) should be calculated per institutional standard.
cPTT may be performed if the local lab is unable to perform aPTT.
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 disease that is suitable for local therapy administered with curative intent.
2.   Has PD within 6 months of completion of curatively intended systemic treatment for 
locoregionally advanced HNSCC.
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3.   Has a life expectancy of less than 3 months and/or has rapidly progressing disease 
(eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator.
4.   Has a diagnosed and/or treated additional malignancy within 5 years prior to allocation 
with the exception of: curatively treated basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, curatively resected in situ cervical cancer, and curatively resected 
in situ breast cancer. Other exceptions may be considered with Sponsor consultation.
Note: The time requirement for no malignancy for 5 years does not apply to the cancer 
for which a participant is enrolled in the study.
Prior/Concomitant Therapy
5.   Has had radiation therapy (or other nonsystemic therapy) within 2 weeks prior to 
allocation or participant has not fully recovered (ie, ≤Grade 1 or at baseline) from adverse 
events due to a previously administered treatment.
Note: Participants with ≤Grade 2 neuropathy, ≤Grade 2 alopecia, or laboratory values in
Table 3 are an exception to this criterion and may qualify for the study.
Note: If the participant had a major operation, the participant must have recovered 
adequately from the procedures and/or any complications from the operation before
starting study intervention.
6.   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 coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
7.   Has received a live or live-attenuated vaccine within 30 days prior to the first dose of 
study intervention. Administration of killed vaccines are allowed. 
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
8.   Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
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Diagnostic Assessments
9.   Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study intervention.

Corticosteroid use as premedication for allergic reactions (eg, IV contrast), or as a 
prophylactic management of AEs related to the chemotherapies specified in the 
protocol is allowed. The use of physiologic doses of corticosteroids may be approved 
after consultation with the Sponsor.
10. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 7 days prior to first dose of study 
intervention.
11. Has a history of any contraindication or has a severe hypersensitivity to any components 
of pembrolizumab (≥Grade 3) or SOC chemotherapy.
12. 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.
13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
14. Has an active infection requiring systemic therapy.
15. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
16. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
17. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
18. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
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Other Exclusions
19. Has had an allogenic tissue/solid organ transplant.
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 allocated in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be re-screened for eligibility following consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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 (pembrolizumab, carboplatin, and paclitaxel) will be packaged to support 
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
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Table 4
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP
or 
NIMP/
AxMP
Sourcing
Arm 1
Experi
mental
Pembrolizu
mab
Drug
Solution for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Day 1 of 
each cycle 
(35 cycles)
Test 
Product
IMP
Central
Arm 1
Experi
mental
Carboplatin
Drug
Solution for 
Infusion
10 mg/mL
AUC 
5 mg/mL/min
IV 
Infusion
Day 1 of 
each cycle 
(6 cycles)
Test 
Product
IMP
Provided
centrally by 
the Sponsor 
or locally by 
the study site
Arm 1
Experi
mental
Paclitaxel
Drug
Solution for 
Infusion
6 mg/mL
100 mg/m2
IV 
Infusion
Day 1 and 
Day 8 of 
each cycle 
(6 cycles)
Test 
Product
IMP
Provided
centrally by 
the Sponsor 
or locally by 
the study site
Arm 1
Experi
mental
Paclitaxel
Drug
Solution for 
Infusion
6 mg/mL
175 mg/m2
IV 
Infusion
Day 1 of 
each cycle 
(6 cycles)
Test 
Product
IMP
Provided 
centrally by 
the Sponsor 
or locally by 
the study site
AUC = area under the curve; IV = intravenous; Q3W = every 3 weeks
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product/Auxiliary Medicinal Product (NIMP/AxMP) in this table is based on 
guidance issued by the European Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification
of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The initial treatment or first course of pembrolizumab consists of up to 35 treatments, and 
chemotherapy (paclitaxel and carboplatin) consists of up to 6 treatments. 
Note: The number of treatments is calculated starting with the first dose.
These participants may be eligible for Second Course described in Section 6.1.2.
6.1.2
Second Course
All participants who have completed the first course (or stopped for confirmed CR) may be 
eligible for up to an additional 17 cycles of pembrolizumab if there is an investigator-
determined progressive disease (by RECIST 1.1) after initial treatment. This retreatment is 
the Second Course of this study.
Participants may enter the Second Course if all of the following criteria are met:

The participant received pembrolizumab

No new anticancer treatment was administered after the last dose of study 
intervention

The participant meets all of the inclusion criteria and none of the exclusion criteria

The study is ongoing
An objective response or disease progression that occurs during the Second Course for a 
participant will not be counted as an event in the primary efficacy analyses in this study.
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6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Dose Preparation for Pembrolizumab
The dose amount required to prepare the pembrolizumab infusion solution will be based on a 
fixed-dose of 200 mg. Details on preparation and administration of pembrolizumab are 
provided in the Pharmacy Manual. 
Dose Preparation for Carboplatin
Carboplatin AUC 5 mg/mL/min is administered as an IV infusion over 15-60 minutes Q3W 
(Day 1 only) for 6 cycles immediately after paclitaxel or per local treatment guidelines and 
product label. The carboplatin dose should be calculated using Calvert formula (see below). 
Carboplatin dose should not exceed 750 mg.
Calvert Formula: Total Dose (mg) = (target AUC) x (CrCl + 25)
The estimated GFR used in the Calvert formula should not exceed 125 mL/min
Maximum carboplatin dose (mg) = target AUC 5 (mg•min/mL) x (125 + 25) = 5 x
150 mL/min = 750 mg
Dose Preparation for Paclitaxel
Refer to Section 8.1.8.1. Paclitaxel may be administered per local treatment guidelines and 
product label.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
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and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using IRT. There is one study intervention arm. 
Participants will be allocated to pembrolizumab, carboplatin, and an investigator’s choice of
paclitaxel dose (paclitaxel 100 mg/m2 Q1W or paclitaxel 175 mg/m2 Q3W). The 
investigator’s choice of paclitaxel dose will be determined prior to allocation and 
documented in the IRT system.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
Although there is no treatment blinding in this study, sites and participants are
blinded/masked to central testing results for PD-L1 status and biomarker testing.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant's medical record.
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruptions of pembrolizumab.
Administration of pembrolizumab, carboplatin, and paclitaxel will be monitored by the 
investigator or study staff. The total volume of study intervention infused will be compared 
with the total volume prepared to determine compliance with each dose administered.
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6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must 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, and the Sponsor.

All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be 
recorded. All concomitant medications administered during SAEs or ECIs are to be 
recorded. SAEs and ECIs are defined in Section 8.4.

If a participant enters the Second Course, all concomitant medications received within 
30 days before the first dose of Second Course treatment should be recorded. After 
the Second Course Safety Follow-up visit, record all concomitant medications 
received for SAEs and ECIs as defined in Section 8.4.
All diagnostic, therapeutic, or surgical procedures relating to malignancy should be recorded.
Palliative and supportive care is permitted during the course of the study for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the study; study intervention must first be discontinued if the 
participant will have oncologic surgery or radiation therapy for the disease under study.
If participants receive additional anticancer therapies, this will be judged to represent 
evidence of disease progression, and study medication will be discontinued. These 
participants should complete all end of treatment assessments and continue to be followed for 
survival in the follow-up period.
If the investigator determines that a participant requires any of the following prohibited 
medications for any reason during the study intervention period, study intervention must be 
discontinued:

Systemic antineoplastic chemotherapy or biological therapy not specified in this protocol.

Immunotherapy not specified in this protocol (with the exception of denosumab).
Note: Bisphosphonate or denosumab therapy is allowed as long as it is begun at least 
2 weeks prior to allocation. If started after allocation and used for reasons other than for 
the prevention of skeletal-related events, it will be determined to be consistent with 
symptomatic progression of disease and clinical progression will be declared at the time 
followed by discontinuation of study intervention, because bisphosphonate/denosumab is 
used in the treatment of bone metastases.

Investigational agents other than those specified in the protocol.
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
Radiation therapy, for the disease under study or for any reason in the anatomical sites of 
the disease under study.
Note: Discussion with the Sponsor’s Clinical Director is required to permit continuation 
of study intervention in specific circumstances where radiation treatment will not impact 
the study endpoints assessment during the study.

Oncologic surgery, to the disease under study.
Note: Discussion with the Sponsor’s Clinical Director is required, to continue with study 
treatment, if surgery is done for palliative relief of symptoms and does not impact study 
endpoints assessment, during study.
The following treatments/vaccines are prohibited during the study, but would not necessarily 
require study intervention discontinuation:

Live or live-attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study.
Note: Killed vaccines are allowed. 
Note: Any licensed COVID-19 vaccine (including for Emergency use) in a particular
country is allowed 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.
If the investigator determines that a participant requires systemic glucocorticoids in doses 
>10 mg/day prednisone (or its equivalent) for any reason that is not an exception in the list 
below, this is prohibited during the study treatment phase. The investigator must consult the 
Sponsor’s Clinical Director to determine if study intervention may be permitted for cases of 
glucocorticosteroid use that do not fall in the exceptions list below:

Systemic glucocorticoids are prohibited, except when used for the following purposes:
o
For inhaled and/or oral steroids as part of a stable regimen for the treatment of 
asthma/COPD or for an asthma/COPD exacerbation (only short-term oral or IV use 
in doses >10 mg/day prednisone equivalent).
o
To modulate symptoms from an AE that is suspected to have an immunologic 
etiology.
o
For treatment of potential irAEs, as indicated in Table 5. 
o
For the prevention of drug-related emesis.
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o
For use as premedication for chemotherapeutic agents specified in the protocol.
o
To avoid allergic reactions (eg, IV contrast dye).
o
For use as premedication or postmedication to prevent allergic reactions (eg, IV 
contrast dye in CT scans).
o
Brief, limited use (≤7 days) of systemic corticosteroids is permitted when considered 
SOC (eg, for exacerbation of asthma or chronic obstructive pulmonary disease).
o
For chronic systemic replacement doses of steroids (eg, not more than prednisone 
10 mg daily or its equivalent) are permitted during the study, as are local steroid 
injections and topical steroids.
o
Topical or ocular steroid administration, intra-articular joint use, oral steroids less
than or equal to 10 mg prednisone daily (or its equivalent), or for any other non-
parenteral steroid administration.
A short, limited course of steroids or physiologic doses of corticosteroids may be used to 
treat medical conditions during the study after Sponsor notification and consultation.
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4. In the absence of formal clinical drug interaction studies, caution should be 
exercised when administering paclitaxel concomitantly with known substrates or inhibitors of 
the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Caution should be exercised when 
paclitaxel is concomitantly administered with known substrates (eg, midazolam, buspirone, 
felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (eg, 
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, and telithromycin), and inducers (eg, rifampin and carbamazepine) of 
CYP3A4.
Note: A current list of strong/moderate inhibitors of CYP3A4 can be found at the following 
website. This list is not all-inclusive. Any substrates or inhibitors not approved in the US will 
not appear in the list. The investigator should also refer to local approved product labels and 
use their best medical judgment. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInter
actionsLabeling/ucm093664.htm
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.
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6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.6
Dose Modification (Escalation/Titration/Other)
Adverse events will be graded using NCI CTCAE v5.0. If appropriate, the investigator may 
attribute each toxicity event to pembrolizumab, paclitaxel, or carboplatin alone, or to the 
combination of all 3 drugs, and determine whether dose modification of paclitaxel or 
carboplatin is required.
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 5 below. See Section 6.5.1 for 
supportive care guidelines, including use of corticosteroids.
Participants may receive a total of 35 pembrolizumab treatments, 6 carboplatin treatments 
and paclitaxel treatments, that may be given either as a total of 6 treatments (175 mg/m2 on 
Day 1) or 12 treatments (100 mg/m2 on Day 1 and Day 8).
When pembrolizumab is withheld or discontinued, study treatment with chemotherapy 
(carboplatin and paclitaxel) may continue for a total of 6 study treatments or until a 
discontinuation criteria is met, whichever occurs first. If pembrolizumab and carboplatin are 
withheld or discontinued, treatment with paclitaxel alone may continue, if appropriate. If 
pembrolizumab and paclitaxel are withheld or discontinued, treatment with carboplatin alone 
may continue, if appropriate.
When chemotherapy (carboplatin and paclitaxel) is withheld or discontinued, treatment with 
pembrolizumab alone may continue, if appropriate. If carboplatin is withheld or 
discontinued, treatment with pembrolizumab and paclitaxel may continue, if appropriate. If 
paclitaxel is withheld or discontinued, treatment with pembrolizumab and carboplatin may 
continue, if appropriate.
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6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
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 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
   Add prophylactic antibiotics for 
opportunistic infections
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
   Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
Withhold
   Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer antihyperglycemic 
in participants with 
hyperglycemia
   Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
   Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
   Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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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
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 associated 
infusion reaction are provided in Table 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the participant should 
be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h (±30 
minutes) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE)
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks, 21 days of the originally 
scheduled dose and within 42 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for study intervention interruption is to be 
documented in the participant's study record.
6.6.2
Dose Modifications for Standard Treatment Chemotherapy
For dose modifications of carboplatin or paclitaxel, refer to the approved product label.
In general, treatment with carboplatin or paclitaxel will be withheld for drug-related Grade 4 
hematologic toxicities and for nonhematologic toxicity ≥Grade 3 and dose modifications will 
be applied for all subsequent doses. Dose modifications for intolerable Grade 2 drug-related 
AEs may be considered after consultation with the Sponsor.
Dose modifications for hematologic AEs must be based on hematology laboratory tests 
performed on or up to 3 days prior to Day 1 (and on or up to 3 days prior to Day 8 for 
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participants assigned to paclitaxel 100 mg/m2) of the treatment cycle. Treatment-related 
toxicity must resolve to Grade ≤1 or baseline prior to resuming the subsequent cycle, with the 
exception of alopecia, Grade 2 fatigue, endocrine-related AEs requiring treatment or 
hormone replacement, which may be Grade ≤2.
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Participants can have a maximum of 2 dose modifications (if applicable) to each of the 
components of study therapy throughout the course of the study for toxicities. If a participant 
experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended should be followed (dose reduction appropriate 
to the most severe toxicity). Participants who require a third dose modification to any 
particular component will have that agent discontinued.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of 3 agents, all 3 agents should be reduced (if applicable), 
interrupted or discontinued according to the recommended dose modifications.
Participants may have chemotherapy discontinued and continue on pembrolizumab. Similarly 
participants may discontinue pembrolizumab and continue on chemotherapy alone during the 
first 6 cycles, if appropriate.
Chemotherapy may be interrupted for a maximum of 6 weeks (calculated from the omitted
Day 1 dose to the next planned dose and must be within 9 weeks of the previously 
administered Day 1 dose). Sponsor consultation is required to administer paclitaxel and/or 
carboplatin study intervention after a >6-week dose interruption of chemotherapy.
The CTCAE v5.0 must be used to grade the severity of adverse events. All dose 
modifications should be based on the AE requiring the greatest dose modification.
Dose modifications for participants receiving carboplatin are provided in Table 7 and 
Table 8. Please refer to the product insert for further details.
Carboplatin
Carboplatin is contraindicated in the following, and warrants discontinuation of carboplatin
for:

Participants with severe myelosuppression

Participants with severe renal impairment (with CrCl of <30 mL per minute)

Participants with bleeding tumors

Concomitant use with yellow fever vaccine
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
Participants with a history of severe allergic reaction to carboplatin or other 
platinum-containing compounds
Renal function impairment is defined as a decrease in the CrCl below 60 mL/min. In 
participants with impaired renal function, the dosage of carboplatin should be reduced, and 
hematological nadirs and renal function monitored. Please refer to Table 8 for additional dose 
modification guidelines.
HUS is a life-threatening side effect. Carboplatin should be discontinued at the first signs of 
any evidence of micro-angiopathic hemolytic anemia, such as rapidly falling hemoglobin 
with concomitant thrombocytopenia, elevation of serum bilirubin, serum creatinine, blood 
urea nitrogen, or LDH. Renal failure may not be reversible with discontinuation of therapy 
and dialysis may be required.
Participants should be monitored for signs and symptoms of abnormal liver function or portal 
hypertension, which do not obviously result from liver metastases.
Carboplatin dose interruption duration for AEs is as per local product label/local institutional 
guidelines. Dose interruption for chemotherapy is up to a maximum of 6 weeks.
Table 7
Dose Modification Guidelines for Febrile Neutropenia or Documented Infection
Adverse Event
Number of 
Occurrencesb
Treatment Modificationb
Febrile neutropeniaa
Documented infection
1
Reduce dose by 1 DL
The use of growth factors and antibiotics 
should be considered per local standards.
2
Reduce dose by 1 DL
Consider prophylactic antibiotics for 
subsequent cycles.
The use of growth factors should be 
strongly considered per local standards
3
Discontinue carboplatin
ANC=absolute neutrophil count; DL=dose level.
a
ANC <1000/mm3 (1.0 x 109/L) and a single temperature >38.3°C or sustained temperature 
≥38°C for >1 hour.
b
The dose levels for carboplatin are as follows:
Dose Level 0 = AUC 5
Dose Level -1 = AUC 4 (20% decrease)
Dose Level -2 = AUC 3 (20% decrease)
Dose Level 3 = Discontinue
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Table 8
Carboplatin Dose Modifications for Drug-related Adverse Events
Category
Toxicity
Hold 
Carboplatin 
Treatment 
for Grade
Timing for 
Restarting 
Carboplatin 
Treatment
Dose for 
Restarting 
Carboplatin 
Treatmentc
Discontinue 
Carboplatinc
Hematologic
Neutropenia
Grade 3a
Neutrophil count 
resolves to 
≥2,000/mm3
(2.0 x 109/L)
No 
Reduction
*consider 
G-CSF
Toxicity does 
not resolve 
within 6
weeks of 
expected
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
Grade 4a
Neutrophil count 
resolves to 
≥2,000/mm3
(2.0 x 109/L)
Reduce by 
1 DL
*consider 
G-CSF
Toxicity does 
not resolve 
within 
6 weeks of 
expected
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
Thrombocytopenia
Grade 2
Platelet count 
resolves to 
≥100,000/mm3
(100 x 109/L) or 
baseline
No 
reduction
Toxicity does 
not resolve 
within 
6 weeks of 
expected
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
Grade 3-4a
Platelet count 
resolves to 
≥100,000/mm3
(100 x 109/L) or 
baseline
Reduce by 
1 DL
Toxicity does 
not resolve 
within 
6 weeks of 
expected
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
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Category
Toxicity
Hold 
Carboplatin 
Treatment 
for Grade
Timing for 
Restarting 
Carboplatin 
Treatment
Dose for 
Restarting 
Carboplatin 
Treatmentc
Discontinue 
Carboplatinc
Nonhematologic
Creatinine 
Increased
Grade 2-4a
Toxicity 
resolves to 
Grade 0-1
Reduce by 
1 DL
Toxicity does 
not resolve 
within 
6 weeks of 
expected
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
Ototoxicity or 
Sensory 
neuropathy
Grade 2
May continue treatment with carboplatin
Grade 3-4
Discontinue carboplatin
All other 
nonhematologic 
toxicitiesb
Grade 3-4a
Toxicity 
resolves to 
Grade 0-1
Reduce by 
1 DL
Toxicity does 
not resolve 
within 
6 weeks of 
expected
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
Laboratory 
adverse eventb
Grade 4
Toxicity 
resolves to 
Grade 2 or less
Reduce by 
1 DL
Toxicity does 
not resolve 
within 
6 weeks of 
expected 
infusion date 
or if >2 Dose 
Level 
reductions 
exceeded
DL=dose level; G-CSF=Granulocyte Colony-Stimulating Factor.
a Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before 
restarting treatment after Grade 4 drug-related AE.
b Participants with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion. Permanently 
discontinue from agent for persistent Grade 2 adverse reactions for which treatment has been held, and did not recover 
to Grade 0-1 within 12 weeks of the last dose. With investigator and Sponsor agreement, participants with a laboratory 
adverse event still at Grade 2 after 12 weeks may continue in the study only if asymptomatic and controlled.
c The dose levels for carboplatin are as follows:

Dose Level 0 = AUC 5

Dose Level -1 = AUC 4 (20% decrease)

Dose Level -2 = AUC 3 (20% decrease)

Dose Level -3 = Discontinue
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Paclitaxel
Duration of dose interruptions to paclitaxel for AEs is as per local product label/local 
institutional guidelines, and up to a maximum of 6 weeks.
Paclitaxel should not be administered to participants with neutrophil count <1500 cells/mm3
(<1.5 × 109/L), as measured on or up to 3 days prior to Day 1 of the cycle (and on or up to 
3 days prior to Day 8 for participants assigned to paclitaxel 100 mg/m2).
Participants should not be retreated with subsequent cycles of paclitaxel until neutrophils 
recover to a level ≥1500 cells/mm3 (≥1.5 × 109/L) and platelets recover to a level 
≥100,000 cells/mm3 (≥100 × 109/L).
For Grade 4 neutropenia (neutrophil count <500 cells/mm3 or 1.5 × 109/L), delay paclitaxel 
until neutrophil count recovers to ≤Grade 1. Resume paclitaxel at a 20% dose reduction for 
all subsequent cycles, once neutrophil count recovers to ≥1500 cells/mm3
Paclitaxel should not be given to participants with bilirubin >ULN, or to participants with 
AST and/or ALT >1.5 × ULN with concomitant alkaline phosphatase >2.5 × ULN as 
participants with laboratory values above these limits are at increased risk of SAEs (refer to 
local product label).
Hypersensitivity reactions: In order to avoid the occurrence of severe hypersensitivity 
reactions, participants should be premedicated with corticosteroids, antihistamines and 
H2-receptor antagonists, as per local product label guidance. Minor symptoms such as 
flushing, skin reactions, dyspnea, hypotension, or tachycardia do not require interruption of 
paclitaxel therapy. However, severe hypersensitivity reactions, such as hypotension requiring 
treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require 
immediate permanent discontinuation of paclitaxel, aggressive symptomatic therapy should 
be initiated, and the participant should not be challenged with paclitaxel. 
If participants develop significant conduction abnormalities during paclitaxel administration, 
appropriate therapy should be administered and continuous cardiac monitoring (ie, ECG 
monitoring) should be performed during subsequent therapy with paclitaxel.
Additional dose modifications for paclitaxel are provided in Table 9. Please refer to the local
product label/institutional guidelines for further details.
If paclitaxel 100 mg/m2 study intervention is administered on Day 1 and withheld on Day 8 
(ie, for unacceptable toxicity) of a given treatment cycle, then paclitaxel should not be given
at Day 15 of the respective treatment cycle. Instead, paclitaxel should be resumed at Day 1 of 
the subsequent treatment cycle.
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Table 9
Paclitaxel Dose Modifications for Drug-related Adverse Events
Toxicity
Grade
Occurrence
Hold 
Treatment
Dose 
Modification
Treatment 
Discontinuation
Liver 
dysfunction
AST/ALT >2.5 to 
≤5 × ULN and AP 
≤2.5 × ULN, or 
AST/ALT >1.5 to 
≤5 × ULN and AP 
>2.5 to ≤5 × ULN
First 
occurrence
Yes
Per product label 
N/A
AST/ALT >5 × 
ULN and/or AP 
>5 × ULN
Discontinue 
on onset
Yes
N/A
Discontinue on
onset
Peripheral 
Neuropathy
Grade 3, 4
Discontinue 
on onset
Yes
N/A
Discontinue on
onset
Ophthalmic 
adverse 
events+
≥Grade 2
First 
occurrence
Per product 
label
N/A
Consult the 
Sponsor
Oral Mucositis
Grade 3, 4
First 
occurrence
Hold until 
resolved
Per product label
Treatment 
discontinuation 
should be 
considered
Grade 3, 4
Second 
occurrence
Hold until 
resolved
Per product label
Treatment 
discontinuation 
should be 
considered
Third 
occurrence
Yes
N/A
Yes
ALT=alanine aminotransferase; AP=alkaline phosphatase; AST=aspartate aminotransferase; N/A=not 
applicable; ULN=upper limit of normal.
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
Although this is an open-label study, the emergency unblinding call center will have the 
intervention schedule for the study available. The emergency unblinding call center should 
only be used in cases of emergency (see Section 8.1.10). The Sponsor will not provide 
random code/disclosure envelopes or lists with clinical supplies.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled 
follow-up, even if the participant has discontinued study intervention. Therefore, all 
participants who discontinue study intervention prior to completion of the protocol-specified 
treatment period will still continue to be monitored in this study and participate in the study 
visits and procedures as specified in Section 1.3 and Section 8.11.3 unless the participant has 
withdrawn from the study per Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.

Diagnosis of any condition or the need for therapy noted in the exclusion criteria.

The participant has a confirmed positive serum pregnancy test.

Radiographic disease progression outlined in Section 8.2.1.5.
Note: The investigator may elect to continue treatment beyond disease progression after 
Sponsor communication and obtaining informed consent (addendum) from the 
participant.

Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
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
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.

Intercurrent illness that prevents further administration of treatment.

Noncompliance with study intervention or procedure requirements.

New anticancer therapy.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from 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.
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
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.

The Day 8 and Day 15 visits are required for all participants for Cycles 1, 2, 3, and 4 to 
monitor the safety of the participant for the first 4 treatment cycles. However, paclitaxel 
study intervention administration on Day 8 is only applicable to participants assigned to 
receive paclitaxel 100 mg/m2 Q1W. For Cycle 5 and Cycle 6, the Day 8 procedures are 
only applicable to participants assigned to receive paclitaxel 100 mg/m2 Q1W. Per the 
SoA, Cycle 5 and Cycle 6 do not require a Day 15 Visit.
The maximum amount of blood collected from each participant over the duration of the study
will be provided 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 future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
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 
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the participant provides documented informed consent. At the time of intervention allocation, 
site personnel will add the treatment/allocation number to the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
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).
8.1.5
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 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
Medications taken 28 days prior to the first dose of Second Course study intervention will be 
recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up visit (approximately 30 days after the last dose 
of study intervention). In addition, concomitant medications started during the Second 
Course Phase through the Second Course Safety Follow-up visit (approximately 30 days after 
the last dose) should be recorded.
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 intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment/allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
It is strongly preferred that participants receive the first dose of study intervention on the day
of allocation. Study intervention should begin within 3 days of allocation. The order of 
administration of study intervention will be pembrolizumab, followed by paclitaxel, followed 
by carboplatin. 
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual.
8.1.8.1
Timing of Dose Administration
Pembrolizumab: Pembrolizumab 200 mg will be administered prior to paclitaxel and 
carboplatin. Pembrolizumab will be administered on an outpatient basis as a 30-minute IV 
infusion on Day 1 of each 21-day cycle. Sites should make every effort to target infusion 
timing to be as closest to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window of – 5 minutes to +10 minutes is permitted (ie, infusion 
time is 30 minutes: –5 min/+10 min). The Pharmacy Manual contains specific instructions 
for pembrolizumab reconstitution, preparation of the infusion fluid, and administration. After 
Cycle 1 Day 1, pembrolizumab may be administered up to 3 days before or after the
scheduled Day 1 of each subsequent cycle due to administrative reasons.
Paclitaxel: Paclitaxel will be administered after pembrolizumab as an IV infusion over 
3 hours for 6 cycles as per local practice and labels. All participants should be premedicated
with oral or intravenous corticosteroid, antihistamines, and H2-receptor antagonists prior to 
paclitaxel administration according to the approved product label and/or standard practice. 
Additional premedications should be administered as per standard practice. Paclitaxel should 
be completely administered before initiating carboplatin dose.

Paclitaxel (100 mg/m2 Q1W): Paclitaxel will be administered on an outpatient basis on 
Day 1 and Day 8 of each cycle.

Paclitaxel (175 mg/m2 Q3W): Paclitaxel will be administered on an outpatient basis on 
Day 1 of each cycle.
Carboplatin: Carboplatin AUC 5 mg/mL/min will be administered on an outpatient basis on 
Day 1 of each cycle.
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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 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the End of Treatment 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.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
Although there is no treatment blinding in this study, sites and participants are 
blinded/masked to central testing results for PD-L1 status and biomarker testing.
8.1.11
Domiciling
At the discretion of the investigator, participants may report to the CRU the evening prior to 
the scheduled day of study intervention administration and remain in the unit until 24 hours 
postdose. At the discretion of the investigator, participants may be requested to remain in the 
CRU longer.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
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about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.13
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required and is to be:

A newly obtained core, incisional, or excisional biopsy of a tumor lesion, which was not 
previously irradiated
Or

An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the laboratory manual.
The central laboratory will use the tissue sample to ascertain PD-L1 status. PD-L1 status will 
be determined by using the PD-L1 IHC 22C3 pharmDx (Investigational Use Only) diagnostic 
kit. The diagnostic test that will be used to confirm the PD-L1 [TPS or CPS] ≥1 status for 
eligibility is identical to the US FDA-approved Dako PD-L1 IHC 22C3 pharmDx diagnostic 
kit. The PD-L1 IHC 22C3 pharmDx assay kit is currently approved to assess PD-L1 status in 
participants with R/M HNSCC for treatment with pembrolizumab.
The PD-L1 result will be masked to the site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term “scan” refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), or other 
methods as specified in this protocol. 
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and transmission to the iCRO can be 
found in the SIM. Tumor scans (head and neck, chest and abdomen) are strongly preferred to 
be acquired by CT. For the head and neck, abdomen and pelvis, contrast-enhanced MRI may 
be used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. The same scan technique should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the response assessment based on scans. Note: For the purposes of assessing 
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tumor scans, the term “investigator” refers to the local investigator at the site and/or the 
radiological reviewer at the site or at an offsite facility.
Scans should include the head and neck, chest and abdomen, at all timepoints specified in 
Section 1.3. Scans of the brain and pelvis are optional (if clinically indicated). For an 
individual participant, scans should be consistent at all timepoints, (ie, follow-up scans 
should image the same areas as the baseline area, using the same imaging modality).
If brain scans are performed, MRI is preferred; however, CT scans will be acceptable if MRI 
is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain X-rays acquired for 
correlation, should be submitted to the iCRO.
Expedited confirmation of measurable disease based on RECIST 1.1 by BICR at Screening 
will be used to determine participant eligibility. Confirmation by the BICR that the 
participant’s scans show at least 1 lesion that is appropriate for selection as a target lesion per 
RECIST 1.1 is required prior to participant allocation.
All scheduled scans for all study participants will be submitted to the iCRO. In addition, a 
scan that is obtained at an unscheduled time point, for any reason (including suspicion of 
progression or other clinical reason), should also be submitted to the iCRO if it shows 
progression, or if it is used to support a response assessment. All scans acquired within the 
protocol-specified window of time around a scheduled scan visit are to be classified as 
pertaining to that visit.
If a participant has local radiographic progression per RECIST 1.1, but the participant is 
achieving a clinically meaningful benefit, the investigator may decide to continue treatment
beyond progression following Sponsor consultation. If approved by the Sponsor, study 
intervention may continue until the next protocol-specified scan or as specified by the 
Sponsor, until study intervention is discontinued. The Sponsor approval is required prior to 
obtaining informed consent addendum and the next dose of study intervention following 
disease progression. Any confirmatory unscheduled scan following initial documentation of 
disease progression is not required.
8.2.1.1
Initial Tumor Scans
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
allocation. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review screening scans to confirm the participant has measurable 
disease per RECIST 1.1.
The screening scans must be submitted to the iCRO to verify eligibility criteria have been 
met before allocation.
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Bone scans are required at Screening for participants with a history of bone metastases and/or 
for those participants with indicative clinical signs/symptoms such as bone pain or elevated 
alkaline phosphatase levels.
Bone scan refers to imaging methods used to assess bone metastasis. The specific methods 
permitted for this study are described in the SIM. 
If brain scans are required to document the stability of existing metastases, the brain scan
should be acquired during screening. The specific methods permitted for this study are 
described in the SIM.
Tumor scans performed as part of routine clinical management are acceptable for use as 
screening tumor scans if they are of acceptable diagnostic quality and performed within 28 
days prior to the date of allocation and can be assessed by the iCRO.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at Week 6 (+7 days, no earlier than Day 42) 
from the date of allocation. Subsequent tumor scans should be performed every 6 weeks 
(42 days ±7 days) or more frequently if clinically indicated. After 1 year, participants who 
remain on treatment will have scans performed every 9 weeks (63 days ±7 days). Scan timing 
should follow calendar days and should not be adjusted for delays in cycle starts. 
Scans are to be performed until disease progression per RECIST 1.1 is identified by the 
investigator, or until any of these conditions are met:
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
All supplemental scans must be submitted to the iCRO if scans show PD or to support 
response assessments.
Objective response should be confirmed by a repeat scan. Tumor scans to confirm PR or CR 
should be performed at least 4 weeks after the first indication of a response is observed. 
Participants will then return to the regular scan schedule, starting with the next scheduled 
time point. Participants who receive additional scans for confirmation do not need to undergo 
the next scheduled scan if it is less than 4 weeks later; scans may resume at the subsequent 
scheduled time point. 
On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if 
other lesions indicate CR and brain or bone lesions existed at baseline).
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8.2.1.3
End of Treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of allocation, refer to Section 8.2.1.2.
Scans are to be continued until one of the following conditions are met:
•
disease progression as defined by RECIST 1.1 is identified by the investigator (refer to 
Section 8.2.1.5 for the alternative options available to the investigator)
•
the start of a new anticancer treatment
•
pregnancy
•
death
•
withdrawal of consent
•
the end of the study
8.2.1.4
Second Course (Retreatment) Tumor Scans
Tumor scans must be performed within 28 days prior to restarting treatment with 
pembrolizumab. Local reading (investigator assessment with site radiology reading) will be 
used to determine eligibility. All second course scans should be submitted to the iCRO for 
quality control, storage, and possible retrospective review.
The first on-study scan should be performed at 6 weeks (+7 days, no earlier than Day 42) 
after the restart of treatment. Subsequent tumor scans should be performed every 6 weeks 
(42 days ±7 days) in Year 1 and every 9 weeks (63 days ±7 days) thereafter (a 12-weekly 
scan schedule may be implemented after Year 1 following consultation with the Sponsor) or 
more frequently, if clinically indicated.
Scans should continue to be performed until PD per RECIST 1.1 is identified by the 
investigator, the start of a new anticancer treatment, pregnancy, withdrawal of consent, death, 
or notification by the Sponsor, whichever occurs first.
For participants who discontinue Second Course study intervention, tumor scans should be 
performed at the time of intervention discontinuation (±4 week window). If previous scans 
were obtained within 4 weeks prior to the date of discontinuation, then scans at intervention 
discontinuation are not mandatory. For participants who discontinue study intervention due 
to documented disease progression, this is the final required tumor scan.
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For participants who discontinue Second Course study intervention without documented 
disease progression, every effort should be made to continue monitoring their disease status 
by tumor scans every 6 weeks (42 days ±7 days) in Year 1 and every 9 weeks (63 days ±7 
days) thereafter (a 12-weekly scan schedule may be implemented after Year 1 following
consultation with the Sponsor) until either the start of a new anticancer treatment, disease 
progression (per RECIST 1.1 as identified by the investigator), pregnancy, death, or the end 
of the study, whichever occurs first.
8.2.1.5
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used 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.
If disease progression is established by the investigator, the process continues as follows:

investigator judgement will determine action

if the participant is clinically stable and study intervention is to continue, communication 
with the sponsor is required and a reconsent addendum must be signed. In addition, the 
following [is/are] to occur:
-
continue scans per protocol schedule (the next scheduled scan should be ≥4 weeks 
from most recent scan acquired)
-
send scans to iCRO until any of these conditions are met:
◦
the start of a new anticancer treatment
◦
pregnancy
◦
death
◦
withdrawal of consent
◦
the end of the study
For the purpose of this decision process, lack of clinical stability is defined as:

unacceptable toxicity

clinical signs or symptoms indicating clinically significant disease progression

decline in performance status
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
rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in Section 8. 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
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard.
A brief directed physical examination will be conducted by an investigator or medically
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a full physical examination during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examinations are described in Section 1.3. After the 
first dose of study intervention, new clinically significant abnormal findings should be 
recorded as AEs.
A full physical examination will include evaluations of the head, eyes, ears, nose, throat, 
neck, chest (including heart and lungs), abdomen, limbs, skin, and a complete neurological 
examination. Height will be measured at Screening only.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs

Temperature, heart rate, respiratory rate, resting blood pressure and weight will be
assessed.

Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.

Blood pressure and heart rate measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions.

Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, heart rate and respiratory rate.
8.3.3
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 using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.

Triplicate ECG may be performed, at the site investigator’s discretion, if medically 
necessary or clinically indicated.  At each time point when triplicate ECG are required, 
3 individual ECG tracings should be obtained as close as possible in succession, but no 
more than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.
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
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).

For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, 
every attempt should be made to perform repeat assessments until the values return to 
normal or baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the study 
laboratory manual. Refer to Section 1.3 for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.4.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 24 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Pregnancy testing requirements during study treatment and in post-treatment are 
described in Appendix 2.
8.3.5
Performance Assessments
8.3.5.1
Eastern Cooperative Oncology Group Performance Scale
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc.) with Grades 0 to 5.
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators 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 allocation 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 allocation through 30 days following cessation 
of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention allocation through 90 
days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator.

All pregnancies and exposure during breastfeeding, from the time of intervention
allocation through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer 
therapy must be reported by the investigator.

Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
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considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 10.
Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE 
including 
Cancer and 
Overdose
Report if:
- due to protocol-specified 
intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing 
to outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention (eg, 
procedure, washout or run-
in treatment including 
placebo run-in)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event.
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 24 
hours of 
learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
ECI (do not 
require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated 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), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
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with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
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 serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor. 
Events of clinical interest for this study include: 

An overdose of Sponsor's product, as defined in Section 8.5.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
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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.
For this study, an overdose of paclitaxel or carboplatin follow standard of care guideline per 
local package insert.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:

Blood for Genetic Analysis

Blood for RNA Analysis

Blood for ctDNA Analysis

Tumor Tissue
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Laboratory Manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic 
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
The planned genetic analysis sample should be obtained predose 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.
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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
Medical Resource Utilization and Health Economics
All-cause hospitalizations and ED visits must be reported in the eCRF, from the time of 
treatment allocation/randomization through 90 days following cessation of study 
intervention, or 30 days following cessation of study intervention, if the participant initiates 
new anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing documented 
informed consent as part of routine clinical management are acceptable in lieu of a screening 
test if performed within the specified time frame. Screening procedures are to be completed 
within 28 days 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 testing which may be performed up to 28 days 
prior to the first dose of study intervention. After Cycle 1, laboratory samples can be 
collected up to 3 days prior to Day 1 of subsequent cycles.

Evaluation of ECOG is to be performed within 7 days (flexible with a maximum of 
7 days) prior to the first dose of study intervention.

For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 hours prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).

Archival tumor sample collection is not required to be obtained within 28 days prior to 
the first dose of study intervention. Newly obtained tumor tissue may be obtained within 
90 days of treatment initiation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Before a participant is rescreened, the participant must be screen failed in IRT and the 
Sponsor must be consulted. Results from assessments during the initial screening period are 
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acceptable in lieu of a repeat screening test if performed within the specified time frame and 
the corresponding inclusion/exclusion criteria is met. Participants who are rescreened will 
retain their original screening number.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
8.11.3
Participants Discontinued From Study Intervention but Continuing to Be 
Monitored in the Study
The Discontinuation Visit should take place at the time study intervention is discontinued for 
any reason. If the Discontinuation Visit takes place 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, the safety visit is not 
required. All procedures required at the Discontinuation Visit and at the 30-day Safety 
Follow-up Visit should be performed. The Discontinuation Visit may either occur within 
21 days after the last dose of study intervention, or approximately 30 days after the last dose
of study intervention if combined with the 30-Day Safety Follow Visit. The study procedures 
for both visits (notably laboratory tests) should be performed before initiation of new 
anticancer therapy.
8.11.4
Post-treatment Visit
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
Participants who are eligible for a Second Course (retreatment) with pembrolizumab may 
have up to 2 safety follow-up visits, 1 after the Initial Treatment Phase and 1 after the Second 
Course.
8.11.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression or the start of new 
anticancer therapy will begin Efficacy Follow-up and should be assessed as outlined in the 
SoA to monitor disease status. Every effort should be made to collect information regarding 
disease status and record it in the eCRF until the start of new anticancer therapy, disease 
progression, pregnancy, death, end of study (or if the participant begins retreatment with 
pembrolizumab as detailed in Section 6.1.2). 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 (tumor scans) must 
enter Survival Follow-Up.
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Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.1.2 will move from Efficacy Follow-up to Second Course when they 
experience disease progression. Details are provided in the SoA (Section 1.3.2) for 
retreatment with pembrolizumab.
8.11.4.3
Survival Follow-up Contacts
Participants 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. Information regarding poststudy anticancer treatment will be 
collected and recorded in the eCRF if a new anticancer treatment is initiated.
The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter Efficacy 
Follow-up, the first survival follow-up contact will be scheduled 12 weeks after the 
Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).

For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up 
visit has been performed.
8.11.5
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. Changes to 
analyses made after the protocol has been finalized, but prior to final database lock, will be 
documented in an sSAP and referenced in the CSR for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase 4 study to evaluate the efficacy and safety of MK-3475 
plus carboplatin and paclitaxel as first-line treatment of R/M 
HNSCC
Treatment Assignment
Approximately 100 participants will be enrolled. This is a single-
arm, open-label study.
Analysis Populations
Efficacy: All Participants as Treated (APaT)
Safety: APaT
Primary Endpoint(s)
ORR per RECIST 1.1 as assessed by BICR
Secondary Endpoints
DOR per RECIST 1.1 as assessed by BICR
PFS per RECIST 1.1 as assessed by BICR
OS
Statistical Methods for 
Key Efficacy Analyses
The point estimate of ORR will be provided, together with 95% CI 
using exact binomial method proposed by Clopper and Pearson 
(1934) [Clopper, C. J. and Pearson, E. S. 1934].
Statistical Methods for 
Key Safety Analyses
Counts and percentages of participants with AEs will be provided.
Interim Analyses
No efficacy interim analysis is planned in this study. Periodic data 
monitoring per Sponsor medical monitoring process will be 
performed.
Multiplicity
No multiplicity adjustment is planned as there is no hypothesis
testing.
Sample Size and Power 
The planned sample size is approximately 100 participants. Section 
9.9 provides the precision of the ORR estimates.
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 is being conducted as a nonrandomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
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The clinical biostatistics department will generate the allocation schedule(s) for study 
intervention assignment.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
The definitions of ORR, DOR and PFS below apply to the endpoints based on RECIST 1.1. 
Per RECIST 1.1, PR and CR should be confirmed by a repeat tumor scan obtained 4 weeks 
or longer from the date the response was first documented. 
ORR: the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as 
assessed by BICR.
DOR: for participants who demonstrate a confirmed CR or PR, DOR is defined as the time 
from first documented evidence of CR or PR until disease progression per RECIST 1.1 by 
BICR or death due to any cause, whichever occurs first.
PFS: time from the first dose to the first documented disease progression per RECIST 1.1 by 
BICR or death due to any cause.
OS: time from the first dose to death due to any cause.
9.4.2
Safety Endpoints
Safety measurements are described in Section 8.3 and Section 8.4.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The APaT population will be used for the analysis of ORR, PFS and OS. The APaT 
population consists of all allocated participants who received at least one dose of study 
intervention.
The analysis population for DOR consists of all responders.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all allocated 
participants who received at least one dose of study intervention. 
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At least one laboratory, vital sign, or ECG measurement obtained after at least one dose of 
study intervention is required for inclusion in the analysis of the respective safety parameter. 
To assess change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
The efficacy analyses for ORR, DOR and PFS will include responses and documented 
progression events that occur prior to Second Course treatment.
ORR
The point estimate of ORR will be provided, together with 95% CI using exact binomial 
method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, E. S. 1934].
DOR
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier median 
and quartiles. Only the subset of participants who show a confirmed CR or PR will be 
included in this analysis. Censoring rules for DOR are summarized in Table 11. 
For the DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anticancer treatment, have not been determined to be lost to follow-up, 
and have had a disease assessment within approximately 5 months of the data cutoff date are 
considered ongoing responders at the time of analysis. If a participant meets multiple criteria 
for censoring, the censoring criterion that occurs earliest will be applied.
Table 11
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(non-event)
Death or progression immediately
after ≥2 consecutive missed 
disease assessments or after new 
anticancer therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anticancer therapy, if any
Censor
(non-event)
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Situation
Date of Progression or Censoring
Outcome
Death or progression after ≤1 
missed disease assessments and 
before new anticancer therapy, if 
any
PD or death
End of 
response
(Event)
DOR=duration of response; PD=progressive disease.
A missed disease assessment includes any assessment that is not obtained or is considered 
inadequate for evaluation of response. 
PFS
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve. Since 
disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR 
and the date of death. Death is always considered a PD event. Censoring rules for PFS are 
summarized in Table 12.
Table 12
Censoring Rules for PFS
Situation
Date of Progression or Censoring
PD or death documented after ≤1 missed 
disease assessment
Progressed at date of documented PD or 
death
Death or progression after ≥2 consecutive 
missed disease assessments without further 
valid non-PD disease assessments, or after 
new anticancer therapy
Censored at last disease assessment prior to 
the earlier date of ≥2 consecutive missed 
disease assessment and new anticancer
therapy, if any
No PD and no death; new anticancer 
treatment is not initiated
Censored at last disease assessment 
No PD and no death; new anticancer 
treatment is initiated
Censored at last disease assessment before 
new anticancer treatment
PD=progressive disease; PFS=progression-free survival.
OS
The non-parametric Kaplan-Meier method will be used to estimate the OS curve.
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 13.
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Table 13
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
ORR per RECIST 
1.1 by BICR
Summary statistics with 
95% CI using Exact method 
based on binomial 
distribution
APaT
Participants with missing 
data are considered non-
responders
Secondary Analyses
DOR per RECIST 
1.1 by BICR
Summary statistics using 
Kaplan-Meier method
Responders 
in APaT 
population
Censored according to rules 
in Table 11
PFS per RECIST 
1.1 by BICR
Summary statistics using 
Kaplan-Meier method
APaT 
Censored according to rules 
in Table 12
OS
Summary statistics using 
Kaplan-Meier method
APaT 
Censored at the date 
participant last known to be 
alive
APaT=all participants as treated; BICR=blinded independent central review; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response 
Evaluation Criteria in Solid Tumors.
9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to Second Course 
Treatment.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory parameters. The percentage of participants with any AE, a Grade 3-5 AE, 
a drug-related AE, a serious AE, an AE which is both drug-related and serious, an AE which 
is both Grade 3-5 and drug-related, and who discontinued due to an AE will be summarized. 
The number and percentage of participants with increased laboratory toxicity grade shift 
from baseline will also be provided.
9.6.3
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment group for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened, allocated, the primary reasons for screening failure, and the primary reason for 
discontinuation will be displayed. Demographic variables (such as age and gender) and 
baseline characteristics will be summarized either by descriptive statistics or categorical 
tables.
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9.7
Interim Analyses
Periodic data monitoring per Sponsor medical monitoring process will be performed.
The final analysis is to be performed 9 months after the last participant is enrolled. 
Participants will continue to be followed after the final analysis until the overall study ends.
9.8
Multiplicity
No multiplicity adjustment will be applied.
9.9
Sample Size and Power Calculations
In this study, approximately 100 participants with R/M HNSCC will be allocated to receive 
pembrolizumab + carboplatin + paclitaxel. Table 14 shows the two-sided 95% CI for ORR 
with 100 participants for different observed ORR’s based on the exact binomial method 
proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, E. S. 1934].
Table 14
Two-sided 95% CI for ORR with 100 Participants
Number of Observed Responders
ORR Estimate (%)
95% CIa of ORR (%)
30
30
(21.2, 40.0)
35
35
(25.7, 45.2)
40
40
(30.3, 50.3)
45
45
(35.0, 55.3)
50
50
(39.8, 60.2)
CI=Confidence interval; ORR=Objective response rate. 
a Based on the two-tailed exact CI of a binomial proportion.
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of ORR (with a nominal 95% CI) will be estimated and plotted within each category 
of the following classification variables: 

Age category (<65, ≥65 years)

Sex (female, male)

Race (white, all others)

Region (North America, Rest of the World)

ECOG performance status (0, 1)
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
HPV status (positive, negative*)

PD-L1 expression level defined by CPS 1, CPS 20, CPS 50 and TPS 50%, respectively

Investigator’s choice of paclitaxel dose (100 mg/m2 Q1W, 175 mg/m2 Q3W)
* Note: that for primary tumor site outside oropharynx, the convention of negative HPV 
status will be used.
A Forest plot with point estimates and CIs will be produced to assess the consistency of the 
treatment effect across the categories of subgroup variables listed above. If the number of 
participants in a category of a subgroup variable is less than 10% of the APaT population, the 
subgroup analysis will not be performed for this category of the subgroup variable, and this 
subgroup variable will not be displayed in the forest plot.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of Exposure for a participant is defined as the number of cycles and number of days 
for which the participant receives the study intervention. Summary statistics will be provided 
on the extent of exposure for the overall study intervention, and for pembrolizumab, 
carboplatin and paclitaxel separately, 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 laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
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source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.5
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.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
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 signed ICF, 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 
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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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
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 15 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose of 
each study intervention(s) as noted in Section 5.1. The length of time required to 
continue pregnancy testing for each study intervention is as follows:
◦
Pembrolizumab: 120 days
◦
Paclitaxel: 30 days
◦
Carboplatin: 6 months
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
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Table 15
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
White Blood Cell (WBC) count with Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red Blood Cell (RBC) Count 
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)b
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
Bicarbonate or 
Carbon Dioxide (CO2)
Chloride
Phosphorus
Creatininec
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
Calciumd
Alkaline 
phosphatase
Thyroid 
Function Tests
Thyroid-stimulating 
hormone (TSH)
Triiodothyronine (T3)
or FT3 (Free 
Triiodothyronine)
Thyroxine Total 
(T4) or Free 
Thyroxine (FT4)e
Coagulationf
International 
normalized ration 
(INR) or 
Prothrombin Time 
(PT)
Activated Partial 
Thromboplastin Time 
(aPTT) or Partial 
Thromboplastin Time 
(PTT)g
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte 
esterase) by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Tests

Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy test 
(as needed for WOCBP).

Serology (HIV antibody, Hepatitis B surface antigen [HbsAg], and Hepatitis C virus 
antibody [HCV RNA]). (if mandated by local health authority).
NOTES:
a
Absolute Neutrophil Count (ANC) is required at Screening to confirm eligibility. After Screening, absolute or % is 
acceptable per institutional standard.
b
Urea is acceptable if blood urea nitrogen (BUN) is not available as per institutional standard.
c
Glomerular filtration rate (GFR; measured or calculated) or creatinine clearance can be used in place of creatinine.
d
Corrected calcium should be checked for participants with hypoalbuminemia.
e
FT4 is preferred, but T4 is acceptable if FT4 cannot be performed locally.
f
Performed as part of the screening assessment and as clinically indicated for participants taking anticoagulants.
g
PTT may be performed if the local laboratory is unable to perform aPTT.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
    An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
    NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
    NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition
    Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
    Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
    New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
    Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
    Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
    For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”

Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
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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.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
b.   Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.   Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a 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, 
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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.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose
10.3.4
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.
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    There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
    The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
    An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality

Did the Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
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their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
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MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to 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 Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)

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 
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 
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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.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
    Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
    If the EDC tool is not operational, facsimile transmission or secure 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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
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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Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:

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 must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

IUSc

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
    The biology of how drugs/vaccines work
    Biomarkers responsible for how a drug/vaccine enters and is removed by the body
    Other pathways with which drugs/vaccines may interact
    The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3.  Summary of Procedures for Future Biomedical Research3, 4
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.  Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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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
Not applicable.
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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: Abbreviations
Abbreviation
Expanded Term
5-FU
5-fluorouracil
1L
First Line
2L
Second Line
ADL
activities of daily living 
AE
adverse event 
AJCC
American Joint Committee on Cancer Staging Manual
ALT
alanine aminotransferase
APaT
All Participants as Treated
AP
alkaline phosphatase
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
BP
blood pressure
C1D1
Cycle 1, Day 1
CD3
cluster of differentiation 3
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CI
confidence interval
CNS
central nervous system 
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
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
d
Day(s)
D1
Day 1
DILI
drug-induced liver injury
DL
dose level
DNA
deoxyribonucleic acid 
DOR
Duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
ED
emergency department
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
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Abbreviation
Expanded Term
EEA
European Economic Area
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
End of Treatment
EU CTR
European Union Clinical Trials Regulation
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FFPE
formalin-fixed, paraffin embedded
FNA
fine needle aspirate
FSH
follicle stimulating hormone
FT3
free triiodothyronine
FT4
free thyroxine
FU
follow-up
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
GFR
glomerular filtration rate
GI
gastrointestinal
HBsAg
Hepatitis B surface antigen
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
HR
hazard ratio
HRT
hormone replacement therapy
HUS
hemolytic-uremic syndrome
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCRO
imaging clinical research organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
IND
Investigational New Drug 
irAE(s)
immune-related AE(s)
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
mAb
monoclonal antibody
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
NCCN
National Comprehensive Cancer Network
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Abbreviation
Expanded Term
NCI
National Cancer Institute
NIMP
Non-Investigational Medicinal Product
NSCLC
non–small cell lung cancer
NSAIDS
nonsteroidal anti-inflammatory drugs
OP
oropharynx
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based PK
PCL
Protocol Clarification Letter
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q1W
weekly
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
RECIST 1.1
Response Evaluation Criteria In Solid Tumors (update and clarification 1.1)
R/M
recurrent/metastatic
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
SHP-1/2
Src homology 2 domain-containing protein tyrosine phosphatase 1/2
SIM
site imaging manual
SNP
single nucleotide polymorphism
SoA
schedule of activities
SOC
Standard of Care
sSAP
supplemental Statistical Analysis Plan
SUSAR(s)
suspected unexpected serious adverse reaction(s)
TMDD
target-mediated drug disposition
TPS
tumor proportion scoring
ULN
upper limit of normal
US
United States
VOP
verification of progression
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WONCBP
woman/women of nonchildbearing potential
ZAP70
zeta-chain-associated protein kinase
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