Conditions: Head and Neck Neoplasms
Keywords: Head and Neck Squamous Cell Carcinoma Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1) Programmed Cell Death Receptor Ligand 2 (PD-L2) PD1 PD-1 PDL1 PD-L1 PDL2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 804
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the efficacy and safety of pembrolizumab given concomitantly with chemoradiation (CRT) and as maintenance therapy versus placebo plus CRT in participants with locally advanced head and neck squamous cell carcinoma (LA HNSCC). The primary hypothesis is that pembrolizumab in combination with CRT is superior to placebo in combination with CRT with respect to event-free survival (EFS).

Detailed description:

Arms:
arm 1: Participants receive a priming dose of pembrolizumab before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of pembrolizumab and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of pembrolizumab alone as maintenance therapy for a total of 17 cycles of pembrolizumab. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with pembrolizumab. arm 2: Participants receive placebo before initiation of CRT (either accelerated or standard fractionation radiotherapy regimen). During CRT, participants receive 2 doses of placebo and up to 3 cycles of Cisplatin (2 cycles during accelerated and 3 cycles during standard fractionation radiotherapy). Participants also receive up to an additional 14 cycles of placebo alone for a total of 17 cycles of placebo. If cisplatin and/or radiation therapy is discontinued, the participant may continue on treatment with placebo.

Interventions: intervention 1: Pembrolizumab intervention 2: Placebo intervention 3: Cisplatin intervention 4: Accelerated Fractionation (AFX) Radiotherapy intervention 5: Standard Fractionation (SFX) Radiotherapy
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion every 3 weeks (Q3W) intervention 2: Normal saline or dextrose solution administered as an IV infusion Q3W intervention 3: 100 mg/m\^2 administered as an IV infusion Q3W intervention 4: 70 Gray (Gy) given in 35 fractions over 6 weeks intervention 5: 70 Gy given in 35 fractions over 7 weeks

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Randomized Phase III study of pembrolizumab 
given concomitantly with chemoradiation and as 
maintenance therapy versus chemoradiation alone 
in subjects with locally advanced head and neck 
squamous cell carcinoma (KEYNOTE-412)
NCT03040999
21-Nov-2022


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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).
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Randomized Phase III study of pembrolizumab given concomitantly with chemoradiation 
and as maintenance therapy versus chemoradiation alone in subjects with locally advanced 
head and neck squamous cell carcinoma (KEYNOTE-412)
IND NUMBER:  122,325
EudraCT NUMBER:  2016-003934-25
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 14
PROTOCOL AMENDMENT SUMMARY OF CHANGES............................................ 16
1.0
TRIAL SUMMARY.................................................................................................. 19
2.0
TRIAL DESIGN........................................................................................................ 20
Trial Design ........................................................................................................... 20
Trial Diagram........................................................................................................ 21
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es).............................................................. 22
Secondary Objective(s) & Hypothesis(es)........................................................... 22
Exploratory Objectives......................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
Pre-clinical and Clinical Trials ........................................................................... 24
Ongoing Clinical Trials....................................................................................... 24
Rationale to Combine Pembrolizumab with Chemoradiation: Potential 
Activity, Treatment Sequence and Safety........................................................... 26
Rationale................................................................................................................ 28
Rationale for the Trial and Selected Subject Population .................................... 28
Human Papillomavirus (HPV) and p16 expression..................................... 29
Rationale for Dose Selection/Regimen/Modification......................................... 29
Rationale for Pembrolizumab Dosage ......................................................... 29
Rationale for Endpoints ...................................................................................... 30
Efficacy Endpoints....................................................................................... 30
4.2.3.1.1
Primary.................................................................................................. 30
Event-Free Survival........................................................................ 30
4.2.3.1.2
Key Secondary...................................................................................... 31
Overall Survival ............................................................................. 31
Safety ........................................................................................................... 31
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Patient Reported Outcomes (PROs)............................................................. 31
4.2.3.3.1
EORTC QLQ-C30 and EORTC QLQ-H&N35.................................... 31
4.2.3.3.2
EQ-5D................................................................................................... 32
Exploratory Endpoints ................................................................................. 32
Planned Exploratory Biomarker Research................................................... 32
Future Biomedical Research........................................................................ 34
Benefit/Risk ........................................................................................................... 34
5.0
METHODOLOGY ................................................................................................... 34
Entry Criteria........................................................................................................ 34
Diagnosis/Condition for Entry into the Trial...................................................... 34
Subject Inclusion Criteria.................................................................................... 35
Subject Exclusion Criteria .................................................................................. 38
Trial Treatment(s) ................................................................................................ 39
Dose Selection/Modification .............................................................................. 43
Dose Selection (Preparation) ....................................................................... 43
Dose Modification ....................................................................................... 43
5.2.1.2.1
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab ..................................................................................... 44
5.2.1.2.2
Dose Modification and Toxicity Management for Cisplatin................ 49
Cisplatin-Related Toxicity ............................................................. 50
Dose Modification and Toxicity Management Guidelines for 
Cisplatin .................................................................................................. 50
Dose Reductions for Neutropenia .................................................. 50
Dose Reductions for Febrile Neutropenia...................................... 51
Dose Reductions for Thrombocytopenia........................................ 51
Dose Reduction for Renal Toxicity................................................ 51
Dose Reduction for Peripheral Neuropathy ................................... 51
Dose Reduction for Ototoxicity ..................................................... 52
Dose Modification for Other Toxicities......................................... 52
5.2.1.2.3
Dose Modification for Radiotherapy .................................................... 53
Timing of Dose Administration.......................................................................... 53
Pembrolizumab/Placebo .............................................................................. 53
Cisplatin....................................................................................................... 53
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Radiotherapy Regimen (AFX or SFX) ........................................................ 55
5.2.2.3.1
Facility and Equipment......................................................................... 55
5.2.2.3.2
Oral and Dental Check-up .................................................................... 56
5.2.2.3.3
Subject position and data acquisition.................................................... 56
5.2.2.3.4
Volume definition................................................................................. 56
Delineation of the Gross Tumor Volume (GTV)........................... 56
Clinical Target Volumes (CTV)..................................................... 57
5.2.2.3.5
Clinical Target Volume at the Primary Site (CTV_7000).................... 57
5.2.2.3.6
Clinical Target Volume at Involved Nodes (CTV_7000) .................... 57
5.2.2.3.7
Clinical Target Volumes for Regions at Risk of Microscopic 
Tumor Involvement (CTV_5600 or CTV_5000) ................................. 57
5.2.2.3.8
Clinical Target Volumes for Regions at Intermediate Risk 
(CTV_6300 or CTV_6000) - Optional ................................................. 57
5.2.2.3.9
Unilateral Neck Treatment.................................................................... 58
5.2.2.3.10 Delineation of the Planning Target Volume (PTV).............................. 58
5.2.2.3.11 Delineation of Organs at Risk (OAR)................................................... 59
5.2.2.3.12 Planning Organ at Risk Volume (PRV)................................................ 59
5.2.2.3.13 Dose prescription, specification and reporting in the PTV................... 60
5.2.2.3.14 Treatment planning............................................................................... 60
5.2.2.3.15 Treatment verification and accuracy..................................................... 61
5.2.2.3.16 Side effects of head and neck radiotherapy .......................................... 61
5.2.2.3.17 Treatment Interruptions / Modifications............................................... 62
Surgery Guidelines ............................................................................................... 62
Pre-operative Assessment ................................................................................... 62
Surgical Procedure Guidelines............................................................................ 63
Technique of Anesthesia.............................................................................. 63
Technique of Surgical Procedure................................................................. 63
5.3.2.2.1
Endoscopy............................................................................................. 63
5.3.2.2.2
Neck Dissection .................................................................................... 63
5.3.2.2.3
Salvage Resection of the Primary Site.................................................. 64
5.3.2.2.4
Complications After Salvage Procedures And/or Neck Dissections.... 64
Post-operative Care...................................................................................... 64
Pathology Specimen..................................................................................... 64
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Evaluation of Post-Operative Complications............................................... 65
5.3.2.5.1
Timing of Assessment of Complications and Mortality....................... 65
5.3.2.5.2
Identification and grading of complications ......................................... 65
Trial Blinding........................................................................................................ 66
Randomization or Treatment Allocation............................................................ 66
Stratification.......................................................................................................... 66
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 67
Acceptable Concomitant Medications ................................................................ 67
Prohibited Concomitant Medications.................................................................. 67
Rescue Medications & Supportive Care............................................................. 69
Supportive Care Guidelines for Pembrolizumab/Placebo .................................. 69
Supportive Care Guidelines for Cisplatin........................................................... 69
Supportive Care Guidelines for Radiation.......................................................... 69
Diet/Activity/Other Considerations..................................................................... 70
Diet...................................................................................................................... 70
Contraception...................................................................................................... 70
Use in Pregnancy ................................................................................................ 72
Use in Nursing Women....................................................................................... 73
Subject Withdrawal/Discontinuation Criteria................................................... 73
Discontinuation of Treatment ............................................................................. 73
Withdrawal from the Trial .................................................................................. 74
Subject Replacement Strategy............................................................................. 74
Beginning and End of the Trial ........................................................................... 75
Clinical Criteria for Early Trial Termination ................................................... 75
6.0
TRIAL FLOW CHART ........................................................................................... 76
Trial Screening and Treatment 1 (Pembrolizumab/Placebo + CRT).............. 76
Treatment 2 (Pembrolizumab or Placebo Maintenance) and Post-CRT 
Follow-up Year 1................................................................................................... 81
Post-Treatment Efficacy Follow-up Visits.......................................................... 85
7.0
TRIAL PROCEDURES ........................................................................................... 88
Trial Procedures ................................................................................................... 88
Administrative Procedures.................................................................................. 88
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Informed Consent......................................................................................... 88
7.1.1.1.1
General Informed Consent.................................................................... 88
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 89
Inclusion/Exclusion Criteria ........................................................................ 89
Subject Identification Card .......................................................................... 89
Medical History ........................................................................................... 89
Disease Details............................................................................................. 89
Prior and Concomitant Medications Review............................................... 89
7.1.1.6.1
Prior Medications.................................................................................. 89
7.1.1.6.2
Concomitant Medications..................................................................... 90
Post-study Anticancer Therapy Status......................................................... 90
Survival Status ............................................................................................. 90
Assignment of Screening Number............................................................... 90
Assignment of Treatment/Randomization Number..................................... 90
Trial Compliance (Medication/Diet/Activity/Other)................................... 91
Clinical Procedures/Assessments........................................................................ 91
Adverse Event Monitoring........................................................................... 91
12-Lead ECG ............................................................................................... 92
Physical Examination................................................................................... 92
7.1.2.3.1
Full Physical Examination.................................................................... 92
7.1.2.3.2
Directed Physical Examination............................................................. 92
Height, Weight and Vital Signs ................................................................... 92
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 92
Oral and Dental Check-up ........................................................................... 93
Neurological Examination ........................................................................... 93
Audiometric Testing .................................................................................... 93
Fiberoptic Examination and Endoscopy...................................................... 93
Neck Dissection (if Clinically Indicated) .................................................... 94
Laboratory Procedures/Assessments .................................................................. 95
Serum or Urine Pregnancy Test................................................................... 95
Pulmonary Function Test............................................................................. 95
HIV, HBV, HCV Serology.......................................................................... 95
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Laboratory Safety Evaluations (Hematology, Chemistry, Coagulation 
and Urinalysis)............................................................................................. 95
Pharmacokinetic Evaluations....................................................................... 97
Planned Genetic Analysis Sample Collection.............................................. 97
Future Biomedical Research Samples ......................................................... 97
Disease Evaluation.............................................................................................. 98
CT/MRI: Head and Neck, Chest and Upper Abdomen ............................... 98
FDG-PET ..................................................................................................... 98
Assessment for Residual Disease and/or Disease Progression.................... 98
Tumor Tissue Collection................................................................................... 105
Patient Reported Outcomes (PROs).................................................................. 105
Other Procedures............................................................................................... 106
Withdrawal/Discontinuation...................................................................... 106
7.1.7.1.1
Withdrawal From Future Biomedical Research ................................. 106
7.1.7.1.2
Lost to Follow-up................................................................................ 106
Subject Blinding/Unblinding ..................................................................... 107
Calibration of Equipment........................................................................... 107
Domiciling ................................................................................................. 108
Visit Requirements............................................................................................ 108
Screening.................................................................................................... 108
Treatment Period........................................................................................ 109
Post-Treatment Visits................................................................................. 109
7.1.8.3.1
End-of-Treatment Visit....................................................................... 109
7.1.8.3.2
Safety Follow-up Visit........................................................................ 109
7.1.8.3.3
Efficacy Follow-up Visits................................................................... 110
Imaging Follow-Up Visits............................................................ 111
7.1.8.3.4
Survival Follow-up Assessments........................................................ 111
Criteria of Evaluation........................................................................................ 111
Evaluation of Efficacy ............................................................................... 111
Measurability of Tumor Lesions at Baseline............................................. 112
7.1.9.2.1
Definitions .......................................................................................... 112
Methods of Measurements......................................................................... 113
Frequency of Tumor Re-evaluation........................................................... 114
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Date of Event/Progression ......................................................................... 114
Event-Free Survival ................................................................................... 115
Local Regional Control.............................................................................. 115
Distant Metastasis Free Survival ............................................................... 116
Overall Survival......................................................................................... 116
Assessment of Response................................................................................... 116
Measurement of Response......................................................................... 116
Local Failure.............................................................................................. 116
Regional Failure......................................................................................... 116
Locoregional Failure.................................................................................. 117
Distant Failure............................................................................................ 117
Post-CRT Neck Surgery ................................................................................... 117
Neck Dissection ......................................................................................... 117
Salvage Neck Dissection............................................................................ 117
Assessing and Recording Adverse Events ........................................................ 118
Definitions of Medication Error, Misuse, and Abuse....................................... 119
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor........................................................................................................ 119
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 120
Immediate Reporting of Adverse Events to the Sponsor.................................. 120
Serious Adverse Events ............................................................................. 120
Events of Clinical Interest.......................................................................... 121
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 122
Evaluating Adverse Events............................................................................... 122
Sponsor Responsibility for Reporting Adverse Events .................................... 125
TRIAL GOVERNANCE AND OVERSIGHT................................................. 125
Scientific Advisory Committee......................................................................... 125
Trial Steering Committee.................................................................................. 125
Executive Oversight Committee....................................................................... 125
Data Monitoring Committee............................................................................. 125
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 126
Statistical Analysis Plan Summary ................................................................... 126
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Responsibility for Analyses/In-House Blinding ............................................... 128
Hypotheses/Estimation....................................................................................... 128
Analysis Endpoints ............................................................................................. 128
Efficacy Endpoints............................................................................................ 128
Primary: Event-Free Survival (EFS).......................................................... 128
Secondary: Overall Survival (OS) ............................................................. 129
Safety Endpoints ............................................................................................... 129
Patient Reported Outcome (PRO) Endpoints ................................................... 129
Analysis Population ............................................................................................ 129
Efficacy Analysis Population............................................................................ 129
Safety Analysis Population............................................................................... 129
PRO Analysis Population ................................................................................. 130
Statistical Methods.............................................................................................. 130
Statistical Methods for Efficacy Analyses........................................................ 130
Event-Free Survival ................................................................................... 130
Overall Survival......................................................................................... 132
Summary of Efficacy Analysis Methods .......................................................... 132
Statistical Methods for Safety Analyses ........................................................... 132
Statistical Methods for PRO Analyses: EORTC QLQ-C30 & QLQ-H&N35.. 134
Summaries of Demographic and Baseline Characteristics ............................... 135
Interim Analyses ................................................................................................. 135
Efficacy Interim Analyses................................................................................. 135
Safety Interim Analyses.................................................................................... 136
Multiplicity .......................................................................................................... 137
Multiplicity Control for Efficacy Analyses ...................................................... 137
Multiplicity Control for Safety Analyses.......................................................... 139
Sample Size and Power Calculations ................................................................ 140
Subgroup Analyses and Effect of Baseline Factors.......................................... 140
Compliance.......................................................................................................... 141
Extent of Exposure.............................................................................................. 141
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 141
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Investigational Product ...................................................................................... 141
Packaging and Labeling Information ............................................................... 142
Clinical Supplies Disclosure............................................................................... 142
Storage and Handling Requirements................................................................ 143
Discard/Destruction/Returns and Reconciliation ............................................ 143
Standard Policies................................................................................................. 143
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 144
Confidentiality..................................................................................................... 144
Confidentiality of Data ..................................................................................... 144
Confidentiality of Subject Records................................................................... 144
Confidentiality of Investigator Information...................................................... 144
Confidentiality of IRB/IEC Information........................................................... 145
Compliance with Financial Disclosure Requirements..................................... 145
Compliance with Law, Audit and Debarment ................................................. 145
Compliance with Trial Registration and Results Posting Requirements...... 147
Quality Management System............................................................................. 147
Data Management............................................................................................... 147
Publications ......................................................................................................... 148
11.0
LIST OF REFERENCES....................................................................................... 150
12.0
APPENDICES......................................................................................................... 156
Code of Conduct for Clinical Trials.................................................................. 156
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 159
Abbreviations ...................................................................................................... 163
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 167
ECOG Performance Status................................................................................ 168
Calculation of the Glomerular Filtration Rate (GFR) .................................... 169
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1....................... 170
Cisplatin Market Authorization (for sites conducting study in France 
only)...................................................................................................................... 171
Technical Note for the Piecewise Constant Hazard Exponential Survival.... 172
Country-specific Requirements......................................................................... 173
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France-specific Requirements.................................................................... 173
Japan-specific Requirements ..................................................................... 173
13.0
SIGNATURES......................................................................................................... 174
Sponsor's Representative ................................................................................... 174
Investigator.......................................................................................................... 174
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values .................................................... 37
Table 2
Trial Treatments.................................................................................................. 40
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs Associated with Pembrolizumab .................................................. 45
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines .......................................................................................................... 48
Table 5
Dose Levels for Cisplatin.................................................................................... 50
Table 6
Cisplatin Dose Reduction for Renal Toxicity..................................................... 51
Table 7
Dose Modification for Cisplatin – Other Toxicities ........................................... 52
Table 8
RT Dose Parameters ........................................................................................... 55
Table 9
Radiologic Anatomic Boundaries of the Various Neck Node Levels ................ 58
Table 10
Standard Organs at Risk...................................................................................... 59
Table 11
Dose Volume Objectives .................................................................................... 61
Table 12
Endoscopy........................................................................................................... 65
Table 13
Neck Dissection .................................................................................................. 66
Table 14
Salvage Surgery at Primary Site with or Without Reconstruction...................... 66
Table 15
Laboratory Tests ................................................................................................. 96
Table 16
Case Scenarios for Residual Disease at the Primary Tumor Site ....................... 99
Table 17
Case Scenarios for Neck Dissections Completed ≤20 Weeks After 
Completion of CRT With NO Evidence of Clinical or Radiographic 
Progression....................................................................................................... 101
Table 18
Case Scenarios for Neck Dissections Completed ≤20 Weeks After 
Completion of CRT With Evidence of Clinical or Radiographic Progression 102
Table 19
Case Scenarios for Neck Dissections Completed >20 Weeks After 
Completion of CRT.......................................................................................... 103
Table 20
Case Scenarios for Recurrent Disease .............................................................. 104
Table 21
Case Scenarios for Metastatic Disease.............................................................. 104
Table 22
Post-Treatment Follow-up Phase Schedule ...................................................... 110
Table 23
Evaluating Adverse Events............................................................................... 123
Table 24
Censoring Rules for Primary and Sensitivity Analyses of EFS........................ 131
Table 25
Analysis Strategy for Key Efficacy Endpoints ................................................. 132
Table 26
Analysis Strategy for Safety Parameters........................................................... 134
Table 27
Summary of Interim and Final Analyses Strategy for Efficacy........................ 136
Table 28
Summary of Interim Analyses Strategy for Safety........................................... 136
Table 29
Efficacy Boundaries and Properties for EFS Analyses..................................... 138
Table 30
Efficacy Boundaries and Properties for OS Analyses ...................................... 139
Table 31
Product Descriptions......................................................................................... 142
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LIST OF FIGURES
          
Figure 1
Trial Design ........................................................................................................ 21
Figure 2
Post-Chemoradiation Neck Evaluation............................................................... 94
Figure 3
Multiplicity Schema.......................................................................................... 137
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 08 – Global 
amendment
21-NOV-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted 
only in an entity name change and update to the address. Additionally, 
scheduled trial assessments/procedures were modified based on the results of 
the final efficacy analysis.
Amendment 07 – Global
amendment
16-DEC-2020
1) To update the assumptions of the survival distribution of the control arm
based on emerging data from JAVELIN 100; and to update the timing of 
efficacy analysis to allow for additional follow-up of all subjects.
2) To allow imaging assessments to continue for subjects who have not 
experienced an event. Censoring rules have been changed accordingly.
3) Collection of FDG-PET reports and corresponding imaging (CT/MRI) 
reports to fulfill a regulatory request.
Amendment 06 – Global 
amendment
30-SEP-2019
1) To align the protocol-specified criteria for locoregional failure with the 
definition of an event considering that protocol- specified locoregional 
failures are also clinically significant events.  2) Events in patients with 
locally advanced head and neck SCC treated with definitive CRT can occur 
in the absence of radiographic progression per RECIST 1.1 by BICR. 
Therefore, the EFS definition is being revised accordingly to clarify the 
scenarios in which histological confirmation of invasive cancer secondary to 
residual and/or progressive disease fulfills criteria for an event in the 
absence of radiographic progression per RECIST 1.1 by BICR.
Amendment 05 – France-specific 
amendment
06-AUG-2018
To align with Keytruda SmPC and regulatory requirements at French sites.
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Document
Date of Issue
Overall Rationale
Amendment 04 – Global 
amendment
26-APR-2018
Updated guidelines for dose modification to align with the most current label 
and safety information for pembrolizumab.
Amendment 03 – France-specific
amendment
13-APR-2017
Revision of inclusion criteria for creatinine clearance to ensure control and 
management of dose reduction for renal toxicity guidelines per France Health 
Authority request.
Amendment 02 – Global
amendment
26-MAY-2017
Revision of RT dose parameters to ensure standardization and uniformity of 
treatment for study while providing flexibility for global radiation therapy 
practices.
Amendment 01 – Germany-
Specific amendment
28-FEB-2017
Provision of additional guidance on highly effective contraception as described
in CTFG.
Original Protocol
18-NOV-2016
Not Applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 412-08
Overall Rationale for the Amendment:
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. Additionally, scheduled trial assessments/procedures 
were modified based on the results of the final efficacy analysis.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
Title Page
12.1 Code of Conduct for Clinical 
Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent 
an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, 
NJ, USA. This conversion resulted only 
in an entity name change and update to 
the address.
1.0 Trial Summary
Updated the duration of the trial to 7 years.
Updated the trial duration to allow for 
additional follow-up.
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Section # and Name
Description of Change
Brief Rationale
5.2 Trial Treatment(s)
5.12 Beginning and End of the Trial
7.2.1 Definitions of Medication Error, 
Misuse, and Abuse
Study intervention table was updated to add 
IMP/NIMP designations.
Added the definition of end of study for the 
purposes of analysis and reporting. Also, 
added the definition of local start of the study 
when a European Economic Area Member 
State is included.
Added a new section with definitions of 
medication error, misuse, and abuse.
To comply with European Commission 
regulations.
5.3.2.5 Evaluation of Post-Operative 
Complications
Deleted the statement about classification of 
post-operative complications.
All post-operative complications are 
reported and graded in the same way as 
other AEs per CTCAE v4.0.
6.1 Trial Screening and Treatment 1 
(Pembrolizumab/Placebo + CRT)
6.2 Treatment 2 (Pembrolizumab or 
Placebo Maintenance) and Post-CRT
Follow-up Year 1
6.3 Post-Treatment Efficacy Follow-up 
Visits
7.1.4.2 FDG-PET
Updated footnotes “t”, “q”, and “l” in 
Sections 6.1, 6.2, and 6.3, respectively, and 
Section 7.1.4.2 to specify that post-baseline 
FDG-PET or FDG-PET/CT reports are no 
longer required to be collected by the 
Sponsor.
Collection of PET scan reports no longer 
required because the final efficacy 
analysis has been completed.
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Section # and Name
Description of Change
Brief Rationale
6.3 Post-Treatment Efficacy Follow-up 
Visits
7.1.6 Patient Reported Outcomes 
(PROs)
Updated footnote ‘m’ in Section 6.3 and 
added a statement to Section 7.1.6 to indicate 
that since completion of the final efficacy 
analysis, any additional ePROs are no longer 
required to be collected by the Sponsor.
Final efficacy analysis of this endpoint 
has been completed.
12.1 Code of Conduct for Clinical 
Trials
Made minor text updates to include diverse 
and underrepresented groups.
Updated based on inclusion of diverse 
and underrepresented groups (age, race, 
ethnicity, gender, etc.) in global clinical 
studies.
12.10.2 Japan-specific Requirements
Text added to clarify the classification of 
placebo for infusion per Japanese local 
regulations.
Added to clarify the category of drug in 
the clinical trial notification submitting to 
the regulatory authority.
Throughout the document
Minor typographic and administrative 
revisions were made.
Minor clarifications, or corrections in 
spelling or grammatical errors.
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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab or placebo in combination with chemoradiation (CRT)
in subjects with locally advanced HNSCC
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase III
Clinical Indication
Locally advanced head and neck squamous cell carcinoma (LA 
HNSCC)
Trial Type
Interventional
Type of control
Placebo 
Route of administration
Pembrolizumab/Placebo – intravenous
Cisplatin - intravenous
Radiotherapy
Regimen
-
Standard Fractionation (SFX; Gy)
or 
Accelerated Fractionation (AFX; Gy)
Trial Blinding
Double-blind
Treatment Groups
    There are two treatment arms:

Pembrolizumab + CRT

Placebo + CRT
Treatment
Arm 1
Arm 2
Pembrolizumab or 
Placebo
Pembrolizumab
200 mg
Placebo
Cisplatin
100 mg/m2
100 mg/m2
Radiotherapy
AFX
or
SFX
AFX
or
SFX
Number of trial subjects
Approximately 780 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 7 years 
from the time the first subject (or their legally acceptable representative) 
provides documented informed consent until the last participant’s last 
study-related contact.
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Duration of Participation
Each subject will participate in the trial from the time the subject 
provides documented informed consent form (ICF) through the final 
protocol-specified contact.
After a screening phase of 28 days, each subject will be assigned to 
receive trial treatment until an event/disease progression is confirmed, 
unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the 
subject, noncompliance with trial treatment or procedure requirements,
administrative reasons requiring cessation of treatment, or until subject 
has received up to 17 administrations of pembrolizumab/placebo 
(approximately 1 year).  
Eligible subjects will be stratified according to 3 stratification factors 
and will receive a priming dose of pembrolizumab, or placebo followed 
by chemoradiation (CRT) plus 2 doses of pembrolizumab/placebo over 
approximately 8 weeks. After completion of CRT, subjects will receive 
up to a year total (~14 doses) of pembrolizumab/placebo maintenance 
doses. Subjects will be evaluated for neck dissection at 12 weeks post-
CRT. Once trial treatment has completed, subjects will be followed for 
disease assessment.
After the end of treatment, each subject will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described under Section 7.2 of the protocol.
Subjects who discontinue for reasons other than disease progression will 
have post-treatment follow-up for disease status until disease 
progression/an event is confirmed as per Section 8.4.1.1, withdrawing 
consent, or becoming lost to follow-up. All subjects will be followed by 
telephone for overall survival until death, withdrawal of consent or the 
end of the study.
A list of abbreviations used in this document can be found in Section 12.3.
2.0 TRIAL DESIGN
Trial Design
This is a Phase III, randomized, placebo-controlled, double-blind study to determine the 
efficacy and safety of pembrolizumab given concomitantly with chemoradiation (CRT) and 
as maintenance therapy versus placebo plus CRT in subjects with locally advanced head and 
neck squamous cell carcinoma (LA HNSCC) to be conducted in conformance with Good 
Clinical Practices (GCP).
Subjects will be enrolled into the trial by documented informed consent. All subjects will be 
required to provide a sample of their tumor for PD-L1 immunohistochemistry (IHC)
expression by central evaluation. In parallel, sites will locally assess the HPV status and the 
eligibility criteria. Sites will be required to submit tissue samples for PD-L1 testing; 
however, central pathological review for PD-L1 will not be required prior to randomization 
in the trial.
Once a subject is confirmed to be eligible, they will be randomized using the Interactive 
Voice Response System (IVRS). Once randomized, all subjects should be dosed within 
3 days of the randomization date.
Randomization Ratio
1:1
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Approximately 780 eligible subjects will be randomized (1:1; approximately 390 subjects 
each), to either: pembrolizumab 200 mg Q3W (every 3 weeks) plus CRT; or placebo Q3W 
plus CRT (Figure 1 and Table 2).
The study will be stratified by radiotherapy (RT) regimen, tumor site/p16 status, and stage.
Stratification factors are described in Section 5.6.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
This trial will use an independent, external Data Monitoring Committee (eDMC). There will 
be one formal interim analysis for efficacy conducted when approximately 86% of the total 
number of expected event-free survival (EFS) events has been observed in the trial.  See 
Sections 7.3.4 and 8.7 for more details about the eDMC/Interim analysis timing.
There will be one safety review by eDMC when the first 30 subjects have completed CRT.  
In addition to the planned interim analysis, periodic evaluations of safety data will be 
performed by the eDMC. If unanticipated safety issues are identified by the medical review 
team, the study team will request advice from the eDMC who will provide recommendations 
concerning the possible continuation, modification or discontinuation of the study (Section 
7.3).
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Design
AJCC=American Joint Committee on Cancer; CRT=chemoradiotherapy; PD=progressive disease; RT=radiotherapy; 
SFU=survival follow-up.
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
All objectives and hypotheses apply to male/female adult subjects (≥18 years of age) with
LA HNSCC.
Primary Objective(s) & Hypothesis(es)
(1)
Objective:
To compare event-free survival (EFS) in subjects treated with
pembrolizumab in combination with CRT and subjects treated with placebo in 
combination with CRT.
Hypothesis: Pembrolizumab in combination with CRT is superior to placebo in 
combination with CRT with respect to EFS.
Secondary Objective(s) & Hypothesis(es)
(1)
Objective: To compare overall survival (OS) in subjects treated with pembrolizumab 
in combination with CRT and subjects treated with placebo in combination with 
CRT.
Hypothesis: Pembrolizumab in combination with CRT is superior to placebo in 
combination with CRT with respect to OS.
(2)
Objective: To evaluate and compare the safety and tolerability profile of 
pembrolizumab in combination with CRT and subjects treated with placebo in 
combination with CRT.
(3)
Objective: To compare mean change from baseline in Global health status/quality of 
life (QoL) and physical functioning using the EORTC QLQ-C30, and swallowing, 
speech and pain symptoms using the EORTC QLQ-H&N35 in subjects treated with 
pembrolizumab in combination with CRT and subjects treated with placebo in 
combination with CRT.
Exploratory Objectives
(1)
Objective: In subjects treated with pembrolizumab in combination with CRT and 
subjects treated with placebo in combination with CRT, to compare:

Local Regional Control

Distant Metastases Free Survival

Incidence of second Head and Neck and Other Cancers
(2)
Objective: In subjects treated with pembrolizumab in combination with CRT and 
subjects treated with placebo in combination with CRT, to evaluate the relationship:

between genetic variation and clinical outcome

between DNA mutational burden and RNA analysis and clinical outcome
(3)
Objective: To characterize utilities using the EuroQoL EQ-5D.
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(4)
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 in combination with CRT
and other treatments.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab.
Pharmaceutical and Therapeutic Background
Pembrolizumab (previously known as MK-3475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between programmed cell death receptor (PD-1) and its ligands, programmed cell 
death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2).
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells/FoxP3+ regulatory T-cells (Tregs) correlates with improved prognosis and 
long-term survival in solid malignancies such as ovarian, 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 [2] [3].
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 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [4] 
[5].
The structure of murine PD-1 has been resolved [6].  PD-1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable–type (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 CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and Zeta-chain–associated protein kinase (ZAP70), which are involved in the CD3 
T-cell signaling cascade [5] [7] [8] [9]. The mechanism by which PD-1 down-modulates 
T-cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
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regulate an overlapping set of signaling proteins [10] [11]. As a consequence, the PD-1/PD-
L1 pathway is an attractive target for therapeutic intervention.
Pembrolizumab (Keytruda®) has been approved by the FDA for the treatment of melanoma, 
non-small cell lung cancer (NSCLC), and metastatic head and neck squamous cell carcinoma 
(HNSCC), and in the EU for melanoma and NSCLC.  Keytruda® has been approved or is 
under review in many countries for the indications of melanoma, NSCLC, or Hodgkin 
lymphoma. 
Pre-clinical and Clinical Trials
In cultured blood cells from healthy human donors, cancer subjects, and primates 
pembrolizumab strongly enhanced T-lymphocyte immune responses. It potentiated existing 
immune responses only in the presence of antigen and did not specifically activate T-cells.
In addition to interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma 
(IFNγ), levels of other cytokines were found to be modulated by pembrolizumab. 
Using an anti-murine PD-1 analog antibody, PD-1 blockade has been shown to significantly 
inhibit tumor growth in a variety of murine tumor models. In these experiments in mice, anti-
PD-1 therapy was synergistic with chemotherapeutic agents such as gemcitabine and 5-
fluorouracil (5-FU) and combination therapy resulted in increased complete tumor regression 
rates in vivo.
In animal studies (cynomolgus monkeys), it was demonstrated that the systemic exposure to 
pembrolizumab, independently of sex, increased with increasing dose. Systemic exposure for 
the 7-day dosing interval increased after repeated dosing from 40 to 200 mg/kg. Area under 
the concentration-time curve (AUC) for the 7-day dosing interval after one dose appeared to 
be dose-proportional from 0.3 to 200 mg/kg, suggesting dose-independent PK. Terminal half-
life (t½) values from individual animals after repeated IV dosing ranged from 11.8 to 23.7 
days (mean values ranged from 15.7 to 22.3 days) across the doses tested.
In cynomolgus monkeys pembrolizumab was well tolerated with systemic exposure over the 
course of the study and no significant in vivo toxicity was observed. In a 1-month and 6-
month toxicology study, with IV pembrolizumab (up to 200 mg/kg) administered once a 
week and once every other week respectively, up to 200 mg/kg resulted in no adverse 
treatment related effects.
Additionally, in the tissue cross-reactivity study of pembrolizumab with human and monkey 
tissues the expected on-target staining of the membranes of mononuclear leukocytes in both 
species was demonstrated. Off-target cross-reactivity staining was also noted in both species 
but was limited to be considered related to the experimental method artifacts, i.e. tissue 
processing for IHC has well recognized limitations of tissue cross-reactivity studies and, thus 
not considered toxicologically relevant.
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, NSCLC, a number of 
advanced solid tumor indications (including head and neck cancer, HNC) and hematologic 
malignancies. For study details please refer to the IB.
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Trials evaluating pembrolizumab in head and neck cancer have demonstrated clinical activity 
in subjects with R/M disease. KEYNOTE-012 is a Phase 1b study of pembrolizumab in 4 
indications, one of which includes subjects with human papillomavirus (HPV)-negative and 
HPV-positive head and neck cancer. This trial enrolled 2 HNSCC cohorts (Cohorts B and 
B2) for a total 192 subjects with R/M squamous cell carcinoma of the head and neck for 
treatment with single agent pembrolizumab.
The efficacy and safety results after long term follow-up based on pooled data from Cohorts 
B and B2 were presented at ASCO 2016 [12]. Among the 192 subjects with R/M HNSCC 
that were enrolled, 60 subjects in Cohort B were treated at 10 mg/kg every 2 weeks (Q2W) 
and 132 subjects in Cohort B2 were treated at 200 mg Q3W. The last subject was enrolled on
08-OCT-2014 and 32 (17%) subjects were still on treatment as of the 01-SEP-2015 data 
cutoff. Median age was 60 years; 83% of subjects were male; 70% had ECOG (Eastern 
Cooperative Oncology Group) PS (Performance Status) 1; and 61% had received ≥2 
therapies for recurrent disease. ORR (confirmed) was 17.7% (95% CI, 12.6%-23.9%; 7 CRs, 
27 PRs). Median follow-up duration in responders was 12.5 months (range, 8.4-24.4). As of 
the data cutoff, median DOR was not yet reached (range, 1.8+ to 21.8+ months) and
responses were ongoing in 22 (76%) subjects. Responses of ≥6 months and ≥12 months were 
noted in 25 subjects and 4 subjects, respectively. Thirty-three (17%) subjects achieved stable 
disease. ORR was 21.9% (95% CI, 12.5%-34.0%) in HPV-positive subjects and 15.9% (95% 
CI, 10.0%-23.4%) in HPV-negative subjects. Median OS was 8.5 months (95% CI, 6.5-10.5),
compared to the historical OS rate of 6 months for subjects who progress following first line 
treatment. The 6-month PFS rate was 24.9%. Treatment-related AEs (TRAEs) occurred in 
122 (64%) subjects, and 23 (12%) subjects had a Grade 3-4 TRAE. No subjects died due to a 
TRAE. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increases 
were the only Grade 3-4 TRAEs observed in >2 subjects.
KEYNOTE-055 is a Phase 2 study of single agent pembrolizumab (200 mg Q3W) in subjects 
with R/M HNSCC who progressed following treatment with platinum and cetuximab.  
Preliminary results from KEYNOTE-055 were presented at ASCO 2016 [13]. A total of 172 
subjects were enrolled for safety, efficacy, and biomarker analyses. Preliminary analyses 
focused on the first 50 subjects enrolled. Median age was 59 years; 80% of subjects were 
male; and 84% had ≥2 prior lines of therapy for metastatic disease. Median follow-up time at 
the time of the data cutoff was 6.8 months (range, 0-12.1). Thirty-five (70%) subjects
experienced a TRAE, with 6 (12.0%) subjects experiencing a Grade 3-5 TRAE. Two (4%) 
subjects discontinued, and 1 (2%) subject died due to a TRAE. AEs of special immunologic 
interest occurred in 11 (22%) subjects; hypothyroidism (n = 7; all Grade 2) and pneumonitis 
(n = 2, Grade 2; n = 1, Grade 5) were the most common. Nine subjects had a confirmed 
partial response (PR) for an ORR of 18.0% (95% CI 8.6-31.4). Five subjects had ongoing 
responses at the data cutoff. The stable disease rate was 18.0% (n = 9; 95% CI 8.6-31.4).
Preliminary biomarker results from KEYNOTE-012 showed that when tumor and 
inflammatory cells were used to score PD-L1 status, an increase in ORR was observed 
between PD-L1+ versus PD-L1- tumors (P = 0.023); when scoring was restricted to tumor 
cells only, this increase was not seen. Improved PFS (P = 0.026) and OS (P = 0.008) were 
also observed in PD-L1+ versus PD-L1- tumors when scoring was conducted in tumor and 
inflammatory cells, but not tumor cells alone. In summary, inclusion of both tumor cells and 
inflammatory cells in IHC scoring (combined positive scoring, CPS) improves the ability to 
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predict response based on PD-L1 status compared to tumor cells alone (tumor proportion 
scoring, TPS) in subjects with R/M HNSCC. PD-L1 prevalence is unknown in locally 
advanced disease and is under investigation with epidemiology studies. CPS PD-L1 IHC will 
thus be explored as a potential biomarker in this study.  
Rationale to Combine Pembrolizumab with Chemoradiation: Potential Activity, 
Treatment Sequence and Safety
Immune checkpoints that regulate the immune response have led to the development of 
strategies that can be positively exploited to impact T-cell activity and generate clinically 
relevant antitumor activity. Antibodies blocking CTLA-4
(ipilimumab) and PD-1
(pembrolizumab and nivolumab) have been approved for the treatment of advanced 
malignant melanoma and nivolumab has been approved for metastatic NSCLC and clear cell 
renal carcinoma [14] [15] [16]. Pembrolizumab has also been approved for treatment of 
NSCLC; in the US it is indicated for the treatment of subjects with metastatic NSCLC whose 
tumors express PD-L1 as determined by an FDA-approved test and who have disease 
progression on or after platinum-containing chemotherapy. In HNSCC nivolumab has been 
shown to improve OS in subjects who progressed within six months of platinum-based 
therapy [17].
Pembrolizumab was investigated in R/M HNSCC. One hundred and thirty-two subjects with 
advanced HNSCC irrespective of PD-L1 expression or HPV status received a fixed dose of 
200 mg pembrolizumab, intravenously, Q3W. ORR was 25% (20% for the HPV-positive 
subgroup and 27% for the HPV-negative subgroup) [18]. Long-term responders were 
observed in this trial. Pembrolizumab was granted accelerated approval for subjects with
R/M HNSCC with disease progression on or after platinum-containing chemotherapy by 
FDA on 05-AUG-2016.
Pre-clinical investigations as well as initial clinical observations provide a strong rationale
for testing RT and cisplatin as potentiators of immune checkpoint inhibitors. The abscopal 
effect refers to a phenomenon of tumor regression at a site distant from the primary site of 
radiotherapy. Following the report of an abscopal effect in a subject with metastatic 
melanoma treated with RT and ipilimumab, interest in potential synergistic treatment 
combining radiation and immunotherapy have emerged [19]. A series of preclinical 
experiments have further developed the rationale for such combinations. RT has been 
combined with inhibitors of PD-1/PD-L1 pathway in various murine models (melanoma, 
breast, glioblastoma, colon) with an improvement in the tumor growth control and survival of 
the mice compared to single treatment modality [20] [21]. 
Recent evidence has shown that besides their effects on DNA, RT and chemotherapy induce 
immunomodulatory effects that could contribute to their therapeutic efficacy. Both have the 
potential to overcome some of the mechanisms of tumor immune escape [22].
RT used at therapeutic doses as well as some cytotoxic agents induce immunogenic cell 
death and the release of tumor antigens that can effectively prime antigen presenting cells. 
RT and chemotherapy act on the microenvironment to decrease its immunosuppressive 
properties by inducing the release of cytokines and chemokines that have the ability to attract 
T-cells [23]. In addition, radiotherapy may augment the tumor-infiltrating lymphocytes 
(TILs) numbers and broaden their TCR (T-cell receptor) repertoire [24] [25] of cytotoxic 
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effectors cells [26]. RT also increases the expression of PD-L1 on tumor cells, which can 
also explain part of the synergism [27]. 
The effects of RT and chemotherapy on the immune system are a dynamic process. A lot of 
uncertainties remain in regard to the optimal dose, sequencing and timing of each modality to 
be used but the results of the current study will certainly contribute to improve our 
knowledge in this field. 
No benefit of maintenance therapy after CRT in HNSCC has been shown so far; the only trial 
assessing this strategy with lapatinib has been negative [28]. Therefore, there is a huge need 
to identify new treatment strategies that can increase the efficacy of CRT. Preclinical studies 
investigating the sequence of anti-PD-1 treatment in relationship to CRT have not been well 
studied.  However preclinical studies suggesting the importance of immune priming would 
support the notion that administering pembrolizumab prior to CRT may be important. This 
sequence is also consistent with the cetuximab/RT studies, and seems reasonable in the 
absence of robust data. This study will randomize high-risk locally advanced HNSCC
subjects between CRT and CRT plus pembrolizumab. Pembrolizumab will be given 
concomitantly with CRT and continued as maintenance (total duration of pembrolizumab 
treatment approximately 1 year). 
An initial phase IB MSD Investigator Studies Program (MSD ISP) study of pembrolizumab 
in combination with CRT for locally advanced HNSCC has been initiated to evaluate the 
safety and tolerability of pembrolizumab combined with cisplatin and RT. Treatment consists 
of a loading dose of pembrolizumab 200 mg IV given 7 days prior to initiation of CRT and 
continued every 3 weeks during CRT and following completion of CRT [29]. An interim 
safety analysis of the MISP study was presented at the Society for Immunotherapy of Cancer 
(SITC) in NOV-2016. At the time of this interim safety analysis, the study enrolled 27 
subjects with 22 having completed CRT. The most commonly reported AEs (all grades) were 
dysphagia (21 subjects/96%) and anemia (21 subjects/96%). The most commonly reported 
AE Grade 3 and 4 was lymphopenia: 15 subjects/68% and 5 subjects/23%, respectively. The 
acute CRT-related toxicities observed are comparable to other HNSCC CRT studies. The 
investigators concluded combination therapy appears safe and did not significantly limit 
radiation (no treatment delays >5 days) or chemotherapy dosing (3 subjects with dose 
reductions and 6 subjects with dose omissions). Pembrolizumab discontinuation rates due to 
irAEs was low (1 subject discontinued due peripheral motor neuropathy [Grade 2], 1 subject
discontinued due to AST increased [Grade 3]) and are comparable to monotherapy studies. 
No new immunologic safety signals were seen [30]. A per protocol DSMB interim efficacy 
analysis approved this study for continuation. The combination of pembrolizumab with CRT 
in this MSD ISP study supports further investigation into the potential activity and safety of 
this treatment regimen.   
Late responders have been observed with pembrolizumab up to 1 year of treatment in the 
R/M setting supporting the 1-year duration of treatment with pembrolizumab. This study will 
be a placebo-controlled trial to avoid any bias in the comparison between the two treatment 
groups.
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Rationale
Rationale for the Trial and Selected Subject Population
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer 
worldwide with around 600,000 new cases diagnosed per year [31]. The most frequent tumor 
sites of HNSCC are the larynx, the pharynx, and the oral cavity. 
Alcohol and tobacco consumption are the main risk factors for oral cavity, larynx, 
oropharynx, and hypopharynx cancers and account for 75% of HNSCC. The oncogenic 
human papillomavirus (HPV) infection, mainly HPV-16, is an established cause of 
oropharyngeal cancer (tonsils and base of tongue) [33] [34]. Globally, the incidence of HPV-
induced oropharyngeal cancer increases but varies from less than 10% to 70% of all 
oropharyngeal cancers depending on the geographic area, being more frequent in 
industrialized countries. The etiologic role of HPV in other HNSCC sites than oropharynx is 
unclear. 
The treatment choice depends on the location of the primary tumor, the stage of the disease, 
and the expected oncological and functional outcomes. Union for International Cancer 
Control/American Joint Committee on Cancer (UICC/AJCC) early stage (I/II) HNSCC is 
usually treated with single modality therapy, i.e., surgery or RT. The management of locally 
advanced disease (UICC/AJCC stage III/IV) generally requires various combinations of RT, 
surgery, and chemotherapy or cetuximab. The survival rates for all subjects with HNSCC are 
around 70% at 1 year and 40-60% at 5 years. 
The standard of care for locally advanced stage III and IV HNSCC cancers not treated by 
surgery is concomitant CRT with cisplatin (level IA evidence) [35]. The updated meta-
analysis of chemotherapy in combination with radiation therapy (RT) for HNSCC (MACH-
NC) showed that the addition of chemotherapy concomitantly to RT improves the absolute 5-
year survival by 6.5% [36]. Concomitant platinum-based CRT with high-dose-cisplatin (100 
mg/m2 day 1 & 22 & 43) is the SOC in locally advanced HNSCC. The MACH-NC meta-
analysis found a greater benefit for platinum-based chemotherapy as compared with non-
platinum-based CRT regimens [37]. However, the various regimens have not been directly 
compared with each other in adequately powered, randomized trials. Alternative cisplatin 
dosing schedules (e.g., 30 to 40 mg/m2 weekly, 6 mg/m2 daily, or 20 mg/m2 daily for 5 days,
on Weeks 1 and 5) are sometimes used for their better subject tolerance. These alternative 
schedules have not been directly compared to high-dose bolus cisplatin.
Cetuximab combined with RT improves locoregional control (median 24 vs. 15 months) and 
OS (median 49 vs. 29 months) compared to RT alone [38]. However, RT alone is no longer 
considered a standard approach for fit subjects with locoregionally advanced disease and how 
concurrent cetuximab plus RT compares with concurrent cisplatin-based CRT has so far not 
been adequately addressed in a randomized trial.
Combined concurrent treatment with the combination of cisplatin plus cetuximab did not 
appear to offer any advantages compared with concurrent cisplatin alone as reported in the 
randomized RTOG 0522 Phase III trial [39]. 
Altered (accelerated) fractionated RT improves locoregional control and OS when compared 
to once-daily RT as single modality treatment [40]. Accelerated RT combined with 2 courses 
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of high-dose cisplatin (RTOG 0129 trial) or carboplatin/5-Fluoruracil (GORTEC 99-02 trial) 
gave similar outcome compared to conventional CRT (7 weeks + 3 courses of chemotherapy) 
[41] [42]. Thus, both altered (accelerated) fractionation and standard fractionation are 
acceptable options.
In subjects treated with primary CRT, when residual disease in the neck is suspected 12 
weeks after the end of CRT, neck dissection is recommended. 
Around 50% of HNSCC are diagnosed at a locally advanced stage. The 5-year OS rate of 
HPV-negative stage III/IV HNSCC remains low (40-60%). Subjects with HPV-positive 
oropharyngeal cancer have a better prognosis, with the exception of subjects with T4 or N3 
disease for which the 5-year OS is around 50-60% (independently of their age and smoking 
status) [43]. This supports the development of new treatment strategies to improve the 
outcome of subjects’ HPV-negative stage III/IV HNSCC and T4 or N3 HPV-positive 
oropharyngeal cancer [44].
Human Papillomavirus (HPV) and p16 expression
Expression of p16 is highly correlated to HPV in oropharyngeal cancer [45] [46] and the 
strong prognostic impact of p16-IHC for oropharynx cancer has been demonstrated in several 
clinical trials [33] [45] [47] [48]. The prevalence of HPV positivity varies by stage of 
disease, with frequencies in HPV endemic areas reported at 50%-59% in local disease (or 
Stages I/II), 75%-78% in regional disease (or Stages III-IVB) and 67% in distant metastatic 
disease [44] [49].
The recommendations on the scoring and classification p16-IHC have been described 
elsewhere [50] [51] [52]. Strong and uniform p16-staining (both cytoplasmic and nuclear) in 
>70% of cancer cells of basaloid nonkeratinized/partially keratinized oropharyngeal 
carcinoma is classified as p16-positive and can be interpreted as HPV-positive [53].
Data from DAHANCA on laryngeal and hypopharyngeal SCC subjects treated with 
radiotherapy did not show the prognostic value of p16-positivity on the contrary to data 
available for oropharyngeal SCC [54]. Similar data have been presented by G. D’Souza at the 
5th World Congress of the International Academy of Oral Oncology in Sao-Paulo (Brazil) in 
JUL-2015. 
Therefore, tumors outside the oropharynx will be considered HPV-negative regardless of 
p16-staining results, per convention.
Rationale for Dose Selection/Regimen/Modification
Rationale for Pembrolizumab Dosage
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab across all indications and regardless of tumor type. As 
outlined below, this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) 
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
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 pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), 
and three studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 F2 
and KN006). All of these studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5 to 7.5-fold difference in 
exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the 
highest doses studied. Subsequently, flat dose-/exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in
KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for Endpoints
Efficacy Endpoints
4.2.3.1.1 Primary
Event-Free Survival
Event-free survival is a common surrogate endpoint for OS that is used to evaluate the 
efficacy of neoadjuvant and adjuvant cancer therapy and is sometimes used as primary 
endpoint.  See Section 8.4 for the primary and secondary endpoint definitions.
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Event-free survival represents a clinically significant endpoint for subjects with this disease, 
given the morbidity associated with recurrent HNSCC and its potentially devastating impact 
on basic functions such as eating, swallowing, speaking and breathing.  The use of BICR and 
RECIST 1.1 to assess disease progression is typically considered acceptable by regulatory 
authorities. Images will be read by a central imaging vendor blinded to treatment assignment 
to minimize bias in the response assessment. In addition, the final determination of radiologic 
progression will be based on the central assessment of progression, rather than a local site 
investigator/radiology assessment. Real time determination of radiologic progression as 
determined by central review will be communicated to the site. 
4.2.3.1.2 Key Secondary 
Overall Survival
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies. In this study, OS 
will be measured as a key secondary endpoint. The OS endpoint may be potentially 
confounded by subsequent therapy, thus limiting its utility as a primary endpoint.  
Safety
The safety objective of this trial is to evaluate the safety of pembrolizumab in combination 
with CRT in subjects with LA HNSCC. The primary safety analysis will be based on subjects 
who experienced toxicities as defined by Common Toxicity Criteria for Adverse Events 
(CTCAE v4.0). The severity (as CTCAE grade), attribution to drug, time-of-onset, duration, 
resolution and any concomitant medications administered will be recorded. Safety 
parameters to be analyzed include but not limited to overall AEs, SAEs, and laboratory 
changes. 
Patient Reported Outcomes (PROs)
The EORTC QLQ-C30, EORTC QLQ-H&N35, and EuroQoL-5D (EQ-5D) patient reported 
outcomes (PROs) are not pure efficacy or safety endpoints because they are affected by both 
disease progression and treatment tolerability.    
The EORTC QLQ-C30, EORTC QLQ-H&N35, and EQ-5D PROs are to be completed by 
subjects on an electronic tablet at various time points as specified in the Trial Flow Chart, 
beginning with a baseline assessment at cycle 1 until year 5.
4.2.3.3.1 EORTC QLQ-C30 and EORTC QLQ-H&N35
EORTC QLQ-C30 is the most widely used cancer specific health related quality of life
(QoL) instrument, which contains 30 items and measures five functional dimensions 
(physical, role, emotional, cognitive and social), three symptom items (fatigue, 
nausea/vomiting, and pain), six single items (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, and financial impact), and a global health and QoL scale [55].
The EORTC QLQ-H&N35 is in use worldwide as one of the standard instruments for 
measuring QoL in HNC subjects and consists of 7 multi-item scales (pain in the mouth, 
problems with swallowing, senses, speech, social eating, social contact, and sexuality), and 
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11 single-item scales (problems with teeth, mouth opening, dry mouth, sticky saliva, 
coughing, feeling ill, use of analgesics, use of nutritional supplements, use of feeding tube, 
weight gain, and weight loss) [56]. The EORTC QLQ-C30 and EORTC QLQ-H&N35 are 
psychometrically and clinically validated instruments appropriate for assessing QoL in 
subjects with HNC [56] [57]. These instruments have been widely used in Phase III trials of 
subjects with locoregionally advanced HNSCC receiving chemotherapy and radiation [58] 
[59] [60].
Clinically meaningful symptoms for HNSCC subjects have been extensively studied, and 
commonly identified symptoms include problems with swallowing, problems with speech, 
and pain in the mouth [43] [61]. Thus, secondary objectives are to assess mean changes from 
baseline in the global health status/QoL and physical functioning scores from the EORTC 
QLQ-C30, as well as the above-mentioned symptom scores from the EORTC QLQ-H&N35. 
A difference of 10 points on the 100-point EORTC QLQ-C30 and EORTC QLQ-H&N35 
scales either from baseline or between the treatment arms is considered as clinically relevant 
[56] [57].
4.2.3.3.2 EQ-5D
The EQ-5D is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [62]. The 5 health 
state dimensions in the EQ-5D include the following: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. This trial incorporates the 5 level EQ-5D (i.e., EQ-
5D-5L): each dimension is rated on a five-point scale from 1 (no problem) to 5 (unable 
to/extreme problems). The EQ-5D also includes a graded (0 to 100) vertical visual analog 
scale on which the subject rates his or her general state of health at the time of the 
assessment. This instrument has been used extensively in cancer studies and published results 
from these studies support its validity and reliability [63]. 
Exploratory Endpoints
Potential predictive biomarkers (PD-L1, etc.) and immune dynamics (translational research) 
will be evaluated 1) in the subgroup of subjects with oropharyngeal p16-negative or 
larynx/hypopharynx/oral cavity HNC, and 2) the overall population.
Planned Exploratory Biomarker Research
Introduction:  Cancer immunotherapies represent an important and novel class of anti-tumor 
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 subjects. Thus, to aid future subjects, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy as well as determinants of 
adverse events in the course of our clinical trials. These efforts will identify novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, we will collect biospecimens (blood components, tumor material, etc.) to support 
analyses of cellular components (e.g., protein, DNA, RNA, metabolites) and other circulating 
molecules.  Investigations may include but are not limited to:
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Germline (blood) genetic analyses (e.g., SNP analyses, whole exome sequencing, whole 
genome sequencing):  This research will evaluate whether genetic variation within a clinical 
trial population correlates with response to the treatment(s) under evaluation. If genetic 
variation is found to predict efficacy or adverse events, the data might inform optimal use of 
therapies in the subject population. Furthermore, it is important to evaluate germline DNA 
variation across the genome in order to interpret tumor-specific DNA mutations. Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (i.e., 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 (i.e., mutations, methylation status, microsatellite instability etc.). Key 
molecular changes of interest to immune-oncology drug development include (for example) 
the mutational burden of tumors and the clonality of T-cells in the tumor microenvironment. 
Increased mutational burden (sometimes referred to as a ‘hyper-mutated’ state) may generate 
neo-antigen presentation in the tumor microenvironment. To conduct this type of research, it 
is important to identify tumor-specific mutations that occur across all genes in the tumor 
genome. Thus, genome wide approaches may be used for this effort. Note that in order to 
understand tumor-specific mutations; it is necessary to compare the tumor genome with the 
germline genome. Microsatellite instability (MSI) may also be evaluated as this is an 
important biomarker for some cancers (i.e., 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 messenger RNA 
(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 (such as 
those capturing IFNγ transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (e.g., IL-10). 
MicroRNA profiling may also be pursued.
Proteomics and immunohistochemistry (IHC) using blood and/or tumor: Tumor and/or blood 
samples from this study may undergo proteomic analyses (e.g., PD-L1 IHC). PD-L1 protein 
level in tumor sections, assessed by IHC, has been shown to correlate with response to 
pembrolizumab in subjects 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 (i.e., TNBC, H&N 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, liquid chromatography/mass spectrometry. This approach could 
identify novel protein biomarkers that could aid in subject selection for pembrolizumab 
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 enzyme-linked immunoassay 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 
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assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  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 trial) and will only be conducted on specimens from 
appropriately consented subjects. 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 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of Future Biomedical Research are presented in Section 12.2 – Collection and Management 
of Specimens for Future Biomedical Research.
Benefit/Risk
Subjects will receive SOC treatment or SOC treatment plus the addition of a new therapy in 
this clinical trial. It cannot be guaranteed that subjects in clinical trials will directly benefit
from treatment during participation, as clinical trials are designed to provide information 
about the safety and effectiveness of an investigational medicine. However, the SOC 
treatment planned for this trial has proven benefit to the LA HNSCC population.
This study will assess the safety and efficacy of pembrolizumab in combination with CRT in 
subjects with previously untreated, locally advanced head and neck squamous cell 
carcinoma. The benefit of pembrolizumab in combination with CRT in this specific subject 
population is unknown. 
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
Chemotherapy with RT is SOC for subjects with LA HNSCC. Pembrolizumab (Keytruda®) 
has been approved for R/M HNSCC with disease progression on or after platinum-containing 
chemotherapy.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with LA HNSCC who are at least 18 years of age will be enrolled 
in this trial.
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Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have a pathologically proven new diagnosis of squamous cell carcinoma of:
a.
Oropharyngeal p16 positive  
i. T4 (N0-N3), M0; or
ii. N3 (T1-T4), M0
OR
b. Oropharyngeal p16 negative
i. any T3-4 (N0-N3), M0; or
ii. any N2a-3 (T1-T4), M0
OR
c.
Larynx/hypopharynx/oral cavity (independent of p16)
i. any T3-4 (N0-N3), M0; or
ii. any N2a-3 (T1-T4), M0 
Note: Subjects with oral cavity tumors need to have unresectable disease.
Note: Subjects with multiple synchronous tumors are not eligible for the study.
2. Be willing and able to provide documented informed consent for the trial. The subject 
may also provide documented informed consent for Future Biomedical Research. 
However, the subject may participate in the main trial without participating in Future 
Biomedical Research.
3. Have results from (local) testing of HPV status for oropharyngeal cancer defined as 
p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point (please 
see Section 7.1.5, Tumor Tissue Collection for details). If HPV status was previously 
tested using this method, no additional testing is required.
Note: Tumor p16 expression must be evaluated by assessment of IHC analysis with 
CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using
standard protocol. Positive p16 expression is defined as strong and diffuse nuclear 
and cytoplasmic staining in 70% or more of the tumor cells.
Note: HPV stratification in this trial will be performed using local testing of HPV 
status in subjects with oropharynx cancer using the specified method.
Note: If local p16 testing results are not available or cannot be assessed locally by the 
specified method, a tumor tissue sample may be submitted for p16 testing at the 
designated central laboratory.
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.
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4. Have provided tissue for PD-L1 biomarker analysis from a core or excisional biopsy 
(fine needle aspirate [FNA] is not adequate). If an excisional or incisional biopsy has 
been performed, subjects remain eligible for the study provided the residual disease 
meets the staging criteria required for the trial (eg, excisional biopsy of a lymph node 
with residual T4 primary). Prior surgical debulking, including tonsillectomy, for the 
head and neck cancer under study is not allowed.  
Note: Central pathological review for PD-L1 will not be performed before inclusion. 
Formalin-fixed paraffin embedded (FFPE) tumor tissue sample blocks are preferred.
If submitting unstained cut slides, freshly cut slides should be submitted to the testing
laboratory within 14 days from the date slides are cut (details pertaining to tumor
tissue submission can be found in the central laboratory manual).
5. Be ≥18 years of age on day of providing documented informed consent.
6. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions) 
assessed by CT scan or MRI, based on RECIST version 1.1.
7. Be eligible for definitive CRT and not considered for primary surgery based on 
investigator decision.
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 
or 1 performed within 10 days of treatment initiation.
9. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial treatment. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required. 
10. Female subjects of childbearing potential (Section 5.9.2) must be willing to use an 
adequate method of contraception, as outlined in Section 5.9.2 Contraception, for the 
course of the study through 180 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
11. Male subjects of childbearing potential (Section 5.9.2) must agree to use an adequate 
method of contraception, as outlined in Section 5.9.2 - Contraception, starting with 
the first dose of study therapy through 180 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
12. Demonstrate adequate organ function as defined in Table 1. All screening labs should 
be performed within 10 days prior to treatment initiation and assessed prior to 
randomizing the subject. If a screening lab does not meet eligibility criteria and is 
repeated and assessed on Day 1 prior to randomization and the Day 1 lab meets 
eligibility criteria, the subject is eligible, i.e., the Day 1 lab result will be used for 
eligibility.  Labs performed within 10 days of treatment initiation during screening do 
not need to be repeated at Treatment 1: Cycle 1, Day 1 unless clinically indicated.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1.5 x 109/L 
Platelets
≥100 x 109/L
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L. Subjects are eligible if 
levels are reached after blood transfusion.
Renal
Measured or calculated creatinine 
clearancea
(GFR can also be used in place of 
CrCl)
≥60 mL/min 
Calcium (corrected for albumin)
≤11.5 mg/dL or ≤2.9 mmol/L
Hepatic
Total bilirubinb
≤1.5xULN or
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels >1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULN 
Coagulation
International Normalized Ratio (INR) 
or Prothrombin Time (PT)
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
Activated Partial Thromboplastin 
Time (aPTT) or Partial 
Thromboplastin Time (PTT)c
≤1.5xULN unless subject 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); ANC=absolute neutrophil 
count; aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum glutamic 
oxaloacetic transaminase); CrCl=creatinine clearance; GFR=glomerular filtration rate; INR=international 
normalized ratio; PT=prothrombin time; PTT=thromboplastin time; ULN=upper limit of normal.
a.
It is preferable for creatinine clearance to be calculated using the Cockcroft-Gault formula (see Appendix 
12.6) but may be done per local institutional standard. The formula used to calculate creatinine clearance 
should be the same and consistent for all subjects at the site.
b.
For subjects with Gilbert's disease, total bilirubin may be >1.5 x ULN; however, direct bilirubin must be 
normal.
c.
PTT may be performed if the local lab is unable to perform aPTT.
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Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has current participation or treatment with an investigational agent or use of an 
investigational device within 4 weeks of the first dose of trial treatment.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with 
an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, 
CD137 or other immune checkpoint inhibitors) or has previously participated in MSD
MK-3475 clinical trials. 
3. Has received a live vaccine within 30 days prior to the first dose of study treatment.
4. Has cancer outside of the oropharynx, larynx, hypopharynx or oral cavity, such as 
nasopharyngeal, sinus, other para-nasal, or other unknown primary HNC.
5. Has had prior systemic therapy, targeted therapy, radiotherapy treatment or radical 
surgery for the head and neck cancer under study.
6. Has Grade ≥2 audiometric hearing loss. Note: Audiometric abnormalities without 
corresponding clinical symptoms of Grade ≥2 hearing loss will not be grounds for 
exclusion.
7. Has Grade ≥2 neuropathy.
8.
Has Grade 3-4 bleeding due to the underlying malignancy.
9. If subject has received major surgery, and the subject has not recovered adequately 
from the toxicity and/or complications from the intervention prior to starting trial 
treatment.
10. Has known active Hepatitis B (e.g., HBsAg reactive) or C (e.g., HCV RNA 
[qualitative] is detected).
11. Has known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. Corticosteroid use as pre-medication for allergic reactions (e.g., IV 
contrast) or as a prophylactic management of adverse events related to the 
chemotherapies specified in the protocol is allowed. A short course of steroids may be 
used as concomitant medication for either treatment of an adverse event or medical 
condition with Sponsor approval.  
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
14. Has an active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e.,
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.
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15. Has history of a diagnosed and/or treated hematologic or primary solid tumor 
malignancy, unless in remission for at least 5 years prior to randomization. A T1-2 
prostatic cancer Gleason score ≤6, superficial bladder cancer, non-melanomatous skin 
cancer or carcinoma in situ of the cervix is eligible. Other exceptions may be 
considered with Sponsor consultation.
16. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
17. Has had previous allogeneic tissue/solid organ transplant.
18. Has active infection requiring systemic therapy.
19. Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema, 
hypotension, bronchospasm, angioedema or anaphylaxis) to pembrolizumab, cisplatin 
or radiotherapy or their analogs.
20. Is a female subject who is pregnant or breast feeding or expecting to conceive or a 
male expecting to father children within the projected treatment phase of the trial, 
starting with the screening visit through 180 days after the last dose of trial treatment.
21. Have severe comorbidities that, in the opinion of the Investigator, might hamper 
participation in the study and/or the treatment administration.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate in the opinion of the treating investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
Trial Treatment(s)
The treatment(s) to be used in this trial are outlined below in Table 2.
Country-specific differences are noted in Section 12.10.
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Table 2
Trial Treatments
Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experi-
mental
Pembrolizumab
Biological/
Vaccine
Solution 
for Infusion
100 mg/
4 mL
200 mg
IV Infusion
Day 1 of each 3-
week (Q3W) cycle 
up to 17 doses (in 
Treatment 1 and 
Treatment 2 Phases)
Test 
Product
IMP
Central 
Sponsor
Arm 1
Experi-
mental
Cisplatin
Drug
Solution 
for Infusion
1 mg/mL
100 
mg/m2
IV Infusion
Cycle 1, Day 8; 
Cycle 2, Day 8; and 
Cycle 3, Day 8 of 
Treatment 1 Phase
(Cycle 3, Day 8 
only applies for 
SFX RT regimen)
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor 
or locally 
by the site
Arm 1
Experi-
mental
Radiotherapy:
Accelerated 
Fractionation 
(AFX)
OR
Standard 
Fractionation 
(SFX)
Radiation
N/A
2 Gy/
fraction
70 Gy
Accelerated 
Fractionation 
(AFX)
OR
Standard 
Fractionation 
(SFX)
6 weeks (35 
fractions; [5 
fractions on final 
week])
Study Weeks 2 
through 7
OR
7 weeks (35 
fractions)
Study Weeks 2 
through 8
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
locally by 
the site
Arm 2
Placebo 
Comparator
Placebo
Other
Solution 
for Infusion
N/A
N/A
IV Infusion
Day 1 of each 3-
week (Q3W) cycle 
up to 17 doses (in 
Treatment 1 and 
Treatment 2 Phases)
Placebo
IMP
Provided 
locally by 
the site
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Arm 
Name
Arm Type
Intervention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Active 
Comparator
Cisplatin
Drug
Solution 
for Infusion
1 mg/mL
100 
mg/m2
IV Infusion
Cycle 1, Day 8; 
Cycle 2, Day 8; and 
Cycle 3, Day 8 of 
Treatment 1 Phase
(Cycle 3, Day 8 
only applies for 
SFX RT regimen)
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor 
or locally 
by the site
Arm 2
Active 
Comparator
Radiotherapy:
Accelerated 
Fractionation 
(AFX)
OR
Standard 
Fractionation 
(SFX)
Radiation
N/A
2 Gy/
fraction
70 Gy
Accelerated 
Fractionation 
(AFX)
OR
Standard 
Fractionation 
(SFX)
6 weeks (35 
fractions; [5 
fractions on final 
week])
Study Weeks 2 
through 7
OR
7 weeks (35 
fractions)
Study Weeks 2 
through 8
Back-
ground 
Treatment
NIMP/
AxMP
Provided 
locally by 
the site
IMP=investigational medicinal product; IV=intravenous.; N/A=not applicable; NIMP/AxMP=noninvestigational/auxiliary medical product.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the 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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Notes:

A pembrolizumab or placebo priming dose will be administered one week prior to the start of CRT, followed by 2 pembrolizumab 
or placebo infusions during CRT, and then continued for an additional 14 doses of pembrolizumab or placebo after CRT for a total 
number of pembrolizumab or placebo infusions of 17 (total duration of pembrolizumab/placebo is 1 year).

If pembrolizumab/placebo and cisplatin are delayed for reasons such as toxicity, when they are resumed, they may be administered 
on the same day if they were given more than 21 (±3) days since the last dose for both study medications.

It is recommended that cisplatin start on the first day of RT (±2 days). Follow local product label and institutional guidelines (for 
France only: see Section 12.8). Cisplatin will not be administered after completion of RT (AFX or SFX regimen).

If excessive toxicity with cisplatin is detected, the cisplatin dose will be changed to 40 mg/m2 weekly (Weeks 2-8) for any new 
subjects enrolled into the study only upon formal notification by the Sponsor. An amendment to the protocol will be issued to
incorporate the change into the trial.
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Trial Treatment should begin within 3 days of the date on which the subject is randomized to 
start pembrolizumab/placebo priming dose. CRT should begin 1 week ±3 days after Cycle 1,
Day 1. A delay in Cycle 1, Day 1 or initiation of CRT due to an adverse event is allowed. 
Other reasons for a delay in starting Cycle 1, Day 1 or initiation of CRT can be considered 
with Sponsor consultation. 
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial 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.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
The rationale for selection of dose of pembrolizumab to be used in this trial is provided in 
Section 4.0 – Background & Rationale. Details on preparation and administration of 
pembrolizumab/placebo are provided in the Pharmacy Manual.
Preparation of cisplatin should follow the local product label (for France only: see Section 
12.8). The body surface area (BSA) in m2 should be calculated per local guidance.
Dose Modification
If appropriate, the Investigator may attribute each toxicity event to cisplatin, radiation or 
pembrolizumab/placebo alone and use a stepwise dose reduction according to Table 3 to
Table 7.
For individual subjects requiring a dose modification, treatment for each new cycle may be 
delayed if the scheduled off-drug periods are not adequate to allow for recovery to Grade ≤1 
or the baseline status of the subject. Every effort should be made to continue RT without 
interruption even in the case of pembrolizumab/placebo or cisplatin toxicity. Subjects who 
require a 3rd dose modification to cisplatin will have that agent discontinued.
Pembrolizumab/placebo dose reductions are not permitted.
Pembrolizumab/placebo 
treatment should be interrupted or discontinued due to toxicity. If a dose reduction for 
toxicity occurs with cisplatin, the dose may not be re-escalated. Subjects can have a 
maximum of 2 dose modifications throughout the course of the study for toxicities. If a 
subject experiences several toxicities and there are conflicting guidelines, please follow the 
most conservative dose adjustment guideline (dose reduction appropriate to the most severe 
toxicity).  
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Reduction of one systemic 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 more than one systemic agent, all related drugs 
should be interrupted/withheld and for cisplatin, adjusted according to required dose 
modifications. 
If one or more of the study medications (i.e., pembrolizumab/placebo, cisplatin and/or 
radiation therapy) is discontinued, the subject may continue with the other study medications 
if indicated.  The only exception is if radiation therapy is discontinued, cisplatin must also be 
discontinued.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) must be 
used to grade the severity of adverse events. All dose modifications should be based on the 
AE requiring the greatest dose modification. Exceptional circumstances that may prohibit a 
site from following the dose modification tables below may be considered after consultation 
with the Sponsor.
5.2.1.2.1 Dose Modification and Toxicity Management Guidelines for Pembrolizumab
If cisplatin and/or radiation therapy is discontinued, the subject may continue on treatment 
with pembrolizumab/placebo.
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (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 trial 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. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 3.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced 
to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects 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).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects 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.
Grade 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies
Monitor and follow-up
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5-1 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 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects 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 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies
Monitor and follow-up
Nephritis and 
Renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 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
All other immune-
related AEs2
Intolerable/ 
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 type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Guillain-
Barre Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
GI=gastrointestinal; irAE=immune-related adverse event; T1DM=Type 1 diabetes mellitus.
1.
Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating physician. If AE association to pembrolizumab 
is suspected or unknown, pembrolizumab may be interrupted and restarted if association to pembrolizumab is later ruled out.
2.
Refer to Appendix 12.10.1 for France-specific guidelines for recurrent Grade 3 colitis, Stevens-Johnson Syndrome and toxic-epidermal necrolysis.
NOTE:
For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
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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 4. 
Table 4
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 subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
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 subject 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 subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5 hrs (± 30 minutes) prior to 
infusion of pembrolizumab 
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 (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
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 subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; IV-intravenous; NCI=National Cancer Institute; 
NSAIDs=non-steroidal anti-inflammatory drugs.
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 v4.0 (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/surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 6 weeks of the last dose administered, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the 
subject's study record.
5.2.1.2.2 Dose Modification and Toxicity Management for Cisplatin
Subjects can have 2 levels of dose reductions to cisplatin throughout the course of the study 
for toxicities as described in Table 5 and Table 6. If further toxicity occurs or the criteria for 
resuming treatment are not met, the subject must be discontinued from that drug and continue 
to participate in the study. If a subject experiences several toxicities and there are conflicting 
guidelines, follow the most conservative dose adjustment guideline (dose reduction 
appropriate to the most severe toxicity).
If excessive toxicity with cisplatin is detected, the cisplatin dose will be changed to 40 mg/m2
weekly (Weeks 2-8) for subsequent new subjects enrolled in the study only upon formal 
notification by the Sponsor. An amendment to the protocol will be issued to incorporate the 
change into the trial. If pembrolizumab/placebo is discontinued, the subjects may continue 
with cisplatin and radiation therapy.
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Table 5
Dose Levels for Cisplatin
Dose Level 0
Dose Level -1
Dose Level -2
Dose Level -3
Cisplatin
100 mg/m2
80 mg/m2
60 mg/m2
Discontinue
Cisplatin-Related Toxicity
The major dose-limiting toxicities observed with single-agent cisplatin are the following:

Gastrointestinal toxicity: nausea and vomiting.

Nephrotoxicity: renal function impairment associated with tubular damage and 
manifested with elevation in serum creatinine and urea and decrease in creatinine 
clearance (CrCl). It is also associated with serum electrolyte disturbances, like 
hypomagnesaemia, 
hypocalcaemia, 
hypernatremia, 
hypokalemia
and 
hypophosphatemia.

Ototoxicity: cumulative and not reversible damage, manifesting with hearing loss in 
the high frequency.

Hemotoxicity: neutropenia, thrombocytopenia, anemia.

Neurotoxicity: manifesting with peripheral neuropathy and paresthesia in both upper 
and lower extremities.
Dose Modification and Toxicity Management Guidelines for Cisplatin
For every treatment infusion, a full dose of cisplatin will be given if neutrophils are 
≥1.0 × 109/L and platelets ≥75 × 109/L. If these levels are not reached, blood counts should 
be performed at the investigator's judgment, but it is recommended at least weekly to 
document recovery. If hematological toxicity has resolved, cisplatin should resume 
immediately per local institutional standard. If hematological toxicity has not resolved, the 
subject should not receive further cisplatin. The subject can continue with RT and 
pembrolizumab/placebo and will be followed according to study protocol. Cisplatin will not 
be administered after completion of RT (AFX or SFX regimen).
Permanent discontinuation of cisplatin should be considered for any severe or life-
threatening event. In the event that cisplatin treatment is stopped, no substitution with, for 
example, carboplatin or cetuximab, will be allowed. Cessation of cisplatin therapy is not, in 
itself, a reason for discontinuing the subject from the study. The following dose reductions of 
cisplatin must be applied and carried over through all subsequent infusions (ie, no dose 
escalation).
Dose Reductions for Neutropenia
In the case of treatment delay due to delayed neutrophil recovery, these following policies 
are to be followed:

If neutrophil count has resolved to ≥1.0 × 109/L in ≤1 week, administer the full dose 
of cisplatin.
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
If neutrophil count has resolved to ≥1.0 × 109/L in >1 week but ≤2 weeks, proceed 
with a dose reduction of cisplatin.
Dose Reductions for Febrile Neutropenia
In case of any febrile neutropenia (at least CTCAE v4.0 Grade 3: absolute neutrophil count 
<1000/mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour), it is recommended 
that the subject is hospitalized and treated with antibiotics as appropriate. After a period of 
febrile neutropenia, additional precautions have to be taken for the subsequent infusions and 
the cisplatin dose should be reduced.
Dose Reductions for Thrombocytopenia
If complicated thrombocytopenia ≥Grade 3, with hemorrhage and/or requiring 
prophylactic/therapeutic platelet transfusions (recommended at <10 × 109/L, but dependent 
upon local transfusion policy) occurs at any point during the treatment, appropriate 
supportive care should be given, and cisplatin treatment should be delayed until platelets are 
>75 × 109/L.
In any case at the occurrence of Grade 4 thrombocytopenia at nadir (<25 × 109/L), cisplatin 
dose reduction should take place in the subsequent infusion.
Dose Reduction for Renal Toxicity
In case of renal toxicity, the cisplatin dose must be reduced as in Table 6.  Cisplatin should 
be dose modified based on CrCl measured within 24 hours prior to cisplatin administration.
Table 6
Cisplatin Dose Reduction for Renal Toxicity
Creatinine Clearance
Cisplatin
≥60 mL/min
100 mg/m2
50-59 mL/min
80 mg/m2
40-49 mL/min
60 mg/m2
<40 mL/min
Discontinue
Dose Reduction for Peripheral Neuropathy
A neurological examination should be performed at screening, before the second cisplatin 
injection and every subsequent injection per local regulations by the investigator or qualified 
designee. In case of symptoms or signs experienced by the subject, more frequent 
examinations should be performed per local regulations by the investigator or qualified 
designee and the following dose modifications are required:

Grade 0, 1 (CTCAE v4.0): No change.

Grade 2 (CTCAE v4.0): Cisplatin will be reduced to 60 mg/m2.

Grade ≥3 (CTCAE v4.0): Cisplatin will be discontinued.
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Dose Reduction for Ototoxicity
Cisplatin is known to cause high frequency hearing loss. Follow local product label and 
institutional guidelines. The following dose modifications are required:

If Grade 1 or 2 hearing loss (CTCAE v4.0) occurs, the risk of additional hearing loss 
versus the potential benefit of continuing cisplatin chemotherapy should be made.

Grade 3 and 4 hearing loss (CTCAE v4.0) is an indication to discontinue cisplatin.
Dose Modification for Other Toxicities
If toxicity has resolved, cisplatin should resume immediately per local institutional standard.  
If toxicity has not resolved, the subject should not receive further cisplatin. The subject will 
continue with radiation treatment and will be followed-up according to the study protocol. 
Cisplatin will not be administered after completion of RT (AFX or SFX regimen).
Please also refer to the Multinational Association of Supportive Care in Cancer (MASCC)
and European Society for Medical Oncology (ESMO) guidelines for treatment and 
prevention of emesis caused by highly emetic compounds [32]. Dose Modification for 
cisplatin for other toxicities are presented in Table 7.
Table 7
Dose Modification for Cisplatin – Other Toxicities
Category
Toxicity
Hold 
Cisplatin 
Treatment 
for Grade
Timing for 
Restarting 
Cisplatin 
Treatment
Dose Level (DL)
for Restarting 
Cisplatin 
Treatment
Discontinue 
Platinum
Non-
hematologic
All other non-
hematologic 
toxicities2
3-41
Toxicity 
resolves to 
Grade 0-1
Reduce by 1 DL
Toxicity does not 
resolve or if >2 Dose 
Level reductions 
exceeded
Laboratory 
adverse event2
4
Toxicity 
resolves to 
Grade 2 or 
less
Reduce by 1 DL
Toxicity does not 
resolve or if >2 Dose 
Level reductions 
exceeded
AE=adverse event; DL=dose level.
1 Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor 
before restarting treatment after Grade 4 drug-related AE
2 Subjects with intolerable or persistent Grade 2 drug-related AEs may hold at physician discretion.  
Permanently discontinue from cisplatin for persistent Grade 2 adverse reactions for which treatment has been 
held and did not recover to Grade 0-1 of the last dose. With investigator and Sponsor agreement, subjects 
with a laboratory adverse event still at Grade 2 may continue in the trial only if asymptomatic and controlled.
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5.2.1.2.3 Dose Modification for Radiotherapy 
All RT treatments must begin within 1 week (±3 days) after Cycle 1, Day 1 as per Trial Flow 
Chart (Section 6.0). Treatment interruptions are to be avoided unless medically necessary. 
Missed treatments should be compensated for with a twice a day (BID) treatment delivered
per local SOC or continue until all 35 fractions are completed. If cisplatin and/or 
pembrolizumab/placebo are discontinued, subjects may stay on study treatment to complete 
radiation therapy.
Timing of Dose Administration
The dose and schedule modifications of pembrolizumab/placebo, cisplatin and radiotherapy
are provided in Section 5.2.1.2 – Dose Modification.
Pembrolizumab/Placebo
Pembrolizumab or placebo will be administered as a priming dose 1 week prior to the 
beginning of chemoradiation (CRT (Cycle 1 Day 1 [Week 1]) followed by 2 infusions during 
CRT (Cycle 2 Day 1 [Week 4] and Cycle 3 Day 1 [Week 7]) and then continued for up to an 
additional 14 doses of pembrolizumab or placebo post-CRT for a total number of 17 
pembrolizumab or placebo infusions (total duration of pembrolizumab/placebo one year).
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion. 
Placebo will be prepared and provided by the local unblinded pharmacist (see Pharmacy 
Manual), dosed and administrated in the same manner as the investigational product.
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between 
-5 
minutes 
and 
+10 
minutes 
is 
permitted 
(i.e., 
infusion 
time 
is 
30 minutes -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the unblinded pharmacist for the 
preparation of the pembrolizumab and placebo infusions and administration of infusion 
solutions.
Cisplatin
Cisplatin will be administered after all procedures and assessments are completed according 
to the Trial Flow Chart in Section 6.0.
Cisplatin is given as a dose of 100 mg/m2 using an infusion duration of 60 minutes (or 
infusion duration according to local practice).
N.B. For body surface area (BSA) over 2 m2 the cisplatin dose will be capped at the one 
calculated for BSA=2 m2.
Cisplatin should start on the first day of RT (±2-day window). Before and after 
administration of cisplatin, adequate hydration is required and can be given as normally used 
in each institution. It is advised that subjects can be hospitalized for at least 24 hours to allow 
optimal hydration before and after drug injection, if required per local regulations; or 
cisplatin may be administered on an outpatient basis if adequate hydration can be managed 
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and if allowed per local regulations. If hydration is performed as a planned hospitalization, it 
would not meet that criterion for SAE.
Administration of Cisplatin
The administration of cisplatin can follow the standard local practice and/or international 
guidelines. However, it is highly recommended to follow the instructions as reported below.
The first course of cisplatin should begin on the first day of RT (±2-day window).
Recommendations:

Encourage the subject to drink 2-3 liters of water per day during the days preceding 
and following cisplatin infusion.

Any pre-existing dehydration must be corrected before starting the hydration related 
to cisplatin administration.

Assess the hydration status during physical examination.

Antiemetic medications should include: 
o
5-HT3 antagonist (e.g., granisetron 1-3 mg IV or ondansetron 8-32 mg IV or 
palonosetron IV 0.25 mg IV 30 minutes before cisplatin infusion).
o
aprepitant (e.g., 125 mg PO 30 minutes before cisplatin infusion and 80 mg/day 
PO during the 2 following days or 150 mg IV on Day 1).
o
corticosteroids (e.g., dexamethasone 20 mg once per day [12 mg once per day if 
given with aprepitant] 30 minutes before cisplatin infusion and dexamethasone 8 
mg twice per day [8 mg once per day if given with aprepitant] PO during the 3
following days). Another equivalent corticosteroid regimen is allowed according 
to local practice. The maximum dose of steroids for antiemetic treatment or 
prophylaxis is 20 mg/day dexamethasone or its steroid equivalent.
o
any "as-needed" antiemetics according to each institutional guideline 
(metoclopramide, alizapride, additional steroids, etc.). 

Intravenous pre- and post-hydration per local guidelines. Following cisplatin infusion, 
an overnight additional hydration is also allowable, per local regulations.

Cisplatin infusion: mannitol before cisplatin infusion is allowed according to local 
practice. Cisplatin should be prepared according to local practice and should be 
infused over 60 minutes.

Urinary output: >100 mL/hour before starting cisplatin infusion and also after 
cisplatin infusion during at least 4-6 hours (400 mL/4 hours). If this level is not 
reached, furosemide (Lasix®) 20 mg IV should be given.

Subjects may be weighed before and after cisplatin infusion; if weight gain,
furosemide (Lasix®) could be given.

Replace potassium (K) and magnesium (Mg) as needed.

Check for presence of ototoxicity.
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Before starting the treatment with cisplatin, the following criteria must be met:

Neutrophils:
>1.0 × 109/L

Platelets:
>75 × 109/L

Creatinine clearance: ≥60 mL/min 
(using 
Cockcroft-Gault 
formula
or 
local 
institutional standard)
Radiotherapy Regimen (AFX or SFX)
The administration of RT regimen (AFX or SFX) should follow the dose parameters for 
either a single phase or multi-phase plan in Table 8. Intensity Modulated Radiation Therapy
(IMRT) planning is required.
Table 8
RT Dose Parameters
Single Phase IMRT 
(Simultaneous 
Integrated Boost)
Multi-Phase Plan
(Delivered with IMRT)
Primary Site/Gross 
Nodes*
70 Gy in 35 fractions
70 Gy in 35 fractions (50 Gy + 20 Gy)
Regions at Microscopic 
Risk**
56 Gy in 35 fractions
50 Gy in 25 fractions
Intermediate Risk 
Areas***
63 Gy in 35 fractions
60 Gy in 30 fractions (50 Gy + 10 Gy)
* primary and nodal GTVs plus 0.5 cm to define CTV_7000
**CTV_5600 or CTV_5000 defined to include 1.0 cm expansion on all GTVs and in addition nodal regions at 
risk of microscopic spread according to standard anatomic guidelines relative to location and extent of gross 
disease
*** optional volumes, defined as CTV_6300 or CTV_6000 as a 0.5 cm expansion on individual nodes thought 
to be at intermediate risk of involvement, such nodes will not meet criteria defined for gross involvement will 
be <1.5 cm in axial dimensions and in locations considered at intermediate risk such as close proximity to 
grossly involved nodes or primary site; other optional regions of intermediate risk would include the entire 
anatomic nodal level containing grossly involved nodes beyond the 70 Gy volumes defined to treat these.
All PTVs defined as 0.3 to 0.5 cm expansions on CTVs based on method and frequency of Image-Guided 
Radiation Therapy (IGRT).
Treatment will be delivered over 6 weeks for AFX regimen by incorporating 6 fractions per 
week (example: 6 doses over 5 days, 2 days off, or 6 doses over 6 days, 1 day off; 5 fractions 
on final week); or delivered over 7 weeks for SFX regimen by incorporating 5 fractions per 
week (example: 5 doses over 5 days, 2 days off). 
5.2.2.3.1 Facility and Equipment
All subjects participating in the study will be treated with 6 to 10 MV photons. The preferred 
mode of treatment is Simultaneous Integrated Boost Intensity Modulated Radiation Therapy 
(SIB-IMRT) delivered by static or dynamic techniques. However, multi-phase IMRT plans 
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are also permitted. See Table 8 for dose parameters for SIB and multi-phase techniques. 
Linear accelerator or Tomotherapy based equipment is allowed.
Center credentialing will be performed according to criteria defined in the RT QA manual. 
Participating institutions must comply with the Radiation Therapy Quality Assurance (RT
QA) requirements and procedures described in the RT QA manual. Sites that do not conform 
to the requirements of the credentialing will not be allowed to participate.
5.2.2.3.2 Oral and Dental Check-up
See Section 7.1.2.6.
5.2.2.3.3 Subject position and data acquisition
All subjects will be irradiated in supine position. Immobilization devices such as customized 
masks have to be used to secure the accuracy and reproducibility of subjects positioning 
during RT. Preferably, mask immobilization of the head, neck and shoulders will be used. 
For all subjects, a planning CT will be performed in the immobilization device to capture 
slices extending from the level of the base of skull to the lower border of the clavicle. Slice 
thickness of preferably 2-3 mm will be used. Images will be constructed with at least 512 x 
512-pixel matrixes.
To enhance vascular and soft tissue contrast and to facilitate delineation of both target 
volumes and organs at risk (OARs), the use of intravenous contrast enhancement is strongly 
recommended except if medically contraindicated. If intravenous contrast is not used for the 
planning scan, it is mandatory the subject has either a contrast enhanced diagnostic CT 
and/or MRI performed no longer than 4 weeks prior to simulation. These images will have to 
be co-registered to the planning CT for contouring purposes and will be submitted along with 
the planning CT for quality assurance.  
5.2.2.3.4 Volume definition
The definition of volumes will be in accordance with International Commission on Radiation 
Units & Measurements (ICRU) Reports #50, #62 and #83 [ICRU 1993; ICRU 1999; ICRU 
2010]. Volumes will be named according to the target and organ at risk naming convention 
published by Santanam et al (2012) [64].
Delineation of the Gross Tumor Volume (GTV)
The GTV will encompass the primary tumor volume (named GTVp) and involved lymph 
nodes (labeled GTVn) defined with respect to physical exam and imaging studies. Involved 
nodes are defined as those >1.5 cm in long axis or >1cm in short (axial) axis. Nodes of any 
size with radiologic evidence of necrosis or extracapsular extension (ECE) are to be 
considered involved. Smaller nodes in close proximity to either the primary site and/or other 
grossly involved nodes may be considered involved. Acceptable diagnostic imaging studies 
will include contrast enhanced CT and MRI and may be co-registered with the planning CT 
data set to facilitate GTV delineation. FDG-PET if available may be used to guide tumor
identification but should not be used to define GTV borders given the uncertain relationship 
between the margin of the PET signal and tumor border. 
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Clinical Target Volumes (CTV)
CTVs will be defined and named according to the doses intended to be delivered. The 
CTV_7000 will encompass all gross tumor volume (primary and nodal) and the CTV_5600 
or CTV_5000 will encompass areas beyond the CTV_7000 considered at risk of microscopic 
tumor involvement (beyond GTVp and GTVn including nodal levels at risk). CTVs will be 
defined as described below according to specific isotropic expansions, limited according to 
natural barriers of spread and expanded to include anatomic regions at risk of microscopic 
spread.
5.2.2.3.5 Clinical Target Volume at the Primary Site (CTV_7000)
The CTV_7000 at the primary site will consist of a 5 mm isotropic expansion of the GTVp. 
The CTV_7000 should be constrained to exclude regions protected by physical or anatomic 
barriers such as air (cavities or external to subject contour), bone (mandible or vertebral 
body) or fascial planes through which tumor spread is not apparent.
5.2.2.3.6 Clinical Target Volume at Involved Nodes (CTV_7000)
The CTV_7000 at involved nodes will consist of a 5 mm isotropic expansion of the GTVn. 
The CTV_7000 should be constrained within the CTV_5600 or CTV_5000 defined to cover 
the microscopic/prophylactic nodal regions at risk (Table 9).
5.2.2.3.7 Clinical Target Volumes for Regions at Risk of Microscopic Tumor 
Involvement (CTV_5600 or CTV_5000)
The CTV_5600 or CTV_5000 will encompass:
1) A 10 mm expansion on GTVp and GTVn constrained to exclude regions protected by 
physical or anatomic barriers such as air (cavities or external to subject contour), bone 
(mandible or vertebral body) or facial planes through which tumor spread is not 
apparent.
2) Nodal levels deemed at risk of microscopic tumor involvement. The neck node levels 
will be delineated on each CT slice according to the updated guidelines defined by a 
consensus panel for the node-negative and the node-positive neck [65]. In case of 
infiltration (or suspicion of infiltration) of the sterno-cleido-mastoid muscle, the 
muscle will be included in the CTV_5600 or CTV_5000. 
5.2.2.3.8 Clinical Target Volumes for Regions at Intermediate Risk (CTV_6300 or 
CTV_6000) - Optional
An intermediate risk volume may be defined at the clinical discretion of the treating 
physician with defined individual department protocols. This optional volume can be used 
when the investigator prefers to give a higher dose than the microscopic risk region 
understanding it does not harbor gross tumor. Often, this volume abuts regions of gross 
tumor. See Table 9.
Radiologic anatomic boundaries of the various neck node levels are presented in Table 9 and
as published by Grégoire et al [65].
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Table 9
Radiologic Anatomic Boundaries of the Various Neck Node Levels
Nodal stage (AJCC 7th
edition*)
Levels to be included in the CTV
Ipsilateral neck
Contralateral neck
N0 - N1
II-III-IV
II-III-IV
N2a – N2b
(Ib), II, III, IV, V + RP
II-III-IV
N2c
(Ib), II, III, IV, V + RP
According to N stage in 
contralateral neck
N3
I, II, III, IV, V + RP
According to N stage in 
contralateral neck
* The 8th edition of the AJCC Cancer Staging Manual should be used for TNM staging of head and neck 
cancers starting 01-JAN-2018.
Peculiarities:

Level Ib for N0: any oral cavity tumor or any primary tumor with extension to the 
oral cavity, e.g., to retromolar trigone, mobile tongue, inferior gum, oral side of 
anterior tonsillar pillar.

Level VI: any primary site with trans- or sub-glottic extension or extension to 
pyriform sinus or esophagus.

Retropharyngeal (RP): included in all cases with primary tumor extension to posterior 
pharyngeal wall irrespective on N stage, in such cases if primary tumor crosses 
midline the contralateral RP must be treated as well. 

Retrostyloid: Must be included when level II is involved. For larynx primary with N2 
or greater, may treat retrostyloid node and omit RP.

Medial Supra-clavicular fossa nodes: systematic irradiation of the supra-clavicular 
fossa lymph nodes in case of level IV nodal infiltration is recommended.
5.2.2.3.9 Unilateral Neck Treatment
Unilateral neck treatment is recommended for subjects with lateralized tonsilar primaries 
with <1cm extension into soft palate or base of tongue presenting with N0 or N1 nodal stage. 
Similarly, oral cavity primaries >1cm from midline and N0-N1 nodal stage may be 
considered for unilateral neck treatment. Unilateral treatment may be offered to subjects with 
N2a or N2b with <3 nodes confined to zone II as long as the primary site is lateralized as 
defined above. Bilateral treatment is mandatory for N2c or N3 and all laryngeal or 
hypopharyngeal primaries or oropharynx arising in palate, tongue base or posterior 
pharyngeal wall.
5.2.2.3.10 Delineation of the Planning Target Volume (PTV)
PTV_7000, PTV_6300 or PTV_6000, and PTV_5600 or PTV_5000 will be defined to 
enclose the corresponding CTV, respectively. Radiation dose will be prescribed, planned, 
and evaluated to these PTVs. PTVs are used to account for subject movement, variation and 
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residual error in day-to-day setup and will be generated by an isotropic expansion of their 
associated CTVs. Centers employing image guided radiation therapy (IGRT) using daily 
volumetric imaging (accelerator mounted kV or MV cone beam or tomotherapy MV CT) 
may generate PTVs with a 3 mm expansion. All others must use a 5 mm expansion.
In cases for which disease extends close to the subject external contour, depending on the 
equipment used, tissue equivalent bolus may be used to properly irradiate all parts of the 
CTV and the PTV extended to the external contour beneath the bolus. PTVs will also be 
limited in regions where they may overlap with critical organ PRVs (spinal cord and brains 
stem) see Table 10. In cases that do not have skin involvement with disease, the PTV does 
not have to extend beyond the skin surface.
5.2.2.3.11 Delineation of Organs at Risk (OAR)
Standard OARs are included in the following list and must be contoured on the planning CT 
data set according to the guidelines of Brouwer et al utilizing the indicated naming 
convention. Guidelines for OAR contouring are provided in Table 10 and as published by 
Brouwer et al [66].
Table 10
Standard Organs at Risk
OAR
Standard Name
Spinal cord
SpinalCord
Brain stem
BrainStem
Lips
Lips
Oral cavity
OralCavity
Mandible
Mandible
Right Parotid
Parotid R
Left Parotid
Parotid L
Right Submandibular
Submandibular R
Left Submandibular
Submandibular L
Pharynx (beyond PTV)
Pharynx
Cervical Esophagus (beyond PTV)
Esophagus
Larynx (beyond PTV)
Larynx
External border of subject
External
5.2.2.3.12 Planning Organ at Risk Volume (PRV)
A PRV for the critical OARs spinal cord and brainstem will be generated with an isotropic 
expansion for the purpose of dose evaluation and limitation to these structures. The PRVs 
represent a safety margin for these critical structures to account for variability in day-to-day 
positioning. As such centers utilizing daily volumetric imaging (accelerator mounted kV or 
MV cone beam or tomotherapy MV CT) may generate PRVs with a 3 mm expansion. All 
others must use a 5 mm expansion. 
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5.2.2.3.13 Dose prescription, specification and reporting in the PTV
Dose prescription, specification and reporting will be done according to ICRU report 83 
recommendations. 
Subjects will preferably be treated by SIB-IMRT. A median dose of 70 Gy will be prescribed 
to PTV_7000 in 35 fractions of 2 Gy. A median dose of 56 Gy will be prescribed to 
PTV_5600 in 35 fractions of 1.6 Gy. Alternately, IMRT multi-phase plans are permitted. A 
median dose of 50 Gy in 25 fractions to PTV_5000 followed by 20 Gy in 10 additional 
fractions for a total dose of 70 Gy to PTV_7000 in 2 Gy fractions. Dose-volume constraints 
will be used for both dose specification and dose reporting in PTV and PRV/OAR. 
Treatment will be delivered over 6 weeks for AFX regimen by incorporating 6 fractions per 
week (example: 6 doses over 5 days, 2 days off, or 6 doses over 6 days, 1 day off; 5 fractions 
on final week); or delivered over 7 weeks for SFX regimen by incorporating 5 fractions per 
week (example: 5 doses over 5 days, 2 days off).
5.2.2.3.14 Treatment planning
Subjects will be treated by IMRT using 6 to 10 MV photons. For linear accelerators, field 
arrangements are left to the discretion of the medical physicists to produce an optimal dose 
distribution matching the dose-volume constraints for PTV, PRV and OAR. Non-coplanar 
field arrangements are allowed, but beam directions through the eyes are not allowed unless 
really unavoidable. All field entrance and exits should be within the planning CT range in 
order to avoid any inadequate dose calculations.
Treatment plans will be computed using modern type B dose calculation algorithms such as 
convolution/superposition, Monte Carlo, collapsed cone or equivalent algorithms. The dose 
calculation matrix to be used must be below 4 mm. Dose calculations will be performed 
using density heterogeneity corrections. 
The following dose-volume objectives (Table 11) will be used for planning, dose 
specification and dose reporting in PTV, PRV, and OAR:
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Table 11
Dose Volume Objectives
PTV
D95%1
Dnear-
min
Dnear-max
D5%
Median 
Dose
OAR / PRV
Or D98 %
Or D2%
Or D50%
Mean Dose
PTV_7000
≥95% of 
planned 
dose
≥90% of 
planned 
dose
≤107% 
of 
planned 
dose
70 Gy ± 2%
-
PTV_6300 or 
PTV_6000
≥95% of 
planned 
dose
≥90% of 
planned 
dose
63 Gy or 60 
Gy ± 2%
PTV_5600 or 
PTV_5000
≥95% of 
planned 
dose
≥90% of 
planned 
dose
56 Gy or 50 
Gy ±2%
-
PRV spinal cord
-
≤45 Gy
-
-
PRV brain stem
-
≤50 Gy
-
Contralateral 
parotid
-
-
-
≤25 Gy
Ipsilateral 
parotid
-
-
-
≤30 Gy
Oral cavity
-
-
-
≤30 Gy
Larynx
-
-
<55Gy
-
≤44 Gy
Mandible
-
≤70 Gy
-
-
1 Dv: Dose in v% of the volume
5.2.2.3.15 Treatment verification and accuracy
All subjects must have routine imaging performed to verify treatment set up. The minimum 
imaging requirement is once weekly orthogonal KV images commencing on the first day of 
treatment and reviewed by the managing radiation oncologist. Centers are strongly 
encouraged to employ daily volumetric image guidance with either accelerator mounted KV 
or MV conebeam CT or tomotherapy CT images utilizing matching of bony anatomy. 
5.2.2.3.16 Side effects of head and neck radiotherapy
Radiation-induced head and neck toxicity is well known and has been well described. It is 
expected to vary according to the total dose and the concomitant use of chemotherapy. 
Locoregional toxicity will be monitored during treatment using CTCAE v4.0 and will be 
reported in the database.
Reversible mucositis and pharyngitis is expected, and supportive care will be initiated (e.g.,
pain killers, mouth wash, adaptation of the diet, use of a nasogastric or percutaneous
endoscopic gastrostomy feeding tube). In very rare cases of severe Grade 4 mucositis (e.g.,
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bleeding); it may be necessary to interrupt RT for a few days. However, it is mandatory to 
limit the break to a strict minimum.
Various degrees of skin reaction (typically Grade 2, less frequently Grade 3) are expected in 
the treated area. Other expected acute reactions include fatigue, xerostomia, dysgeusia, 
ageusia and dysphagia. 
Central nervous system events in terms of nausea and vomiting are expected.
Late effects include some degree of xerostomia and occasionally persistent dysphagia.
Mandibular osteoradionecrosis may occur in less than 5% of the subjects. Thorough dental 
evaluation and, if necessary, adequate care performed before the start of RT, will 
substantially decrease this risk.
5.2.2.3.17 Treatment Interruptions / Modifications
Radiotherapy should begin within 1 week ±3 days after Cycle 1, Day 1. Treatment 
interruptions are to be avoided unless medically necessary. Missed treatments should be 
compensated for with a BID treatment delivered. This should be limited to a maximum of 
twice during the 6 weeks of treatment with a minimum of 2 days between BID treatments for 
AFX regimen and twice during the 7 weeks of treatment with a minimum of 2 days between 
BID for SFX regimen. Any breaks in RT should be minimized. 
Surgery Guidelines
Neck imaging (MRI or CT scan) and FDG-PET scan will be performed at 12 weeks after the 
end of CRT + pembrolizumab/placebo to evaluate the neck for a potential neck dissection. A 
neck dissection will be recommended in case of persistent disease in the neck based on a 
positive FDG-PET scan [25]. Neck dissection should be performed by Week 16 after the last 
dose of CRT but no later than Week 20 after the end of CRT and according to standard 
guidelines at each center.
In case of PET-positivity of the primary site, an endoscopy has to be performed within 2 
weeks and a biopsy taken from the suspicious lesion. Exceptions to this may be considered 
with Sponsor consultation. A salvage intervention will then be performed no later than 6
weeks after the endoscopy at the discretion of the treating head and neck surgeon and 
Multidisciplinary Team (MDT), if the subject is found fit for the chosen intervention and 
accepts the intervention and its potential complications and side effects. 
Pre-operative Assessment
Subject’s Charlson co-morbidity index, ASA-score, and nutritional status are recommended
pre-operatively. Also, coagulation parameters and routine labs (CBC, chemistry profile, and 
coagulation tests) will be performed. In case of procedures with potential long-term 
swallowing compromise the treating surgeon may obtain pulmonary function tests. Subjects
deemed unfit for the chosen procedure will not undergo salvage. This decision will be taken 
individually by the treating surgeon in close collaboration with the multidisciplinary team
together with the subject, assuring that the goals of quality-of-life the subject wishes to 
obtain are met.
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Pre-operative diagnostics are comprised of a CT scan with contrast, in case of questionable 
soft tissue involvement an additional MRI, in case of possible bone involvement a CT scan is 
mandatory. An MRI of the head and neck only will suffice, if clinically bone involvement 
can be affirmatively excluded. An endoscopy has to be performed pre-operatively in case a 
salvage of the primary site is planned. In case of a negative FDG-PET scan in the primary 
site, but positive FDG-PET scan in the neck, a neck dissection without endoscopy suffices. A 
histological diagnosis at the primary site for a salvage resection is mandatory. 
All results should be discussed in the MDT to determine whether or not and to what extent a 
subject with a positive FDG-PET scan in the neck or histologically proven disease at the 
primary site should be operated on.
Endoscopies in case of positive FDG-PET scans at the primary site should be performed 
within 2 weeks of FDG-PET result; and if positive and accepted by the MDT for surgery,
should be taken for salvage intervention no later than 6 weeks after the endoscopy. A neck 
dissection for a FDG-PET positive neck should be done within 4 weeks from the FDG-PET
result but no later than 20 weeks after the last dose of CRT.
Surgical Procedure Guidelines
Technique of Anesthesia
For the endoscopy a regular general anesthesia according to institutional guidelines should be 
performed. The same accounts for neck dissections and salvage resections with or without 
reconstructions.
Technique of Surgical Procedure
5.3.2.2.1 Endoscopy
The endoscopy can comprise of an examination of the oral cavity, nasopharynx, oropharynx, 
larynx, hypopharynx, esophagus, and tracheobronchial system (upper airways). The 
instruments for this examination under general anesthesia are at the discretion of the 
performing surgeon. A representative biopsy has to be taken from the site at which 
recurrence is suspected. If biopsies are returned to be inconclusive, a re-biopsy has to be 
performed. Exceptions to this may be considered with Sponsor consultation.
5.3.2.2.2 Neck Dissection 
The neck dissection has to be at minimum a selective neck dissection comprising of the neck 
levels containing the suspicious nodes and in addition one adjacent level. If in other words 
level 3 nodes are described positive on the FDG-PET scan, a level 2, 3, 4 selective neck 
dissection has to be performed. In case of involvement of the sternocleidomastoid muscle, 
the internal jugular vein, or the spinal accessory nerve, these structures then have to be 
removed in addition. The surgeon should describe in his operation report the extent of 
macroscopic disease. Incisions and instrumentation are at the discretion of the surgeon 
performing the procedure.
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5.3.2.2.3 Salvage Resection of the Primary Site
Salvage procedures are tailored to the location of the recurrence. The resection at each site 
should provide margins of at least 5 mm in the primary specimen, unless there are surgical 
contra-indications i.e., proximity of great vessels. The choice of procedure as well as the 
choice of reconstruction, if deemed necessary, is at the discretion of the surgeon.  
5.3.2.2.4 Complications After Salvage Procedures And/or Neck Dissections
Complications after salvage procedures and/or neck dissections are common, and every 
center has certain strategies to manage them. This refers to common complications like 
chylous fistulas, other pharyngeal fistulas after pharyngotomies, compromise of the spinal 
accessory nerve, other wound healing problems, etc. In the absence of guidelines for the 
management of those, it will be at the discretion of the treating surgeon to manage these 
complications to the best of his/her knowledge.
Post-operative Care
The post-operative care is closely related to the site of intervention. In general, all efforts 
should be made to de-cannulate subjects with tracheostomies as fast as possible and start the 
subject on an oral diet. It is critical that early on in the process of swallowing and speech 
rehabilitation speech pathologists get involved to work on a regular basis with the subject. It 
is also critical to mobilize the subject as fast as his/her condition allows. These decisions 
need to be taken by the treating head and neck surgeon and should be individualized to the 
subject’s ability and needs. In case of a poor swallowing rehabilitation prognosis given by 
the speech pathologist of the individual center, a percutaneous gastrostomy (PEG) needs to 
be inserted.  
Pathology Specimen
Biopsies taken from the subject during an endoscopy should be kept in formalin and
transported to the pathologist. 
The neck dissection specimen should be sent to the pathologist level by level. In other words, 
in case of a selective neck dissection level 2, 3, 4, the surgeon has to send every level 
separately to the pathologist. It is not necessary to orient these pieces. 
The primary resection specimen in case of primary site salvage has to be sent as a whole and 
oriented with either sutures or colors. A free margin is hereby considered to be ≥5 mm, a 
close margin considered to be between 1-5 mm, and a positive margin considered to be 
<1 mm in the primary resection specimen. If additional resections based on frozen sections 
are done that are considered to be part of the primary resection, these pieces have to be 
oriented and either sutured to the main specimen or the new true margin has to be marked 
through inking and the pathologist informed.
Communication from surgeon to pathologist, transport, processing (time to freezing) and 
reporting of the specimen should follow local practice and institutional guidelines. 
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Remaining tissue is required to be sent to the central laboratory (see central laboratory 
manual). If invasive cancer is not found at time of biopsy or surgery that was performed on 
study, tissue does not need to be sent to central laboratory for biomarker testing.
Evaluation of Post-Operative Complications
Surgical complications will depend on the extent of the procedures, the site of intervention, 
and the technique of reconstruction. Given the variety of possible interventions a large 
variety of complications have to be foreseen.  
5.3.2.5.1 Timing of Assessment of Complications and Mortality
Complications and mortality as a consequence of the surgical procedures will be assessed 
and reported as described in Sections 5.3.2 and 5.3.2.5.1. All AEs considered to be 
post-surgical complications by the investigator from time of protocol-specified surgery 
through 30 days following surgery must be reported by the investigator to the Sponsor. All 
AEs meeting serious criteria considered to be post-surgical complications by the investigator 
from the time of protocol-specified surgery through 90 days following surgery or 30 days if 
the subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator to the Sponsor.
The reporting has to include all measures taken to manage the complication that includes 
operative or endoscopic interventions and all diagnostics deemed necessary.
5.3.2.5.2 Identification and grading of complications
The following tables (Table 12, Table 13, and Table 14) provide the identification and 
grading of post-operative complications (but not limited to):
Table 12
Endoscopy
Endoscopy:
Dysphagia
Grade 1-3
Odynophagia
Grade 1-3
Voice changes and hoarseness
Grade 1-3
Dyspnea
Grade 1-5
Teeth damage
Grade 1-3
Esophageal perforation
Grade 4
Mediastinitis
Grade 4
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Table 13
Neck Dissection
Neck Dissection:
Bleeding
Grade 1-5
Infection
Grade 1-5
Wound healing complication
Grade 1-5
Spinal accessory nerve damage
Grade 1-3
Hypoglossal nerve damage
Grade 1-3
Vagal nerve damage
Grade 1-3
Phrenic nerve damage
Grade 1-3
Sympathetic trunk damage (Horner syndrome)
Grade 1-3
Chyle leak
Grade 1-3
Table 14
Salvage Surgery at Primary Site with or Without Reconstruction
Salvage at Primary Site with or Without Reconstruction (Free or Regional/local Flap):
Bleeding
Grade 1-5
Infection
Grade 1-5
Fistula
Grade 1-5
Wound healing complication
Grade 1-5
Dysphagia
Grade 1-3
Odynophagia
Grade 1-3
Trismus
Grade 1-3
Loss of voice and hoarseness
Grade 1-3
Partial or total flap loss
Grade 1-5
Trial Blinding 
Pembrolizumab or placebo will be prepared by the unblinded pharmacist and dispensed in a 
blinded fashion by an unblinded pharmacist or qualified trial site personnel. The subject, the 
investigator who is involved in the treatment or clinical evaluation of the subjects and the 
Sponsor are unaware of the group assignments. See Section 7.1.7.2
Subject 
Blinding/Unblinding, for a description of the method of unblinding a subject during the trial, 
should such action be warranted.
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). Subjects will be assigned randomly in a 1:1 ratio to 
receive either pembrolizumab or placebo in combination with chemotherapy and radiation.
RT regimen per subject will be assigned by the site through IVRS prior to randomization to 
ensure subjects are balanced between the arms with respect to type of RT regimen selected.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Radiotherapy Regimen (AFX or SFX)
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2. Tumor site/p16 status: 2 levels (Oropharynx – p16 positive vs. Oropharynx – p16 
negative or larynx/hypopharynx/oral cavity HNSCC)
3. Stage III vs. Stage IV
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date should also be included on the CRF.
Supportive care is permitted for managing drug-related toxicities. See guidelines in Section 
5.8. All prior/concomitant medications received within 28 days before the first dose of trial 
treatment through 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial:

Antineoplastic systemic chemotherapy or biological therapy; 

Immunotherapy not specified in this protocol;

Chemotherapy not specified in this protocol;

Radiation therapy not specified in this protocol;

Investigational agents other than pembrolizumab/placebo.

Administration of palliative radiation therapy will be considered clinical progression for 
the purposes of determining EFS.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
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(oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g., Flu - Mist®) are 
live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
adverse event of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
o
Note: A short course of steroids may be used as concomitant medication for either 
treatment of an adverse event or medical condition with Sponsor approval.
o
Note: Inhaled steroids are allowed for management of asthma.
o
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV 
contract dye) is permitted.
o
Note: Use of steroids for antiemetic purposes is permitted.
o
Note: Use of steroids for premedication for trial treatment is permitted.

No prophylactic growth factor support such as erythropoietin or granulocyte-colony
stimulating factor is allowed during chemoradiation treatment. An exception is that 
treatment of neutropenia with granulocyte-colony stimulating factor is allowed, if 
clinically indicated.

During cisplatin treatment only: Cisplatin is a potentially nephrotoxic drug which can be
potentiated by other nephrotoxic agents such as aminoglycoside antibiotics. Use of 
aminoglycosides (such as streptomycin, dihydrostreptomycin, kanamycin, gentamicin, 
neomycin, tobramycin, netilmicin, and amikacin) should be administered with caution 
given the risk of nephrotoxicity. The serum creatinine, blood urea nitrogen (BUN), and 
electrolytes should be monitored carefully when additional nephrotoxic agents are used. 
Subjects receiving cisplatin and other potentially ototoxic drugs, such as 
aminoglycosides, should also be closely monitored for signs of ototoxicity. If the 
administration of aminoglycosides is required, additional audiometric testing may be 
necessary for further safety monitoring. Please contact the Sponsor if aminoglycosides
are administered to a study subject in order to discuss renal management as well as 
frequency of audiometric assessments.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications that are prohibited in this trial.
There are no prohibited therapies in the Post-Treatment Follow-up Visits.
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Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab/Placebo
Subjects 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 5.2.1.2, Table 3.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Supportive Care Guidelines for Cisplatin
See Section 5.2.2 - Timing of Dose Administration
Supportive Care Guidelines for Radiation 
Radiation-induced head and neck toxicity is well known and has been well described. It is 
expected to vary according to the total dose and the concomitant use of chemotherapy. 
Locoregional toxicity will be monitored during treatment using the CTCAE v4.0 scaling 
system and will be reported in the CRFs.
Reversible mucositis and pharyngitis is expected, and supportive care will be initiated (e.g.,
pain killers, mouth wash, adaptation of the diet, use of a nasogastric or percutaneous
endoscopic gastrostomy feeding tube). In very rare cases of severe Grade 4 mucositis (e.g.,
bleeding), it may be necessary to interrupt RT for a few days. However, it is important to 
limit the break to a strict minimum.
Various degrees of skin reaction (typically Grade 2, less frequently Grade 3) are expected in 
the treated area. Other expected acute reactions include fatigue, xerostomia, dysgeusia, 
ageusia and dysphagia. 
Central nervous system events in terms of nausea and vomiting are expected and may be 
managed with an NK-1 receptor antagonist such as (aprepitant, aloxi, zofran, or compazine) 
per local standards of care and local product label. Late effects include some degree of 
xerostomia and occasionally persistent dysphagia and may be managed according to local 
standards of care.
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Mandibular osteoradionecrosis may occur in less than 5% of the subjects. A thorough dental 
evaluation and adequate care must be performed prior to the start of radiotherapy to
substantially decrease this risk.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Insertion of feeding tube is allowed for nutritional purposes and, if procedure is performed as 
a planned hospitalization, would not meet that criterion for SAE.
Contraception
Pembrolizumab, cisplatin, and radiotherapy may have adverse effects on a fetus in utero.  
Furthermore, it is not known if pembrolizumab, cisplatin, and radiotherapy have transient 
adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they meet 1 of the 
following criteria: 

She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause. In women <45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening.

She has a congenital or an acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving trial drug and for 180 days after the 
last dose of trial drug by complying with 1 of the following: 

Practice abstinence from heterosexual activity.
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable 
by 
local 
regulatory 
agencies 
and 
European 
Research 
Councils 
(ERCs)/Institutional Review Boards (IRBs). Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception. 
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
Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:

Single method (1 of the following is acceptable):
o
Intrauterine device
o
Vasectomy of a female subject’s male partner 
o
Contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)  
o
Contraceptive sponge (nulliparous women only) 
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial.  In order to participate in 
the trial, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of trial medication initiation (or 14 days prior to the initiation 
of trial medication for oral contraception) throughout the trial period up to 180 days after the 
last dose of trial medication.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the trial.
For countries (e.g., Germany) or sites that follow the Clinical Trial Facilitation Group 
guidance, please use the following:
In accordance with Clinical Trial Facilitation Group guidance, acceptable methods of 
contraception are those that can achieve a failure rate of less than 1% per year when used 
consistently and correctly and are considered as highly effective birth control methods.  Such 
methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal
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
Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable

Intrauterine device

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomised partner

Sexual abstinence
Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 180 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
Monthly pregnancy testing is recommended per local standards if applicable.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment on either arm of this study, 
the subject will immediately be discontinued from study treatment. The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner the study personnel at the site must 
be informed immediately and the pregnancy reported to the Sponsor and followed as 
described above and in Section 7.2.3.
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Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Cisplatin has been 
reported to be found in human milk. Since many drugs are excreted in human milk, and 
because of the potential for serious adverse reactions in the nursing infant, subjects who are 
breast-feeding are not eligible for enrollment. 
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.8.3.1 –End of Treatment Visits.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.7 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Radiographic disease progression as determined by central imaging vendor
Exception note:
A subject
with BICR-verified
progression prior to neck 
dissection/salvage surgery of the primary tumor site or biopsy of the primary 
tumor/neck lymph nodes/metastatic site can continue with study treatment if invasive 
cancer is not identified based on local pathological assessment of the surgically 
resected or biopsied specimens.
o
Salvage surgery for persistent or residual disease at the primary tumor performed for 
clinical progression with invasive cancer present on final pathology
o
Neck dissection or surgery performed for clinical progression at any time with 
invasive cancer present on final pathology
o
Biopsy of the primary tumor/neck lymph nodes/metastatic site positive for invasive 
cancer if criteria for event is fulfilled, as defined in Section 7.1.4.3
o
Unacceptable adverse experiences as described in Section 5.2.1.2
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o
Intercurrent illness that prevents further administration of treatment
o
Investigator’s decision to withdraw the subject
o
The subject has a confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Completed 17 doses of treatment with pembrolizumab/placebo
Note: 17 doses of study medication (pembrolizumab/placebo) are calculated in 3-
week intervals from the date of first dose.    
o
Administrative reasons
The End of Treatment and Follow-up Visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.1.8 (Visit Requirements). After the end of treatment, each subject will 
be followed for 30 days for AE monitoring (serious adverse events will be collected for 90 
days after the end of treatment as described in Section 7.2.4.1). Subjects who discontinue for 
reasons other than PD/event will have post-treatment follow-up for disease status until 
experiencing an event/disease progression, withdrawing consent or becoming lost to follow-
up. After documented disease progression each subject will be followed by telephone for 
survival until death, withdrawal of consent, or the end of the study, whichever occurs first.
Subjects who discontinue trial treatment for a reason other than either experiencing an 
event/disease progression or starting a new anticancer therapy will move into the Post-
Treatment Efficacy Follow-Up Phase to be assessed every 3 months (91 ± 7 days) for 
Follow-up Years 1 through 3 and then every 6 months (± 14 days) for Follow-up Years 4
through 5 and every 6 months (± 28 days) after Year 5 after randomization according to
procedures outlined in the Trial Flow Chart (see Section 6.3).
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.7
– Other Procedures.
Subject Replacement Strategy
A subject who discontinues from trial treatment will not be replaced.
  
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Beginning and End of the Trial
The overall trial begins when the first subject (or their legally acceptable representative) 
provides documented informed consent.  The overall trial ends when the last subject 
completes the last study-related contact, withdraws consent, or is lost to follow-up (i.e. the 
subject is unable to be contacted by the investigator).
For the purposes of analysis and reporting, the overall study ends when the Sponsor receives 
the last laboratory result or at the time of final contact with the last participant, whichever 
comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
The trial may be stopped early for efficacy or safety at the recommendation of the eDMC. 
Section 7.3.4 describes the eDMC and its responsibilities.
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6.0 TRIAL FLOW CHART
Trial Screening and Treatment 1 (Pembrolizumab/Placebo + CRT)
Trial Period:
Screening
Treatment 1
(3-Week Cycles) a
Visit Number/Title:
Screening
Pembro / 
Placebo
Pembrolizumab / Placebo + Chemoradiation (CRT) 
Cycle:
Cycle 1
Cycle 2
Cycle 3
Week:
1
2
3
4
5
6
7
8
Scheduled Day(s):
-28 to -1
-10 to -1
1
8
15
1
8
15
1
8
Scheduling Window Days (unless noted):
+3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent b
X
Informed Consent for Future Biomedical Research 
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Complete Medical History
X
Disease Details
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
X
X s
Clinical Procedures/Assessments
Review Adverse Events
X
----Continuous Reporting-----
12-Lead Electrocardiogram (local)
X
Full Physical Examination c
X
Directed Physical Examination c
X
X
X
X
X
X
X
X s
Height d
X
Weight and Vital Signs (heart rate, blood pressure, 
respiratory rate, temperature) d
X
X
X
X
X
X
X
X
X s
ECOG Performance Status
Xe
Xe
X
X
X
X
X
X
X s
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Trial Period:
Screening
Treatment 1
(3-Week Cycles) a
Visit Number/Title:
Screening
Pembro / 
Placebo
Pembrolizumab / Placebo + Chemoradiation (CRT) 
Cycle:
Cycle 1
Cycle 2
Cycle 3
Week:
1
2
3
4
5
6
7
8
Scheduled Day(s):
-28 to -1
-10 to -1
1
8
15
1
8
15
1
8
Scheduling Window Days (unless noted):
+3
±3
±3
±3
±3
±3
±3
±3
Oral and dental check-up f
X
Neurological examination g
X
X
X s
Audiometric Testing h
X
Fiber optic examination and endoscopy i
X
Laboratory Procedures/Assessments
Serum or Urine Pregnancy Test – if applicable j
X
X
X
X
HIV/HBV/HCV serology (testing optional per site 
SOPs)
X
Hematology k
X
X
X
X
X
X
X
X
X s
Comprehensive Chemistry l
X l
X
X m
X
X
X m
X
X
X s, m
Coagulation tests n
X
Urinalysis o
X
Thyroid function p
X
Blood for Genetic Analysis q
X
X
X
Blood for RNA Analyses r
X
X
X
Blood for Plasma Biomarker Analyses r
X
X
X
Blood for Serum Biomarker Analyses r
X
X
X
Blood for ctDNA r
X
X
X
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Trial Period:
Screening
Treatment 1
(3-Week Cycles) a
Visit Number/Title:
Screening
Pembro / 
Placebo
Pembrolizumab / Placebo + Chemoradiation (CRT) 
Cycle:
Cycle 1
Cycle 2
Cycle 3
Week:
1
2
3
4
5
6
7
8
Scheduled Day(s):
-28 to -1
-10 to -1
1
8
15
1
8
15
1
8
Scheduling Window Days (unless noted):
+3
±3
±3
±3
±3
±3
±3
±3
Trial Treatment Administration
Pembrolizumab/Placebo Administration s
X
X
X
Cisplatin 100 mg/m2 s
X
X
X s
Radiotherapy (AFX) s
X
X
X
X
X
X
Radiotherapy (SFX) s
X
X
X
X
X
X
X s
Disease Evaluation
CT/MRI: head-and-neck, chest, upper abdomen t
X
FDG-PET or FDG-PET/CT t
X
Tumor Tissue Collection
Histology/Cytology, including p16 evaluations (p16 
tested locally) u
X
Tissue Collection for Biomarker Analysis (Tested 
Centrally) u
X
Patient Reported Outcomes 
EORTC QLQ-C30 v
X
X
EORTC QLQ-H&N35 v
X
X
EuroQol EQ-5D v
X
X
a. Treatment 1 includes pembrolizumab/placebo priming, CRT plus two pembrolizumab/placebo doses. Treatment cycles are 3 weeks (21 days).  If radiation 
therapy is interrupted, pembrolizumab/placebo can continue to be given during radiation therapy so that it is given every 21 (±3) days. Treatment 1: Cycle 1,
Day 1 treatment (pembrolizumab/placebo priming) must be given within 3 days of randomization. The window for each visit is ±3 days unless otherwise 
noted. The last dose of CRT is the end of treatment for Treatment 1 phase. Subjects who did not receive all pembrolizumab/placebo doses in Treatment 1 
may make up these missed doses in Treatment 2 to ensure all 17 doses are administered. Pembrolizumab/placebo doses administered after CRT completion 
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are considered part of Treatment 2 maintenance phase. It may be necessary to perform procedures at unscheduled time points if deemed clinically necessary 
by the investigator. Imaging should be performed per Trial Flow Chart time points regardless of any treatment delays.
b. Documented informed consent must be obtained prior to performing any protocol-specified procedures. Results of a test performed prior to the subject 
providing informed consent as part of routine clinical management are acceptable in lieu of a screening test, if performed within the specified time frame.
c. Weekly Physical Examination (Full or Directed, as noted): including presence/absence of feeding tube, assessment for clinical symptoms of hearing loss and 
hydration status. Full physical exam and directed physical exam to be performed by the investigator or qualified designee.  
d. Vital Signs to include temperature, heart rate, respiratory rate, blood pressure, and weight. Height will be measured at Screening Visit only.
e. ECOG performance status at Screening to be performed within 10 days prior to the first dose of trial treatment. ECOG performance status must be 0 or 1 on 
the first day of dosing.
f. Oral and dental check-up (including radiological examination) should be performed at Screening per local standards by the investigator or qualified 
designee.  Teeth extraction, if appropriate, should be performed ideally before the locoregional imaging to avoid feeling dental artifacts. Documented routine 
oral and dental check-up performed within 6 weeks of trial treatment is acceptable and does not need to be repeated in Screening.
g. Neurological exam should be performed at Screening and before the second dose of cisplatin and every subsequent cisplatin injection; and at end of CRT per 
local standards by the investigator or qualified designee. Documented routine neurological exam performed within 6 weeks of trial treatment is acceptable 
and does not need to be repeated in Screening.
h. Audiometric testing will be performed at baseline and repeated during the study if hearing loss is suspected and as clinically indicated per the investigator or 
qualified designee. Documented routine audiometric testing performed within 6 weeks of trial treatment is acceptable and does not need to be repeated in 
Screening. Follow cisplatin label for ototoxicity management. Audiometry testing is required for all subjects as a screening procedure within 6 weeks prior 
to initiation of trial treatment.
i.
A fiberoptic exam and endoscopy of the upper aerodigestive tract is required for all subjects within 8 weeks prior to randomization. Biopsies of the primary
lesion(s) are also required, if appropriate. Photograph(s) of the lesion(s) and/or drawing of the finding(s) should be routinely performed to ease Gross Tumor 
Volume delineation according to local standards. Documented routine fiberoptic exam and endoscopy performed within 8 weeks of trial treatment is 
acceptable and does not need to be repeated in Screening.
j.
Serum or urine pregnancy test occurs 72 hours prior to administration of trial treatment. Monthly pregnancy testing should be conducted as per local 
regulations where applicable.
k. Hematology: Baseline and weekly thereafter. Labs performed within 10 days of treatment initiation during screening, do not need to be repeated at 
Treatment 1: Cycle 1, Day 1 unless clinically indicated. For cisplatin administration, it is best practice to obtain within 24 hours prior to cisplatin treatment.
For pembrolizumab/placebo administration, it is best practice to obtain within 3 days prior to pembrolizumab/placebo treatment. See Section 7.1.3 for list of 
laboratory tests.
l.
Comprehensive Chemistry: Baseline and weekly thereafter. Labs performed within 10 days of treatment initiation during screening, do not need to be 
repeated at Treatment 1: Cycle 1, Day 1 unless clinically indicated. For cisplatin administration, it is best practice to obtain within 24 hours prior to cisplatin 
treatment. For pembrolizumab/placebo administration, it is best practice to obtain within 3 days prior to pembrolizumab/placebo treatment. See Section 7.1.3
for list of laboratory tests. 
m. Creatinine clearance to be repeated within 24 hours prior to cisplatin treatment initiation (Treatment 1: Cycle 1, Day 8) and within 24 hours prior to start of 
each cisplatin administration for management of dose reduction renal toxicity guidelines.
n. Coagulation tests (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. PTT may be performed if the local lab is unable to 
perform aPTT. Any subject receiving anticoagulant therapy should have coagulation tests monitored closely throughout the trial. See Section 7.1.3 for list of 
laboratory tests.
o. Urinalysis: Baseline (within 10 days prior to the start of trial treatment). See Section 7.1.3 for list of laboratory tests.
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p. TSH: In case of elevated TSH result, add Free T3 and Free T4. Free T4 should be performed on all subjects with elevated TSH; Free T3 only needs to be 
performed if it is done as a part of local standard of care. If the Free T3 and Free T4 are not available locally, they can be sent to the central laboratory to be 
performed (see lab manual for details).
q. This 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 subject (or their legally acceptable representative) 
provides documented informed consent for the FBR. If the planned genetic analysis is not approved, but FBR is approved and documented informed consent 
is provided, this sample will be collected for the purpose of FBR.
r. Whole blood samples should be collected pre-dose. Leftover specimens will be stored for future biomedical research if the subject provides documented 
informed consent for future biomedical research.
s. Dosing and procedures outlined for Treatment 1: Cycle 3 Day 8 are to be followed for SFX RT regimen only. For AFX RT regimen, Treatment 1: Cycle 3, 
Day 8 will not be conducted, i.e., the 3rd dose of cisplatin will not be administered. If CRT administration is delayed, follow the dosing schedule and 
procedures in the Treatment 1 phase until CRT dosing has completed.
t.
Contrast enhanced head and neck, chest and upper abdomen (to cover liver in its entirety) CT-scan, or chest CT scan plus head and neck and upper abdomen 
MRI, should be acquired within 6 weeks prior to randomization. The choice between CT and MRI for head and neck and upper abdominal imaging is left to 
the discretion of the investigator but will have to be used consistently for response evaluation, primary endpoint and follow-up unless medically 
contraindicated. FDG-PET or FDG-PET/CT should be acquired within 6 weeks prior to randomization. All FDG-PET reports and corresponding imaging 
reports (CT/MRI) obtained during screening and on-study for all randomized subjects who have completed at least one post-baseline FDG-PET scan will be 
collected by the Sponsor as required by the regulatory agency. Since completion of the final efficacy analysis, any additional post-baseline FDG-PET or 
FDG-PET/CT reports are no longer required to be collected by the Sponsor.
u. Baseline tumor tissue from a core or excisional biopsy (FNA not adequate) from subjects with oropharynx cancer must be tested locally for HPV status (if 
HPV status not known) prior to randomization for stratification. Baseline tumor tissue must also be provided to the central vendor for retrospective PD-L1 
biomarker testing. Refer to Section 7.1.5 for additional information about tissue requirements. Detailed instructions for tissue collection, process and 
shipment are provided in the central laboratory manual. If the subject provides documented Future Biomedical Research (FBR) informed consent, any 
leftover tissue that would ordinarily be discarded at the end of the main study will be retained for FBR.
v. It is a best practice and strongly recommended that PROs are administered to randomized subjects prior to drug administration, adverse event evaluation, and 
disease status notification. The PROs are to be completed by subjects on an electronic PRO (ePRO) tablet in the following order: EQ-5D, EORTC QLQ-
C30, EORTC QLQ-H&N35.  If the subject does not complete the ePROs for any reason, the Miss Mode form must be completed to capture the reason the 
assessment was not performed.
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Treatment 2 (Pembrolizumab or Placebo Maintenance) and Post-CRT Follow-up Year 1 
Trial Period:
Treatment 2
Pembrolizumab/Placebo Treatment & Post-CRT Follow-up Year 1
End of Treatment
Post-
Treatment
Treatment (3-Week Cycles)a
Pembrolizumab / Placebo Maintenance (~14 doses)
Visit Number/Title:
Discontinuation
30-Day Safety 
Follow up t
Cycle:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Week:
1
4
7
10
13
16
19
22
25
28
31
34
37
40
At time of  
Treatment
Discontinuation or 
Last Dose
±3
Scheduled Day(s):
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window Days 
(unless noted):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Review Adverse Events
----------------Continuous reporting------------
X
X
Full Physical Examination b
X
Directed Physical Examination b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and Vital Signs (heart rate, 
blood pressure, respiratory rate, 
temperature) c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral and dental check-up d
X
Neurological examination e
X
Fiber optic examination and 
endoscopy f
X
X
X
X
Neck Dissection (per site discretion)
± biopsy / photograph g
X
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Trial Period:
Treatment 2
Pembrolizumab/Placebo Treatment & Post-CRT Follow-up Year 1
End of Treatment
Post-
Treatment
Treatment (3-Week Cycles)a
Pembrolizumab / Placebo Maintenance (~14 doses)
Visit Number/Title:
Discontinuation
30-Day Safety 
Follow up t
Cycle:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Week:
1
4
7
10
13
16
19
22
25
28
31
34
37
40
At time of  
Treatment
Discontinuation or 
Last Dose
±3
Scheduled Day(s):
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window Days 
(unless noted):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Trial Treatment Administration
Pembrolizumab/Placebo 
Administration h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Procedures/Assessments
Serum or Urine Pregnancy Test – if 
applicable i
X
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
(x)
Pulmonary Function Tests j
X
Hematology k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X t
Comprehensive Chemistry l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X t
Coagulation Tests m
-----If Clinically Indicated-----
Urinalysis n
X
X
X
X
X
Thyroid function o
X
X
X
X
X
X
X
X
X
Disease Evaluation
CT/MRI: head and neck, chest and
upper abdomen p
X
X
X
FDG-PET or FDG-PET/CT q
X
Tumor Tissue Collection
Biopsy (optional as part of neck 
management)
Xr
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Trial Period:
Treatment 2
Pembrolizumab/Placebo Treatment & Post-CRT Follow-up Year 1
End of Treatment
Post-
Treatment
Treatment (3-Week Cycles)a
Pembrolizumab / Placebo Maintenance (~14 doses)
Visit Number/Title:
Discontinuation
30-Day Safety 
Follow up t
Cycle:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Week:
1
4
7
10
13
16
19
22
25
28
31
34
37
40
At time of  
Treatment
Discontinuation or 
Last Dose
±3
Scheduled Day(s):
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Scheduling Window Days 
(unless noted):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Patient Reported Outcomes 
EORTC QLQ-C30 s
X
X
X
X
X s
X s
EORTC QLQ-H&N35 s
X
X
X
X
X s
X s
EuroQol EQ-5D s
X
X
X
X
X s
X s
a. Treatment 2 includes pembrolizumab/placebo maintenance dosing and post-CRT follow-up (Year 1) procedures. Treatment cycles are 3 weeks. The 
window for each visit is ±3 days unless otherwise noted. It may be necessary to perform procedures at unscheduled time points if deemed clinically 
necessary by the investigator. Imaging should be performed per Trial Flow Chart time points regardless of any treatment delays. Subjects who discontinue 
pembrolizumab/placebo for reasons other than an event/disease progression or starting a new anticancer therapy will move into the Post-Treatment Efficacy 
Follow-Up Phase (see Section 6.3 Trial Flow Chart) to be assessed every 3 months (91 ± 7 days) for Follow-up Years 1 through 3 and then every 6 months 
(± 14 days) for Follow-up Years 4 through 5 to monitor disease status. Imaging after 5 years should be done every 6 months (± 28 days).
b. Physical Examination (Full or Directed, as noted) – Day 1 of each Cycle: including presence/absence of feeding tube and assessment for clinical symptoms 
of hearing loss. Audiometric testing should be repeated during the study if hearing loss is suspected and as clinically indicated per the treating physician or 
qualified designee.
c. Vital Signs to include temperature, heart rate, respiratory rate, blood pressure, and weight. Height will be measured at Screening Visit only.
d. Oral/dental check-ups are recommended every 6 months throughout the trial (can be per site discretion).
e. Neurological exam should be performed as clinically indicated per local standards by investigator or qualified designee.
f. Fiberoptic exam and endoscopy of the upper-aerodigestive tract with biopsies of the primary lesion(s), if clinically indicated. Photograph(s) of the lesion(s) 
and/or drawing of the finding(s) should be routinely performed, if clinically indicated.
g. Neck Dissection: See Section 7.1.2.10 for Algorithm (Figure 2). Can be performed approximately 16-20 weeks post-CRT.
h. Pembrolizumab / placebo may be dosed in total for up to 17 doses.
i.
Serum or urine pregnancy test occurs within 72 hours prior to administration of trial treatment. (x) = Monthly pregnancy testing is optional unless required 
per local regulations where applicable.
j.
Pulmonary Function Tests may be checked as part of pre-operative procedures for Post-CRT Neck Evaluation, if indicated.   
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k. Hematology: Every cycle (e.g., Day 1 of each 3-week cycle) prior to pembrolizumab/placebo treatment and as clinically indicated during the remainder of 
the Year 1 follow-up visits. See Section 7.1.3 for list of laboratory tests.
l.
Comprehensive Chemistry: Every cycle (e.g., Day 1 of each 3-week cycle) prior to pembrolizumab/placebo treatment and as clinically indicated during the 
remainder of the Year 1 follow-up visits. See Section 7.1.3 for list of laboratory tests. 
m. Any subject receiving anticoagulant therapy should have coagulation tests monitored closely throughout the trial. PTT may be performed if the local lab is 
unable to perform aPTT. Coagulation tests (PT/INR and aPTT) may be checked as part of pre-operative procedures for Post-CRT Neck Evaluation, if 
indicated.   
n. Urinalysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic examination if needed. See Section 7.1.3 for details.
o. TSH: in case of elevated TSH add Free T3 and Free T4.
p. Contrast enhanced head and neck, chest and upper abdomen (to cover liver in its entirety) CT-scan, or chest CT scan plus head and neck and upper abdomen
MRI, (use the same modality as screening unless medically contraindicated). The examination should be performed at 12 weeks (± 7 days) after the end (last 
dose) of CRT, then every 3 months (± 7 days) during Years 1-3 after randomization; then every 6 months (± 14 days) during Years 4-5 and every 6 months
(±28 days) after Year 5.
q. FDG-PET or FDG-PET/CT scan should be performed at 12 weeks (± 7 days) after the last dose of CRT. The neck dissection could be performed at 
approximately 16-20 weeks after the end of CRT, if indicated. All FDG-PET reports and corresponding imaging reports (CT/MRI) obtained during 
screening and on-study for all randomized subjects who have completed at least one post-baseline FDG-PET scan will be collected by the Sponsor as 
required by the regulatory agency. Since completion of the final efficacy analysis, any additional post-baseline FDG-PET or FDG-PET/CT reports are no 
longer required to be collected by the Sponsor.
r. Tumor tissue collection for diagnostic purposes and biomarker analysis should be timed with the neck dissection procedure. Remaining tissue is required to 
be sent to the central laboratory (see central laboratory manual). If invasive cancer is not found at time of biopsy or surgery that was performed on study, 
tissue does not need to be sent to central laboratory for biomarker testing.
s. It is a best practice and strongly recommended that PROs are administered to randomized subjects prior to drug administration, adverse event evaluation, and 
disease status notification. The PROs are to be completed by subjects on an electronic PRO (ePRO) tablet in the following order: EQ-5D, EORTC QLQ-
C30, EORTC QLQ-H&N35. If the subject does not complete the ePROs for any reason, the Miss Mode form must be completed to capture the reason the 
assessment was not performed.
t.
A subject may discontinue from trial treatment for a reason other than experiencing an event/disease progression or starting a new anticancer therapy but will 
remain in the trial for post-treatment follow-up to monitor disease progression as outlined in Section 7, as long as the subject does not withdraw consent. 
Unresolved abnormal lab results associated with drug-related AEs should be followed until resolution.
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Post-Treatment Efficacy Follow-up Visits
Trial Period:
Post-Treatment Follow-up Visits a
Visit Title:
Follow up 1
Follow up 2
Follow up 3
Follow up 4
After 5 years
Time Period:
Year 2c
Year 3
Year 4
Year 5
Scheduled Interval:
Q3M
Q3M
Q12M
Q6M
Q12M
Q6M
Q12M
Q6M
Scheduling Window Days 
(unless noted):
±7
±7
±14
±14
±14
±14
±14
±28
Administrative Procedures
Prior and Concomitant 
Medication Review
----If Clinically Indicated------
Post-study Anticancer Therapy
Status
X
X
X
X
X
Survival Status b
------------------------------------------------------------------------------------------------------------------------------------------
Clinical 
Procedures/Assessments
Review Adverse Events d
----------------Continuous reporting-------------
Directed Physical Examination e
X
X
X
X
Weight and Vital Signs (heart 
rate, blood pressure, respiratory 
rate, temperature) f
X
X
X
X
Oral and dental check-up g
X
X
X
ECOG Performance Status
X
X
X
X
Fiber optic examination and 
endoscopy 
----If Clinically Indicated------
Tumor Biopsy h
----If Clinically Indicated------
Laboratory 
Procedures/Assessments
Hematology i
----If Clinically Indicated------
Comprehensive Chemistry j
----If Clinically Indicated------
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Trial Period:
Post-Treatment Follow-up Visits a
Visit Title:
Follow up 1
Follow up 2
Follow up 3
Follow up 4
After 5 years
Time Period:
Year 2c
Year 3
Year 4
Year 5
Scheduled Interval:
Q3M
Q3M
Q12M
Q6M
Q12M
Q6M
Q12M
Q6M
Scheduling Window Days 
(unless noted):
±7
±7
±14
±14
±14
±14
±14
±28
Coagulation tests
----If Clinically Indicated------
Urinalysis k
----If Clinically Indicated------
Thyroid function
X
----If Clinically Indicated------
Disease Evaluation
CT/MRI: head-and-neck, chest 
and upper abdomen l
X
Xl
X
X
X
Patient Reported Outcomes 
EORTC QLQ-C30 m
X
X
X
X
EORTC QLQ-H&N35 m
X
X
X
X
EuroQol EQ-5D m
X
X
X
X
a. It may be necessary to perform procedures at unscheduled time points if deemed clinically necessary by the investigator. Imaging should be performed per 
Trial Flow Chart time points regardless of any treatment delays. All visit procedures/assessments should be done every 3 months (i.e., at Months 3, 6, 9 and 
12) during Follow up 1 and 2, and every 6 months (i.e., at Months 6 and 12) during Follow up 3 ,4 and thereafter , and the assessments listed under Q12M 
should be done at Month 12 only of each year.  Note: The post-treatment assessments and imaging schedule start time begins on the last day of CRT.  The 
timeframe for the Post-Treatment Follow-up phase (Follow-up 1 through 4 and thereafter) begins at randomization.  The imaging visit schedule is the same 
as the post-treatment follow-up visit schedule.
b. Survival status will be collected during the post-treatment follow-up visits. Subjects who do not/will not have a scheduled study visit during the Sponsor-
defined time period will be contacted by telephone or have their medical records reviewed for their survival status (excluding subjects that have had a death 
event previously recorded). After 5 years, subjects will be followed by telephone to monitor survival and anticancer treatment status every 6 months 
(± 28 days), until consent withdrawal from trial, becoming lost to follow-up, death or end of the study, whichever is earlier. The Sponsor may request 
survival status to be assessed at additional time points during the course of the study. At the time of obtaining survival status, evidence of an 
event/progression confirmed by biopsy and/or surgery (e.g., biopsy and/or surgery reports) will also be collected for subjects in survival follow-up who have 
not yet experienced an event/progression, if available, and maintained in source documentation and recorded in the database, as appropriate. Additionally, 
imaging assessment performed as a part of standard of care to evaluate disease status for subjects in survival follow-up who have not yet experienced an 
event/progression, should be collected during survival follow-up. All available images should be submitted to the central imaging vendor and recorded in the 
database.
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c. For subjects who discontinue study treatment early, the remainder of their post-treatment follow-up for the 1st year should be completed as specified in 
Follow-up 1. These subjects should remain in Follow-up 1 for up to a total of 2 years.  
d. Treatment-related late toxicity meeting serious criteria may be collected for up to 5 years.
e. Physical Examination (Directed) to include ECOG and may include presence/absence of feeding tube, gastrostomy or tracheostomy positioning and 
assessment for clinical symptoms of hearing loss. Audiometric testing should be repeated during the study if hearing loss is suspected and as clinically 
indicated per the treating physician or qualified designee.
f.
Vital Signs to include temperature, heart rate, blood pressure, respiratory rate, and weight. 
g. Oral/dental check-ups are recommended every 6 months throughout the follow-up visits (or as per site discretion).  
h. Remaining tissue should be sent to the central laboratory (see central laboratory manual) if invasive cancer is found at time of biopsy.
i.
Hematology: if clinically indicated. See Section 7.1.3 for list of laboratory tests.
j.
Comprehensive Chemistry: If clinically indicated. See Section 7.1.3 for list of laboratory tests. 
k. If clinically indicated. Urinalysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic examination if needed. See 
Section 7.1.3 for details. 
l.
Contrast enhanced head and neck, chest and upper abdomen CT-scan, or chest CT scan plus head and neck and upper abdomen MRI, (use the same modality 
as screening unless medically contraindicated). The examination should be similar to the one performed during the work-up procedure: every 3 months (± 
7 days; 3 months = 91 days) during Years 1-3 after randomization; then every 6 months (± 14 days) up to and including Year 5 and every 6 months (± 28 
days) after Year 5 after randomization. All FDG-PET (if acquired) reports and corresponding imaging reports (CT/MRI) obtained during screening and 
on-study for all randomized subjects who have completed at least one post-baseline FDG-PET scan will be collected by the Sponsor as required by the 
regulatory agency. Since completion of the final efficacy analysis, any additional post-baseline FDG-PET or FDG-PET/CT reports are no longer required to 
be collected by the Sponsor.
m. It is a best practice and strongly recommended that PROs are administered to randomized subjects prior to AE evaluation, and disease status notification. 
The PROs are to be completed by subjects on an electronic PRO (ePRO) tablet in the following order: EQ-5D, EORTC QLQ-C30, EORTC QLQ-H&N35.  
If the subject does not complete the ePROs for any reason, the Miss Mode form must be completed to capture the reason the assessment was not performed.  
Since completion of the final efficacy analysis, any additional ePROs are no longer required to be collected by the Sponsor. 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented informed consent from each 
potential subject (or their legally acceptable representative) prior to participating in this 
clinical trial or Future Biomedical Research. If there are changes to the subject’s status 
during the trial (e.g., health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate documented informed consent is in place.
7.1.1.1.1 General Informed Consent
Informed consent given by the subject or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the subject (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 subject (or 
their legally acceptable representative) before participation in the study.
The initial informed consent, any subsequent revised informed consent, and any written 
information provided to the subject must receive the IRB/IEC’s approval/favorable opinion 
in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the trial.  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 subject’s or the subject’s legally acceptable 
representative’s dated signature.
Specifics about the trial and the trial population are to be included in the trial informed 
consent form.  
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, or the subject'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 subject 
before performing any procedure related to future biomedical research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides documented informed consent. At the time of treatment allocation/randomization, 
site personnel will add the treatment/randomization number to the Subject Identification 
Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
Demographics and a complete medical history will be obtained by the investigator or 
qualified designee. The medical history will consist of age, smoking and alcohol habits, use 
of recreational drugs, concurrent illnesses, use of adequate contraception, history of past 
oncological or chronic diseases, assessment of symptoms suggestive of peripheral 
neuropathy and weight loss.
Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s HNC.
Prior and Concomitant Medications Review
7.1.1.6.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before the first dose of trial treatment. Prior treatment for other cancers will 
also be recorded as a prior medication.
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7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Post-study Anticancer Therapy Status
Investigator or qualified designee will record anticancer therapy medication, if any, taken by 
the subject after discontinuing from trial treatment.
Survival Status
Once a subject experiences an event/disease progression, the survival status will be collected 
during the follow-up visits for the first five years and thereafter to assess for survival status 
until death, withdrawal of consent, or at the end of the study, whichever occurs first. Survival 
status could be collected by telephone. 
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 subjects 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 subjects that have a previously recorded 
death event in the collection tool). At the time of obtaining survival status, evidence of an 
event/progression confirmed by biopsy and/or surgery (e.g., biopsy and surgery pathology 
reports) will also be collected for subjects in survival follow-up who have not yet 
experienced an event/progression, if available, and maintained in source documentation and 
recorded in the database, as appropriate.  Additionally, imaging assessment performed as a 
part of standard of care to evaluate for disease status for subjects in survival follow-up who 
have not yet experienced an event/progression, should be collected during survival follow-
up. All available images should be submitted to the central imaging vendor and recorded in 
the database.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.8.1.  
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
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occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol-specified treatment plan due to medical/surgical events or 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical 
events, subject vacation, and/or holidays) >6 weeks between pembrolizumab/placebo doses 
and/or >12 weeks between pembrolizumab/placebo doses for drug-related adverse events 
associated with pembrolizumab exposure (see Section 5.2.1.2.1 for dose modification 
guidelines for drug-related events) require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
Subjects may receive up to 17 doses of pembrolizumab/placebo. If an interruption occurs, the 
subject should restart pembrolizumab/placebo as soon as medically appropriate with the 
subsequent cycle and should not skip cycles. The subject, after an interruption, may restart 
pembrolizumab/placebo cycles as a monotherapy without delay from the original 3-week 
interval schedule, but all future doses should be recalculated in 3-week intervals. Subjects 
should be administered all planned 17 cycles, which could extend beyond the 1-year 
timeframe of the study in order to be considered as having completed study treatment. A 
subject may, if medically appropriate, stop treatment at the end of 1 year.
Administration of trial medication will be monitored by the investigator and/or institution 
staff.  The total volume of pembrolizumab/placebo infused will be compared to the total 
volume prepared to determine compliance with each dose of pembrolizumab/placebo
administered.  
The instructions for preparing and administering pembrolizumab/placebo are provided in the 
Pharmacy Manual.  Treatment with standard therapies will be prepared and administered as 
per the approved product label.
Clinical Procedures/Assessments
Adverse Event Monitoring
All adverse events (AEs) will be recorded; the investigator or qualified designee will assess 
whether those events are drug-related (reasonable possibility, no reasonable possibility) and 
this assessment will be recorded in the database for all AEs. Adverse events will be graded 
and recorded throughout the study and during the follow-up period according to NCI CTCAE 
v4.0. Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment. The collection period will begin 
during registration. All AEs must be followed until resolution or stabilization.
Hematological and biochemistry AEs will be assessed on the basis of regular blood counts. 
The nadir count will be computed at each study medication administration and graded 
according to the CTCAE v4.0 (see Section 7.2.4). Non-hematological acute side effects will 
be assessed and reported separately for each study medication administration and graded 
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according to the CTCAE v4.0. Post-treatment treatment-related late toxicity meeting serious 
criteria will be recorded as well up to 5 years. 
Refer to Section 7.2 for detailed information regarding the assessment and recording of AEs.  
12-Lead ECG
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
Physical Examination
7.1.2.3.1 Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  Additional full physical exams should be performed as specified in the Trial Flow 
Chart.  After the first dose of trial treatment, new clinically significant abnormal findings 
should be recorded as AEs.
The physical examination at Screening will include height, weight and assessment of 
presence or absence of a feeding tube. During CRT, weekly physical examinations will 
consist of weight according to standard practice, evaluation for the signs of dehydration, and 
evaluation for the need for feeding tube, audiometry and hydration.
During the post-treatment follow-up visits for disease evaluation, physical examinations will 
be performed at each visit.
7.1.2.3.2 Directed Physical Examination
For cycles that do not require a full physical examination per the Trial Flow Chart, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to dosing on Day 1 of each treatment cycle or other specified time point in the 
Trial Flow Chart – Section 6.0.  New clinically significant abnormal findings should be 
recorded as AEs.
Height, Weight and Vital Signs
Vital signs include weight, heart rate, blood pressure (diastolic and systolic blood pressures), 
respiratory rate and temperature. Vital signs will be measured at Screening and weekly 
during CRT (prior to the start of the cisplatin infusion on the day of chemotherapy 
administration) and on Day 1 of each cycle during pembrolizumab/placebo maintenance, and 
at each post-treatment follow up visit. 
Height will be measured at Screening only.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG performance status (See Section 
12.5) at Screening, prior to dosing during each treatment cycle and during regular Follow-up 
visits.
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Oral and Dental Check-up
All subjects should have an oral and dental examination including clinical and radiological 
examination by the investigator or other appropriate healthcare provider, per local 
institutional guidelines, during Screening. When clinically indicated, extraction of dental 
elements should be carried out. The interval between extractions and start of CRT should be 
as long as possible to permit healing and subject comfort prior to the commencement of 
treatment. If more than 2 teeth are to be extracted, this should be done prior to CT simulation.  
Oral/dental check-ups are recommended every 6 months throughout the trial (can be per site 
discretion).
Adequate dental care (including daily fluorine application) should be 
recommended as an option to all subjects, at least during follow-up. Documented routine oral 
and dental check-up performed within 6 weeks of trial treatment is acceptable and does not 
need to be repeated in Screening.
Neurological Examination
A neurological examination must be performed at Screening, before the second cisplatin 
injection, and every subsequent injection per local standards by the investigator or qualified 
designee. In case of symptoms or signs experienced by the subject, more frequent 
examinations should be performed per local standards by the investigator or qualified 
designee and the following dose modification (see Section 5.2.1.2.2.7). Documented routine 
neurological exam performed within 6 weeks of trial treatment is acceptable and does not 
need to be repeated in Screening.
Audiometric Testing
Audiometric assessments should be performed by a qualified audiologist, investigator, or 
qualified designee for all subjects at Screening (within 6 weeks prior to randomization).  The 
procedure used for the audiometric exam should be conducted in accordance with local 
institutional practice. As part of the screening assessment, the audiologist, Investigator or 
qualified designee will assess hearing aid use prior to the start of study treatment. If auditory 
symptoms develop after the screening assessment and prior to treatment initiation, the 
audiometric assessments should be repeated prior to treatment initiation. Additional 
comprehensive audiometric assessments should be conducted as deemed appropriate by the 
audiologist, Investigator, or qualified designee and following local cisplatin product label
(For France only: see Section 12.8) to provide continued safety assessment (see also, Section 
6.0 Study Flow Chart). Documented routine audiometric testing performed within 6 weeks of 
trial treatment is acceptable and does not need to be repeated in Screening.
Fiberoptic Examination and Endoscopy
Fiberoptic examination and endoscopy will be performed (under general anesthesia, as 
appropriate) of the upper-aerodigestive tract.
An endoscopy/fiberoptic exam is required during Screening for all subjects within 8 weeks 
prior to the initiation of trial treatment. Documented routine fiberoptic exam and endoscopy 
performed within 8 weeks of initiation of trial treatment is acceptable and does not need to be 
repeated during the 28-day screening period.
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Following randomization, as stated in Section 5.3 and as per Figure 2, an 
endoscopy/fiberoptic exam is also required between 12-14 weeks after completion of CRT 
for subjects whose primary tumor site is positive on FDG-PET scan and suspicious for 
residual disease.
Fiberoptic examination and endoscopy can also be performed (under 
general anesthesia, as appropriate) of the upper-aerodigestive tract if clinically indicated per 
the Trial Flow Chart.
Photographs of the lesion(s) and/or drawing of the finding(s) should be routinely performed 
to ease Gross Tumor Volume delineation, if clinically indicated. 
Neck Dissection (if Clinically Indicated)
Neck imaging (see Section 7.1.4) will be performed per the Trial Flow Chart (see 
Section 6.0) to evaluate the neck for a potential neck dissection. A neck dissection will be 
recommended in case of persistent disease in the neck post CRT based on the results of the 
FDG-PET or FDG-PET/CT scan. If clinically indicated, neck dissection must be performed 
before 20 weeks after the end of CRT and according to standard guidelines at each center.
During the procedure, pembrolizumab/placebo should be held.
Figure 2
Post-Chemoradiation Neck Evaluation
1. Note: Complications and mortality should be assessed after Neck Dissection and Salvage 
Surgery according to Section 5.3.2.5.1.
2. Exceptions to completing biopsy may be considered with sponsor consultation (see 
Section 5.3).
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Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the central laboratory 
manual.
Only safety labs affecting potential treatment must be reviewed prior to study therapy 
administration following the Screening Visit. Labs that would not affect potential treatment 
of the subject can be reviewed, in a timely manner, by an investigator after the date of study 
therapy administration. Similarly, if a site is unable to obtain the thyroid function testing 
(thyroid stimulating hormone [TSH], free T3 and free T4) results prior to scheduled dosing, 
review of the thyroid function test results after dosing is acceptable and poses no additional 
immediate safety risk to subjects.
Serum or Urine Pregnancy Test
Serum or urine pregnancy test occurs within 72 hours prior to administration of trial 
treatment. Monthly pregnancy testing should be conducted as per local regulations where 
applicable.
Pulmonary Function Test
Pulmonary function tests may be performed pre-operatively for neck management per local 
institutional practice and as clinically indicated thereafter.
HIV, HBV, HCV Serology
HIV, HBV, and HCV serology will be conducted on subjects per local regulations and site 
SOPs. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is 
defined by a known positive Hep C Ab result and known quantitative HCV RNA results 
greater than the lower limits of detection of the assay.
Laboratory Safety Evaluations (Hematology, Chemistry, Coagulation and 
Urinalysis)
Laboratory tests for hematology, chemistry, coagulation, and urinalysis are specified in Table 
15.  All laboratory tests to determine eligibility and Drug-Induced Liver Injury (DILI) (see 
Sections 5.1 Entry Criteria Table 1 and 7.2.4.2 Events of Clinical Interest, respectively), 
creatinine clearance prior to cisplatin dosing, creatinine and thyroid testing as specified in 
footnote b are mandatory; all other laboratory tests are recommended and may be performed 
according to your local institutional standard.
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Table 15
Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood (dipstick)
Hemoglobin
Alkaline phosphatase
Glucose
Serum human chorionic 
gonadotropin (hCG)a
Platelet count
Alanine 
aminotransferase (ALT)
Protein
PT (INR)
WBC (total and 
differential)
Aspartate 
aminotransferase (AST)
Specific gravity
aPTT f
RBC count
A measure of carbon 
dioxide (CO2 or 
bicarbonate) d
pH
Hepatitis h
Absolute Neutrophil 
Count (ANC)
Calcium c
Microscopic exam, as 
needed
HIV
Absolute Lymphocyte 
Counts / Lymphocytes
Chloride
Creatinine
Creatinine clearance g
FT3 b
GGT h
FT4 b
Glucose
TSH
Magnesium
HBV, HCV
Phosphorus
Potassium
Sodium
Direct Bilirubini
Total Bilirubin
Total protein
Blood Urea Nitrogen 
(BUN) e
Uric Acid h
Urea e
LDH h
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Hematology
Serum Chemistry
Urinalysis
Other
ALT=alanine aminotransferase, ANC=absolute neutrophil count, aPTT= activated partial thromboplastin 
time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CO2=carbon dioxide, CrCL=creatinine 
clearance, FT3=free triiodothyronine, FT4=free thyroxine, GGT=gamma glutamyl transferase, 
HBV=hepatitis B virus, hCG=human chorionic gonadotropin, HCV=hepatitis C virus, HIV=human 
immunodeficiency 
virus, 
INR=international 
normalized 
ratio, 
LDH=lactate 
dehydrogenase;
PT=prothrombin time, RBC=red blood cell, TSH=thyroid stimulating hormone, WBC=white blood cell.
a During the concomitant chemo-radio-immunotherapy treatment phase and the pembrolizumab/placebo 
maintenance phase, monthly pregnancy testing should occur within 72 hours prior to administration of trial 
treatment and be conducted as per local regulations where applicable.
b In case of elevated TSH result, add Free T3 and Free T4. Free T4 should be performed on all subjects with 
elevated TSH; Free T3 only needs to be performed if it is done as a part of local standard of care. If the free 
T3 and free T4 are not available locally, they can be sent to the central laboratory to be performed (see lab 
manual for details).
c. Corrected calcium should be checked for subjects with hypoalbuminemia.
d If available as standard of care in your region. The carbon dioxide may be either a measurement of CO2 or 
bicarbonate as an electrolyte.
e Blood Urea Nitrogen is preferred; if not available urea may be tested.
f PTT may be performed if the local lab is unable to perform aPTT.
g CrCl during screening is required within 10 days prior to treatment initiation and should be assessed prior 
to randomization.  It does not need to be repeated within 24 hours prior to treatment initiation (Treatment 1: 
Cycle 1, Day 1), unless clinically indicated.  CrCl must be repeated within 24 hours prior to start of each 
cisplatin administration for management of dose reduction for renal toxicity guidelines.  
h Only if clinically indicated
i
Only if total bilirubin is elevated above the upper limit of normal
Pharmacokinetic Evaluations
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
the clinical pharmacology of pembrolizumab across indications. Therefore, upon approval of 
Amendment 04 each site is to stop the collection of PK and ADA samples for all subjects. 
Blood samples for PK and ADA collected prior to Amendment 04 may be stored. Analysis 
will be performed only if required.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the central laboratory manual.
Future Biomedical Research Samples
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover RNA from RNA analyses

Leftover plasma from plasma biomarker analyses

Leftover serum from serum biomarker analyses

Leftover plasma from ctDNA

Leftover main study tumor
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Disease Evaluation
CT/MRI: Head and Neck, Chest and Upper Abdomen 
During screening, contrast enhanced head and neck, chest and upper abdomen CT scan or 
chest CT scan plus head and neck and upper abdomen MRI should be acquired within 
6 weeks of randomization. The choice between CT and MRI for head and neck imaging is 
left to the discretion of the investigator but will have to be used consistently for response 
evaluation, primary endpoint and follow-up. The upper abdomen imaging anatomy should
cover the liver in its entirety.
The follow-up imaging should be acquired at Week 12 post-CRT and then every 3 months
(91 ± 7 days) for three years after randomization, then every 6 months (±14 days) for Years 4
through 5.  Imaging after 5 years should be done every 6 months (±28 days). For all imaging, 
the clock will start at the end of CRT (i.e., last dose of CRT). All of these visits should stay 
on track using the last dose of CRT as the starting clock, i.e., if one of the imaging visits is 
late (even Week 12), the subject will stay on the original schedule starting with the last dose 
of CRT for all future visits; do not recalculate.
The same modality used at screening should be used during pembrolizumab maintenance or 
placebo treatment and during the post-treatment follow-up visits as described in Section 6.0.  
If there is a medical contraindication to using the same modality, a different imaging 
modality may be used.
FDG-PET
During screening, an FDG-PET or FDG-PET/CT scan should be acquired within 6 weeks of 
randomization. Then, at 12 weeks post-CRT ±1 week (approximately Week 19 or Week 20) 
an FDG-PET or FDG-PET/CT scan should be acquired as part of neck management
(see Figure 2, See Section 7.1.2.10). The timing of the FDG-PET or FDG-PET/CT scan 
should be such that the neck dissection could be performed approximately 16-20 weeks post-
CRT, if indicated.
The FDG-PET/CT may replace the CT/MRI scan if the CT is of diagnostic quality when this 
is the local standard practice.
All FDG-PET or FDG-PET/CT and corresponding CT/MRI imaging reports obtained during 
screening and on-study for all randomized subjects who have completed at least one post-
baseline FDG-PET or FDG-PET/CT scan will be collected by the Sponsor as required by the 
regulatory agency.  Since completion of the final efficacy analysis, any additional post-
baseline FDG-PET or FDG-PET/CT reports are no longer required to be collected by the 
Sponsor.
Assessment for Residual Disease and/or Disease Progression
The assessment of residual disease and/or disease progression of a subject based on
radiographic progression per RECIST 1.1 by BICR as well as local pathological evaluation 
of disease, as indicated, is described below and in Table 16.
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Criteria for events of the primary tumor site:
The management of the primary tumor site will be based on investigator-assessed response 
seen on FDG-PET/CT scan 12 weeks after completion of CRT, as illustrated in Figure 2. As 
per Section 8.4.1.1, salvage surgery of the primary tumor site completed at any time with 
invasive cancer present meets criteria for local treatment failure and is an event. 
A biopsy confirming the presence of residual invasive cancer in the primary tumor site 
completed <12 weeks after completion of CRT is only an event if there is also radiographic 
progression per RECIST 1.1 by BICR.
If more than 12 weeks after completion of CRT, salvage surgery is indicated but not possible 
based on MDT assessment, a biopsy of the primary tumor site confirming the presence of 
invasive cancer in the absence of radiographic progression per RECIST 1.1 by BICR is
sufficient evidence alone to fulfill the criteria for an event/treatment failure.
Table 16
Case Scenarios for Residual Disease at the Primary Tumor Site
Scenario 
Number
Radiographic Progression 
per RECIST 1.1 by BICR
Biopsy
Surgery
Oncology 
Assessment
1
Pos or neg
Pos
Pos
Event
2
Neg
Pos if completed
≥12 weeks post CRT
Not done or 
inoperable 
Event
3
Pos
Pos
Not done or 
inoperable
Event
4
Pos
Not done
Not done or 
inoperable
Event
5
Pos or neg
Neg or Not done
Pos
Event
6
Pos or neg
Pos
Neg
No Event
7
Neg
Neg
Not indicated or Not 
done
No Event
8
Pos
Neg
Not done or 
inoperable
No Event
9
Pos or Neg
Neg or Not done
Neg
No Event
10
Neg
Not done
Not done
No Event
BICR=blinded independent central review; CRT=chemoradiotherapy; Neg=negative; Pos=positive; RECIST= Response 
Evaluation Criteria in Solid Tumors.
Criteria for events of neck lymph node dissection:
Figure 2 indicates the management of the neck lymph nodes based on local radiological 
assessment of response observed on FDG-PET/CT scan obtained 12 weeks after completion 
of CRT. When neck dissection is indicated as per Figure 2, this procedure should be 
completed ≤20 weeks after completion of CRT as per Section 7.1.4.2.
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As per Section 7.1.10.3, a neck lymph node dissection or surgery performed in the absence of 
clinical or radiographic progression ≤20 weeks from the end of CRT is not an event/local 
failure if neck disease is completely resected. This is regardless of whether invasive cancer is 
present based on local pathological assessment. Neck dissection or surgery completed >20 
weeks from end of CRT is an event if invasive cancer is found to be present based on local 
pathological assessment (Section 8.4.1.1). 
Neck dissection completed at any time based on clinical progression or radiographic findings 
of progressive disease meets criteria for an event/progressive disease provided the local 
pathology report confirms the presence of invasive cancer. 
If subject proceeds to neck dissection and involved lymph nodes cannot be completely 
resected at time of neck dissection, this is an event irrespective of timing of neck dissection 
(Section 7.1.10.3).
If a biopsy is done <12 weeks post CRT and confirms residual invasive cancer, it is only an
event if there is also radiographic progression per RECIST 1.1 by BICR.
If a subject is not able to undergo a neck dissection that is indicated, a biopsy of a neck 
lymph node confirming the presence of invasive cancer in the absence of radiographic 
progression per RECIST 1.1 by BICR completed ≥12 weeks post CRT is sufficient evidence 
alone to fulfill the criteria for an event/treatment failure.
The development of any new positive nodes not present at baseline or recurring/progressing 
nodes will be considered evidence of regional progression (Section 7.1.10.3). If there is 
radiographic progression per RECIST 1.1 by BICR, this is not an event if subsequent biopsy 
OR neck dissection is negative for invasive cancer per Table 17 through Table 19.
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Case scenarios for neck dissection
Table 17
Case Scenarios for Neck Dissections Completed ≤20 Weeks After Completion of 
CRT With NO Evidence of Clinical or Radiographic Progression
Scenario 
Number
Radiographic Progression per 
RECIST 1.1 by BICR or 
Clinical Progression by 
Physical Exam
Biopsy
Surgery
Oncology 
Assessment
1
Neg
Pos if
completed 
≥12 weeks 
post CRT
Inoperable or Not 
done
Event
2
Neg
Not indicated 
or Neg
Pos and 
incomplete 
resection of 
suspected 
involved LNs
Event
3
Neg
Not indicated 
or Neg
Pos
No Event*
4
Neg
Not indicated 
or Neg
Neg
No Event*
5
Neg
Pos
Pos
No Event*
6
Neg
Pos
Neg
No Event*
7
Neg
Not done
Not done
No Event
8
Neg
Neg
N/A
No Event
BICR=blinded independent central review; CRT=chemoradiation therapy; LN=lymph node; N/A=not applicable; 
Neg=negative; Pos=positive; RECIST=Response Evaluation Criteria in Solid Tumors.
* Neck dissection must be a complete resection of all suspected involved lymph nodes.
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Table 18
Case Scenarios for Neck Dissections Completed ≤20 Weeks After Completion of 
CRT With Evidence of Clinical or Radiographic Progression
Scenario 
Number
Radiographic Progression per 
RECIST 1.1 by BICR or 
Clinical Progression by 
Physical Exam
Biopsy
Surgery
Oncology Assessment
1
Pos
Pos
Neg
No Event*
2
Pos
Not indicated or 
Neg
Neg
No Event*
3
Pos
Neg
Not done
No Event
4
Pos
Not indicated or 
Neg
Pos
Event
5
Pos
Pos
Pos
Event
6
Pos
Pos
Inoperable
or not done
Event**
7
Pos
N/A
N/A
Event***
BICR=blinded independent central review; N/A=not applicable; Neg=negative; Pos=positive; RECIST= Response 
Evaluation Criteria in Solid Tumors.* Neck dissection must be a complete resection of all suspected involved lymph nodes.
**Only an event if:
a.
For clinical PD without evidence of radiographic PD, a biopsy performed ≥12 weeks post CRT is positive 
confirming invasive disease, and the subject is inoperable/surgery not done.
b.
For radiographic PD, a biopsy performed regardless of timing is positive confirming invasive disease, and the 
subject is inoperable/surgery not done.
*** Only an event if evidence of radiographic progression per RECIST 1.1 is assessed by BICR.
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Table 19
Case Scenarios for Neck Dissections Completed >20 Weeks After Completion of 
CRT
Scenario 
Number
Radiographic Progression 
per RECIST 1.1 by BICR or 
Clinical Progression by 
Physical Exam
Biopsy
Surgery
Oncology 
Assessment
1
Pos or Neg
Not done or 
Neg
Pos
Event
2
Pos or Neg
Pos
Pos
Event
3
Neg
Pos
Neg or Inoperable or 
Not done
Event
4
Pos
Pos
Neg or inoperable or 
Not done
Event
5
Pos*
Not done
Not done
Event*
6
Pos or Neg
Not done or 
Neg
Neg
No Event
7
Neg
Not done
Not done
No Event
8
Pos or neg
Neg
Not done
No Event
BICR=blinded independent central review; Neg=negative; Pos=positive; RECIST= Response Evaluation Criteria in Solid 
Tumors.
*Only an event if evidence of radiographic progression per RECIST 1.1 is assessed by BICR.
Criteria for events of Recurrent disease:
An assessment of recurrent disease meets the criteria for progressive disease, as defined in 
Section 8.4.1.1, if one of the following criteria are fulfilled (Table 20):

Radiographic evidence of recurrent disease as per RECIST 1.1 by BICR and biopsy is 
not done and/or not indicated.

Radiographic evidence of recurrent disease as per RECIST 1.1 by BICR and 
subsequent biopsy confirms evidence of invasive cancer based on local pathological 
assessment. 

A biopsy confirming invasive cancer at the site of recurrence regardless of whether 
radiographic progression as per RECIST 1.1 is assessed by BICR.
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Table 20
Case Scenarios for Recurrent Disease
Scenario Number
Radiographic Progression 
per RECIST 1.1 by BICR
Biopsy
Oncology Assessment
1
Pos or Neg
Pos
Event
2
Not done
Pos
Event
3
Pos
Not done
Event
Not done
Neg
No Event
5
Neg
Neg or Not done
No Event
6
Pos
Neg
No Event
BICR=blinded independent central review; Neg=negative; Pos=positive; RECIST= Response Evaluation Criteria in Solid 
Tumors.
Criteria for Events of Distant Metastases
An assessment of metastatic disease meets the criteria for progressive disease, as defined in 
Section 8.4.1.1, if one of the following criteria are fulfilled (Table 21):

Radiographic evidence of metastatic disease as per RECIST 1.1 by BICR and biopsy 
is not done and/or not indicated. 

Radiographic evidence of metastatic disease as per RECIST 1.1 by BICR and 
subsequent biopsy confirms evidence of invasive cancer based on local pathological 
assessment. 

A biopsy confirming invasive cancer at the site of metastasis regardless of whether 
radiographic progression as per RECIST 1.1 is assessed by BICR.
Table 21
Case Scenarios for Metastatic Disease. 
Scenario 
Number
Radiographic Progression 
per RECIST 1.1 by BICR
Biopsy
Oncology Assessment
1
Pos or Neg
Pos
Event
2
Not done
Pos
Event
3
Pos
Not done
Event
4
Not done
Neg
No Event
5
Neg
Neg or Not done
No Event
6
Pos
Neg
No Event
BICR=blinded independent central review; Neg=negative; Pos=positive; RECIST= Response Evaluation Criteria in Solid 
Tumors.
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Tumor Tissue Collection 
HPV
Subjects must have assessment of HPV status from tumor tissue prior to randomization (see 
Section 5.1.2). HPV stratification in this trial may be performed using local testing of HPV 
status in subjects with oropharynx cancer using the specified method.
Note: Tumor p16 expression must be evaluated by assessment of IHC analysis with CINtec® 
p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using standard protocol. 
Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic staining in 
70% or more of the tumor cells.
Note: If local p16 testing results are not available, or cannot be assessed by the specified 
method, a tumor tissue sample may be submitted for p16 testing at the designated central 
laboratory.
Note: Oral cavity, hypopharyngeal, and larynx cancer are not required to undergo local HPV 
testing by p16 IHC as by convention these tumor locations are assumed to be HPV-negative. 
NOTE: However, a tissue sample (regardless of tumor location: oropharyngeal, oral cavity, 
hypopharynx, or larynx cancer) should be sent to the central vendor for testing and can be the 
same tissue sample used for PD-L1 (see central laboratory manual).
PD-L1
All subjects will submit either a core or excisional biopsy (fine needle aspirate [FNA] is not 
adequate) to a central lab for characterization of PD-L1 status.  
This specimen may be the diagnostic sample for subjects with a new diagnosis of LA 
HNSCC.
Detailed instructions for tissue collection, processing and shipment are provided in the 
central laboratory manual.
Patient Reported Outcomes (PROs)
The EQ-5D, EORTC QLQ-C30, and EORTC QLQ-H&N35 PRO questionnaires will be 
administered on an electronic PRO (ePRO) tablet by trained site personnel and completed 
electronically by subjects in the following order: EQ-5D first, then EORTC QLQ-C30, and 
lastly the EORTC QLQ-H&N35 at the time points specified in the Trial Flow Chart.  It is a 
best practice and strongly recommended that ePROs are administered to randomized subjects 
prior to drug administration, adverse event evaluation, and disease status notification. If the 
subject does not complete the ePROs for any reason, the Miss Mode form must be completed 
to capture the reason the assessment was not performed.  See protocol-specific guidance in 
the ePRO manual.  Since completion of the final efficacy analysis, any additional ePROs are
no longer required to be collected by the Sponsor.
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Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.7.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com).  Subsequently, 
the subject'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 subject 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 trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
7.1.7.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of maintaining 
the protocol-specified visit schedule.

The investigator or qualified designee must make every effort to regain contact with the 
subject at each missed visit (e.g., phone calls and/or a certified letter to the subject’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the subject’s medical record.
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Subject Blinding/Unblinding
TRIAL TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE SUBJECT. EVERY EFFORT 
SHOULD BE MADE NOT TO UNBLIND THE SUBJECT UNLESS NECESSARY.
For emergency situations where the investigator or delegate needs to identify the drug used 
by a subject and/or the dosage administered, he/she will contact the emergency unblinding 
call center by telephone and make a request for emergency unblinding.  As requested by the 
investigator or delegate the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the sponsor.  Prior to contacting the emergency 
unblinding call center to request unblinding of a subject’s treatment assignment, the 
investigator or delegate must enter the toxicity grade of the adverse experiences observed, the 
relation to study drug, the reason thereof, etc., in the medical chart etc.
Following Sponsor consultation, patients may be unblinded if they have biopsy-proven 
disease progression and this information is required to guide future treatment decisions for 
the patient.
For trials that require non-emergency unblinding as part of the trial design (eg, in cases of
biopsy proven disease progression in this trial) to support treatment decisions, IVRS should 
be used to unblind the subject. The emergency unblinding center should not be used for this 
purpose.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician should continue to be monitored in the trial.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
Treatment/Vaccine identification information is to be unmasked ONLY if necessary for the 
welfare of the subject.  Every effort should be made not to unblind the subject unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Once an emergency unblinding has 
taken place, the principal investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the subject.
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 trial that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible.  
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
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See protocol-specified guidance in the study-specific Investigator Trial File Binder (ITFB),
Pharmacy Manual, central laboratory manual, and Site Imaging Manual.
Domiciling
At the discretion of the investigator, subjects may report to the clinical research unit (CRU) 
the evening prior to the schedule day of cisplatin administration and remain in the unit until 
24 hours post-dose to ensure proper hydration.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Within 28 days prior to randomization, potential subjects will be evaluated to determine that 
they fulfill the entry requirements as set forth in Section 5.1. Visit requirements are outlined 
in Section 6.0 – Trial Flow Chart.
Results of a test or procedure prior to the subject providing informed consent as part of 
routine clinical management are acceptable in lieu of a screening test or procedure if 
performed within the specified time frame. Screening procedures are to be completed within 
28 days prior to the first dose of trial treatment except the following:

Laboratory tests and ECOG Performance Status (PS) are to be performed within 10 days 
prior to the first dose of trial treatment. ECOG PS must be 0 or 1 on the first day of 
dosing.

For women of reproductive potential, a serum pregnancy test will be performed within 72 
hours prior to the first dose of trial treatment. A urine test may be considered if serum test 
is not appropriate.

CrCl during screening is required within 10 days prior to treatment initiation and should 
be assessed prior to randomization.  It does not need to be repeated within 24 hours prior 
to treatment initiation (Treatment 1: Cycle 1, Day 1), unless clinically indicated.  CrCl 
must be repeated within 24 hours prior to start of each cisplatin administration for 
management of dose reduction for renal toxicity guidelines.  

Tumor sample collection (not required to be obtained within 28 days prior to the first 
dose of trial treatment). 

Documented routine oral and dental check-up (including radiological examination with 
teeth extraction if needed) are acceptable within 6 weeks prior to trial treatment to avoid 
feeling dental artifacts.

Documented routine neurological exam is acceptable within 6 weeks prior to trial 
treatment.
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
Documented routine fiberoptic exam and endoscopy of upper-aerodigestive tract is 
required for all subjects during screening.  Biopsies of the primary lesion(s) are also 
required if appropriate.  Associated photographs and/or drawing of the finding(s) are 
acceptable within 8 weeks of trial treatment.

Documented routine audiometry tests are acceptable within 6 weeks of trial treatment.
The subject’s documented informed consent to undergo screening for the clinical trial must 
be given prior to the performance of any protocol laboratory/imaging tests that are not part of 
local routine guidelines.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria are met.
Treatment Period
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided in Section 7.1 – Trial Procedures. 
Treatment 
1 
includes 
pembrolizumab/placebo 
priming, 
CRT 
plus 
two 
pembrolizumab/placebo doses. Treatment 2 includes pembrolizumab/placebo maintenance 
dosing and post-CRT follow-up (Year 1) procedures.
Subjects who did not receive all pembrolizumab/placebo doses in Treatment 1 may make up 
these missed doses in Treatment 2 to ensure all 17 doses are administered.  
Pembrolizumab/placebo doses administered after CRT completion are considered part of 
Treatment 2 maintenance phase.
Post-Treatment Visits
7.1.8.3.1 End-of-Treatment Visit 
The End of Treatment visit should occur at the time trial treatment is completed or
discontinued for any reason. If the End of Treatment visit occurs 30 days from the last dose 
of trial treatment, at the same time as the mandatory 30-Day Safety Follow-Up visit, the End 
of Treatment visit procedures and any additional Safety Follow-Up procedures should be 
performed. Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
Subjects who discontinue trial treatment for a reason other than an event/disease progression, 
withdrawal of consent, or starting a new anticancer therapy will still be considered on study 
and should continue with scheduled assessments (also refer to Section 5.10.1).
7.1.8.3.2 Safety Follow-up Visit
The mandatory 30-Day Safety Follow-Up Visit should be conducted 30 days after the last 
dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first. All AEs that occur prior to the 30-Day Safety Follow-Up Visit should be 
recorded.
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Additionally, subjects in Post-Treatment Follow-Up will be followed for treatment-related 
late toxicities meeting serious criteria for up to 5 years and should be recorded.  
7.1.8.3.3 Efficacy Follow-up Visits
Subjects who complete trial treatment (all 17 doses of pembrolizumab/placebo) or
discontinue trial treatment for a reason other than an event/disease progression or starting a 
new anticancer therapy will move into the Post-Treatment Efficacy Follow-Up Phase and 
should be assessed every 3 months (91 ± 7 days) for Follow-Up Years 1 through 3 and every 
6 months (± 14 days) for Follow-Up Years 4 through 5 and every 6 months (± 28 days) after 
Year 5 after randomization by radiologic imaging to monitor disease status as well as all 
assessments, as outlined in the Post-treatment Efficacy Follow-up Visits trial flow chart (see 
Section 6.3 and Table 22 below). The radiologic imaging and all assessments and procedures 
noted in the trial flow chart should be conducted on the same day (or if on different days 
should stay on the same schedule) with a clock start date of last dose of CRT. The clock will 
start at the end of CRT (i.e., last dose of CRT). All follow-up visits should stay on track 
using the last dose of CRT as the starting clock, i.e., if one of the follow-up visits is delayed, 
the subject will stay on the original schedule starting with the last dose of CRT for all future 
visits. The schedule should not be recalculated.
For subjects who discontinue study treatment early, the remainder of their post-treatment 
follow-up for the 1st year should be completed as specified in Follow-up 1. These subjects 
should remain in Follow-up 1 for up to a total of 2 years (Table 22).
Table 22
Post-Treatment Follow-up Phase Schedule
Follow-up 1
Follow-up 2
Follow-up 3
Follow-up 4
After Year 5
Remainder of Year 
1 for subjects who 
discontinued 
Pembrolizumab/ 
Placebo treatment 
prior to completion 
of Year 1
Follow up Year 2
Follow up Year 3
Follow up Year 4
Follow up Year 5
Follow up after 
Year 5
Assessed every 3 
months (± 7 days) to 
monitor disease 
status
Assessed every 3 
months (± 7 days)
to monitor disease 
status
Assessed every 6 
months (± 14 days) to 
monitor disease status
Assessed every 6 
months (± 
14 days) to 
monitor disease 
status
Assessed every 
6 months (± 28
days) to monitor 
disease status
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Imaging Follow-Up Visits
Subjects who complete trial treatment (all 17 doses of pembrolizumab/placebo) or subjects 
who discontinue trial treatment without a documented event/disease progression as described 
in Section 5.10.1, should continue with imaging and other clinical assessments per the 
protocol-defined 3- and 6-month visit schedule until: 1) an event/disease progression, 2) 
death, 3) withdrawal of consent or 4) study conclusion or early termination, whichever 
occurs first.
Information regarding post-study anticancer treatment will be collected if new treatment is 
initiated.
7.1.8.3.4 Survival Follow-up Assessments
Once a subject experiences an event/disease progression as defined in the EFS Section 
8.4.1.1, the subject enters the Survival Follow-Up Phase and should be contacted by 
telephone or have their medical records reviewed every 3 months (±7 days) during Follow-
Up Years 1 through 3 and every 6 months (±14 days) during Follow-Up Years 4 through 5 
and every 6 months (±28 days) after Follow-Up Year 5 to assess for survival status until 
death, withdrawal of consent or the end of the study, whichever occurs first. Assessment of 
overall survival should also include evaluation for whether other anticancer therapy has been 
initiated. When assessing for survival status for subjects in survival follow-up who have not 
yet experienced an event/PD, also evaluate for whether the subject has had additional 
imaging assessments or experienced biopsy and/or surgery confirmed progression. The 
Sponsor may request survival status to be assessed at additional time points during the course 
of the study. For example, survival status may be requested prior to the eDMC safety review, 
efficacy interim analyses and final analysis. All subjects who are in the Survival Follow-Up 
Phase and not known to have died prior to the request for these additional survival status time 
points will be contacted or have their medical records reviewed at that time. These additional 
assessments will have no effect on the schedule for the protocol-specified Survival Follow-
Up Phase, i.e., the schedule for Survival Status (see Section 6.3 - Post-Treatment Efficacy 
Follow-up Visits) will continue as planned whether or not an additional survival status 
assessment is conducted.
Criteria of Evaluation
Evaluation of Efficacy
Objective tumor response and time to progression will be measured according to the 
RECIST 1.1 criteria [27], Section 12.7.
Response criteria are essentially based on a set of evaluable lesions (including measurable 
and non-measurable lesions) identified at baseline as target lesions, and/or non-target lesions, 
which are followed until disease progression. When the investigator identifies radiographic 
progression per RECIST 1.1, the central imaging vendor will perform expedited verification 
of radiologic PD and communicate the results to the trial site and Sponsor. Treatment/post-
treatment follow-up should continue until PD has been verified or an event has occurred, 
death, withdrawal of consent, study conclusion or early termination, whichever occurs first. 
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The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The 
complete criteria are included in the published RECIST document (available at 
http://www.eortc.be/RECIST. 
Measurability of Tumor Lesions at Baseline
7.1.9.2.1 Definitions

Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 

Measurable lesions - tumor lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) and as ≥10 mm with CT scan or clinical 
examination [using calipers]. Bone lesions are considered measurable only if assessed 
by CT scan and have an identifiable soft tissue component that meets these 
requirements (soft tissue component >10 mm by CT scan). Malignant lymph nodes 
must be ≥15 mm in the short axis to be considered measurable; only the short axis 
will be measured and followed. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters) by use of a ruler or calipers. Tumor 
lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 

Non-measurable lesions - All other lesions (or sites of disease), including small 
lesions are considered non-measurable disease. Bone lesions without a measurable 
soft tissue component, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic involvement 
of lung or skin and abdominal masses followed by clinical examination are all non-
measurable. Nodes that have a short axis <10 mm at baseline are considered non-
pathological and should not be recorded or followed. 

Target Lesions. When more than one measurable tumor lesion or malignant lymph 
node is present at baseline all lesions up to a maximum of 10 lesions total (and a 
maximum of 5 lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those 
that lend themselves to reproducible repeated measurements. Note that pathological 
nodes must meet the criterion of a short axis of ≥15 mm by CT scan and only the 
short axis of these nodes will contribute to the baseline sum. At baseline, the sum of 
the target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: 
overall maximum of 10 is to be calculated and recorded.

Non-target Lesions. All non-measurable lesions (or sites of disease) including 
pathological nodes (those with short axis ≥10 mm but <15 mm), plus any measurable 
lesions over and above those listed as target lesions are considered non-target lesions. 
Measurements are not required but these lesions should be noted at baseline and 
should be followed as “present” or “absent”.
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All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment.
Methods of Measurements
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be 
identified on a calendar schedule and should not be affected by delays in therapy, which may 
be treatment arm dependent. While on study, all target lesions recorded at baseline should 
have their actual measurements recorded on the CRF at each subsequent evaluation, even 
when very small (e.g., 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned. For lesions which fragment/split, add together the longest diameters of the 
fragmented portions; for lesions which coalesce, measure the maximal longest diameter for 
the “merged lesion”.

Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is recommended. If feasible, imaging is preferred.

Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.

CT, MRI. CT is the best currently available and reproducible method to measure 
lesions selected for response assessment. This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. 
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g., for body scans). While PET scans are not considered adequate 
to measure lesions, FDG-PET CT scans may be used providing that the measures are 
obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast).

Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT must be obtained.

Endoscopy. The utilization of these techniques for objective tumor evaluation is not 
allowed. However, they can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint.

Cytology, Histology. These techniques can be used to differentiate between PR and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types 
such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse effect of treatment (e.g., with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
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neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease.
Frequency of Tumor Re-evaluation
Baseline assessments: Physical examination including head and neck examination, contrast 
enhanced CT scan of head and neck, chest, and upper abdomen (to cover liver in its entirety)
or head and neck and upper abdomen MRI and chest CT-scan. FDG/PET scan is an option to 
replace the chest CT-scan.
Tumor evaluation: Physical examination to assess tumor status and toxicity will be 
performed every 3 months for 3 years; after year 3, physical examination will be performed 
every 6 months until year 5. Imaging after 5 years should be done every 6 months
(± 28 days).
Tumor imaging: disease evaluation will be performed by contrast enhanced CT scan of head 
and neck, chest and upper abdomen or head and neck and upper abdomen MRI and chest CT 
scan 12 weeks (± 7 days) after the end of CRT and then every 3 months (± 7 days) during the 
first 3 years since randomization. During the fourth and fifth Efficacy Follow-Up years,
imaging will be performed every six months (± 14 days). Imaging after 5 years should be 
done every 6 months (± 28 days). When the investigator identifies radiographic progression 
per RECIST 1.1, the site should submit the imaging with verification of progression (VOP) 
request to the central imaging vendor as soon as possible. Expedited VOP read will be 
performed by BICR and the results will be communicated to the site and Sponsor. If initial 
site-assessed PD was not verified by BICR, each subsequent imaging must be submitted to 
central imaging vendor with VOP request until PD has been verified. Treatment should 
continue until PD has been verified by BICR, initiation of a new anticancer treatment, death, 
withdrawal of consent, study conclusion or early termination, whichever occurs first.
Note: The imaging schedule start time begins on the last day of CRT. Years 1-5 and 
thereafter in the Post-Treatment Follow-up year (Follow-up 1 through Follow-up 4 and 
thereafter) start time begins at randomization, and the imaging schedule visits should be
conducted at the same time as the post-treatment follow-up visits.
Evaluation of the neck for potential neck dissection: Neck imaging (MRI or CT-scan) and 
FDG-PET/scan will be performed at week 12 (±7 days) after the end of CRT to evaluate the 
neck in the context of potential neck dissection. Neck dissection will be recommended in 
case of persistent disease in the neck and should be performed before the end of Week 16 
after the last dose of CRT but could be performed out to Week 20 after the last dose of CRT. 
Date of Event/Progression
This is defined as the date of the first of the following events:

The first day when the RECIST (version 1.1) criteria for PD are met.

The first day there is pathological confirmation from surgery or biopsy of progressive 
and/or residual invasive cancer.

Date of death due to any cause.
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Refer to Ref 51 as well as above for further information on what constitutes early 
progression, assessment of progression of non-target disease, new lesions and usage of FDG-
PET to diagnose progression.
Event-Free Survival
Event-free survival is defined as the time from the date of randomization to the date of first 
record of any of the following events:
Progression per RECIST 1.1 by BICR or biopsy as indicated for:

Locoregional progression or recurrence 

Distant metastasis
Surgery:

Salvage surgery for persistent or residual disease at the primary tumor site requiring 
surgical removal when invasive cancer is present on final pathology
o
If salvage surgery of the primary tumor site cannot be performed, biopsy 
completed 12 or more weeks following completion of CRT is an event if invasive 
cancer is present.

Neck dissection or surgery (performed for clinical or radiological disease progression
per RECIST 1.1) ≤20 weeks from end of CRT when invasive cancer is present

Neck dissection or surgery >20 weeks from end of CRT when invasive cancer is 
present 
o
If neck dissection or surgery cannot be performed, biopsy completed 12 or more 
weeks following completion of CRT is an event if invasive cancer is present.
Death due to any cause
Local Regional Control
Time to locoregional failure is defined as the time from the date of randomization to the date 
of the first record of appearance of local or regional progression/recurrence, to the date of 
neck dissection ≤20 weeks performed for clinical or radiological (RECIST 1.1) disease 
progression from end of CRT when invasive cancer is present, to the date of neck dissection 
>20 weeks from end of CRT when invasive cancer is present, or to the date of salvage 
surgery of primary tumor when invasive cancer is present performed for clinical or 
radiological (RECIST 1.1) disease progression, whichever comes first. When neck dissection 
or salvage surgery of the primary tumor site is indicated but not possible, date of locoregional 
failure can be defined as the date of biopsy that confirms presence of invasive cancer.
Distant recurrence/progression diagnosed before locoregional failure and death in absence of 
locoregional failure are not considered events of interest, but as competing risks events in the 
analysis of this endpoint.
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Distant Metastasis Free Survival 
Distant metastasis free survival is defined as the time from the date of randomization to the 
date of first record of appearance of distant metastasis or death for any cause. Locoregional
failure or second cancers diagnosed before the distant metastases are not considered events of 
interest for this endpoint.
Overall Survival
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death for any cause. 
Assessment of Response
Measurement of Response
Due to the difficulties in objectively assessing response following chemoradiation, response 
will not be a study endpoint, but measurements will be recorded to assist with determination 
of progressive disease and locoregional failure status. Measurements will be taken from CT 
or MRI and the same method should be used to follow subjects unless medically 
contraindicated. All subjects will have a clinical and radiological (CT or MRI and FDG-PET 
or FDG-PET/CT) assessment at Week 20 (12 weeks post-completion of CRT) as defined in 
Section 7.1.4.
Local Failure
Local failure will be primarily determined by evidence of progression or recurrence clinically 
or radiologically. For clinical and radiographic assessments, RECIST 1.1 criteria for 
progressive disease shall be used whenever applicable (see Section 7.1.9). In the case of 
nonmeasurable disease or in circumstances where laryngeal oedema complicates the 
interpretation of radiological measurements, unequivocal clinical description of disease 
progression is required. Biopsy proof of progressive disease is desirable but is not essential if 
progression documented. Any form of salvage surgery at the primary site after 12 weeks post 
CRT will be considered either local or regional progression unless the pathology shows no 
evidence of disease. If a subject has a biopsy result showing disease at the primary site at the 
time of or beyond 12 weeks after completion of CRT, this can be used as evidence for local 
failure, even if no other evidence of progression has been documented.
Regional Failure
If neck disease cannot be completely resected at neck dissection, this will be deemed to be 
regional failure. If they have completely resected positive nodes from a neck dissection
performed in the absence of clinical or radiographic progression ≤20 weeks after completion
of CRT, they will not be considered to have experienced regional progression since the neck 
dissection completed within this timeframe is part of the pre-determined treatment package. 
Subjects who do not have a neck dissection because their neck disease is judged to be
unresectable will only be deemed to have failure in the neck after biopsy or cytological 
confirmation is obtained or disease progression is documented. Regardless of the neck 
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management chosen, if he/she undergoes salvage neck dissection at any time based on 
clinical or radiographic findings of progressive disease, then the subject meets the criteria for 
regional failure provided the pathology report confirms the presence of cancer.
Development of any new positive nodes not present at baseline or recurring/progressing 
nodes will be considered evidence of regional progression.
Locoregional Failure
This is defined as local failure, regional failure, or both. For the purposes of determining site 
of first failure, the category of both will be applicable if local and regional failure occurs 
within one month of each other.
Distant Failure
This is defined as the presence of positive pathological or radiological evidence of recurrent 
disease at any site of the body with the exception of those defined as ‘local’ or ‘regional’.
When distant metastases are the first indication of relapse, then the subject must be examined 
for locoregional disease.
Post-CRT Neck Surgery
Neck Dissection
Participating centres will be required to adhere to the following policies regarding post-CRT
neck dissection in subjects who have achieved a complete response at the primary site.
No neck surgery may be performed before the post-CRT assessment in Week 20 from 
randomization (12 weeks following completion of CRT) unless there is evidence of 
progressive disease. Subjects who achieve a complete clinical and complete metabolic 
response as assessed by FDG-PET or FDG-PET/CT in Week 12 post-completion of RT will 
not have any neck dissection. Those subjects with a residual nodal mass and evidence of 
metabolic activity on FDG-PET or FDG-PET/CT at that time should proceed immediately to 
neck dissection. Any residual metabolically inactive mass may be observed for continued 
regression with the FDG-PET or FDG-PET/CT being repeated at 3 monthly intervals up to 9 
months post-CRT or follow local institutional guidelines. If the nodal mass ceases regressing 
or begins to grow and/or a subsequent FDG-PET or FDG-PET/CT scan shows metabolic 
activity the subject must proceed to neck dissection. If the subject has a residual nodal mass 
with short axis >1 cm but <2 cm at 9 months post-CRT that remains static in size and FDG-
PET or FDG-PET/CT negative, it may be continued to be observed.
The extent of neck dissection may be selective or comprehensive according to the initial 
extent of nodal disease. In subjects with limited nodal disease pre-treatment, a selective neck 
dissection is preferred.
Salvage Neck Dissection
Salvage neck dissection for recurrent disease (after achieving a complete response in the 
neck) may be undertaken at any time according to clinical indications.
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Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
All adverse events considered to be post-surgical complications by the investigator from time 
of protocol-specified surgery through 30 days following surgery, must be reported by the 
investigator.
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.4.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
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Definitions of Medication Error, Misuse, and Abuse
Investigators need to document if an SAE is associated with a medication error, misuse, or 
abuse.
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the participant.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired non-therapeutic 
effect.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of pembrolizumab 
and as any dose ≥20% over the prescribed dose for the CRT treatments. No specific 
information is available on the treatment of an overdose of pembrolizumab. In the event of 
overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated.
Cisplatin Overdose
There is no specific antidote for cisplatin overdose. Overdose may result in the side effects 
associated with the drug occurring in an excessive manner.
Otherwise, overdose should be managed according to local label and practice.
Radiation Overdose
There is no specific antidote for radiation overdose. In the event of an overdose, the subject 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated.
Reporting of Overdose to the Sponsor
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
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All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial. 
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
documented 
informed 
consent 
form 
is 
provided
but 
before 
treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
Pregnancies and lactations of subjects and female partners of male subjects that occur from 
the time of treatment allocation/randomization through 180 days following cessation of 
Sponsor’s product must be reported. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events     
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
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●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 23 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.4.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.4.3 for additional details), whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
All serious adverse events that are considered to be post-surgical complications by the 
investigator, from the time of protocol-specified surgery through 90 days following surgery 
or 30 days following protocol-specified surgery if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported by the investigator.
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor. Subjects in post-
treatment follow-up will be actively followed for treatment-related late serious adverse 
events for up to 5 years.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is documented until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
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the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. 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 trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.  
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 subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as an SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
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Table 23
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
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 or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a MSD product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event 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 drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject 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 trials 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
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
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; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject 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 trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
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
Subject 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 subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Trial Steering Committee
This trial will be conducted in consultation with a Trial Steering Committee.  The Trial 
Steering Committee comprises:
•
Sponsor personnel 
•
Investigators participating in the trial 
•
Consulting therapeutic-area experts and clinical trialists 
The Trial Steering Committee will provide guidance on the operational aspects of the trial.  
Specific details regarding responsibilities and governance of the Trial Steering Committee 
will be described in a separate charter.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
external Data Monitoring Committee (eDMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
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facilitation; the trial governance structure; and requirements for and proper documentation of 
DMC reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both subject safety 
and the continued ethical integrity of the trial.
An eDMC recommendation will be communicated to the EOC as agreed to in the DMC 
Charter.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental (sSAP) and referenced in the Clinical Study Report (CSR) for 
the study. Separate analysis plans may be developed for PK/modeling analysis, biomarker 
analysis, and genetic data analysis. Post hoc exploratory analyses will be clearly identified in 
the CSR. The analysis plan for ePRO assessments will be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.  
Study Design Overview
This is a randomized, double-blind, multicenter Phase III trial to 
evaluate efficacy and safety of pembrolizumab in combination with 
CRT versus placebo in combination with CRT in subjects with locally 
advanced HNSCC.
Treatment Assignment
Approximately 780 subjects will be randomized 1:1 into the following 
two treatment arms: Arm 1 will receive the combination therapy of 
pembrolizumab 200 mg administered intravenously (IV) every 3 
weeks (Q3W) in combination with CRT; Arm 2 will receive placebo 
Q3W in combination with CRT. Stratification factors are provided in 
Section 5.6.  This study will be conducted as a double-blind study 
under in-house blinding procedures.
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Event-free survival (EFS)
Key Secondary Endpoints
Overall survival (OS)
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypotheses for EFS will be evaluated by comparing 
pembrolizumab in combination with CRT to placebo in combination 
with CRT using a stratified log-rank test.  Estimation of the hazard ratio 
will be done using a stratified Cox regression model.  Event rates over 
time will be estimated within each treatment group using the Kaplan-
Meier method.  
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Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers 
differ with respect to the analyses that will be performed. In this trial, 
no adverse events of interest warrant inference testing as Tier 1 events.
Tier 2 parameters will be assessed via point estimates with 95% 
confidence intervals (CI) provided for between-group comparisons; 
only point estimates by treatment group are provided for Tier 3 safety 
parameters. The 95% confidence intervals for the between-treatment 
differences in percentages will be provided using the Miettinen and 
Nurminen method with sample size weighting scheme.
Interim Analyses
Efficacy
One interim efficacy analysis will be performed in this study.  Results 
will be reviewed by an external data monitoring committee (eDMC).  
The interim and final analysis timing and purpose is summarized below.  
Details are provided in Section 8.7. 

IA
o Timing: at least 353 EFS events and all subjects have been 
followed up for at least 23 months (~86% of the final required 
EFS events, estimated to be 48 months after study start).
o Testing: Inferential analyses of EFS will be provided. 

FA
o Timing: at least 410 EFS events and all subjects have been 
followed up for at least 35 months (estimated to be 60 months 
after study start).
o Testing: Inferential analyses of EFS will be provided.
Note that if the EFS events accrue slower than expected, the analysis 
can be delayed up to 3 months after the projected timing, i.e., the 
Sponsor may conduct the IA and FA with additional 3 months of follow-
up, or the specified number of events is observed, whichever occurs 
first.
Safety
One interim safety analysis will be performed when the first 30 subjects 
have completed CRT. The eDMC will also review safety data 
periodically in the study.
Multiplicity
The Type I error rate for the EFS and OS hypotheses is strongly 
controlled at 2.5% (1-sided). A group sequential approach will be used 
to allocate alpha between the interim and final analyses of EFS. The 
study will be considered a success if EFS in all subjects is demonstrated 
to be statistically significant under multiplicity control.
If the statistical criterion for success in the primary EFS hypothesis is 
met at the interim analysis or final analysis, the secondary OS 
hypothesis will be tested in all subjects.
Sample Size and Power 
The planned sample size is approximately 780 subjects. For EFS, the 
trial has 94.6% power to demonstrate that pembrolizumab in 
combination with CRT is superior to placebo in combination with 
CRT at an overall one-sided 2.5% alpha-level, if the true hazard ratio 
is 0.7. 
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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee/ Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
The investigator will be blinded to subject-level biomarker results. The independent 
radiologist(s) will perform the central imaging review without knowledge of treatment group 
assignment.
Blinding issues related to the planned interim analyses are described in Section 8.7.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary: Event-Free Survival (EFS)
Event-free survival (EFS) is defined as the time from the date of randomization to the date of 
first record of any of the following events:
Progression per RECIST 1.1 by BICR or biopsy as indicated for:

Locoregional progression or recurrence 

Distant metastasis 
Surgery:

Salvage surgery for persistent or residual disease at the primary tumor site 
requiring surgical removal when invasive cancer is present on final pathology
-
If salvage surgery of the primary tumor site cannot be performed, biopsy 
completed 12 or more weeks following completion of CRT is an event if 
invasive cancer is present.

Neck dissection or surgery (performed for clinical or radiological disease 
progression per RECIST 1.1) ≤20 weeks from end of CRT when invasive cancer
is present 
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
Neck dissection or surgery >20 weeks from end of CRT when invasive cancer is 
present 
-
If neck dissection or surgery cannot be performed, biopsy completed 12 or 
more weeks following completion of CRT is an event if invasive cancer is 
present.
Death due to any cause.
The criteria for an EFS event are comprehensively defined in Section 7.1.4.3. See Section 
8.6.1 for the censoring rules.
Secondary: Overall Survival (OS)
Overall survival (OS) is defined as the time from randomization to death due to any cause. 
Safety Endpoints
Safety endpoints are described in Sections 4.2.3.2.
Patient Reported Outcome (PRO) Endpoints
The following key PRO endpoints will be evaluated as described in Section 4.2.3.3:

EORTC QLQ-C30:  global health status/QoL and physical functioning

Symptom sub-scale and single item scores from EORTC QLQ-H&N35 including the 
following:  
o
problems with swallowing
o
problems with speech
o
pain in the mouth
Additional scales of EORTC QLQ-C30/QLQ-H&N35 and exploratory PRO endpoints as 
described in Section 4.2.3.3 will be evaluated.  Details will be provided in the sSAP.
Analysis Population
Efficacy Analysis Population
The Intention-to-Treat (ITT) population will serve as the population for the primary efficacy 
analyses. All randomized subjects will be included in this population. Subjects will be 
analyzed in the treatment group to which they are randomized.  
Safety Analysis Population
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 1 
dose of study treatment. Subjects will be analyzed in the treatment group corresponding to 
the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
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the treatment group corresponding to the study treatment actually received.  Any subject who 
receives the incorrect study medication for one cycle but receives the correct treatment for all 
other cycles will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set (FAS) population, defined as 
subjects who have at least one PRO assessment available for the specific endpoint and have 
received at least one dose of study medication. Subjects will be analyzed in the treatment 
group to which they were randomized.
Statistical Methods
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.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses but should be interpreted with caution due to 
potential issues of multiplicity.
Event-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the EFS curve in each 
treatment group.
The hypothesis of treatment difference in EFS will be tested by the
stratified log -rank test. A stratified Cox proportional hazard model with Efron's method of
tie handling will be used to estimate the magnitude of the treatment difference (i.e., HR)
between the treatment arms.
The HR and its 95% CI from the stratified Cox model with
Efron's method of tie handling and with a single treatment covariate will be reported.
The stratification factors used for randomization (RT regimen, tumor site/p16 status and 
stage, see Section 5.6 for additional detail) will be applied to both the stratified log-rank test
and the stratified Cox model.  In the event that there are a small number of events in one or 
more strata, for the purpose of analysis, strata will be combined to ensure sufficient number 
of events in each stratum.  Details regarding the combining of strata will be specified in the 
sSAP prior to database lock based on a blinded review of event counts by stratum.  
Since disease progression is assessed periodically, disease progression can occur any time in
the time interval between the last assessment where PD was not documented and the
assessment when PD is first documented.
For the primary analysis, for the subjects who
have PD, the true date of the EFS event will be approximated by the date of the first
assessment at which PD, surgery, or death is objectively documented. 
In order to evaluate the robustness of the EFS endpoint, one primary and three sensitivity 
analyses with a different set of censoring rules will be performed.  The primary analysis 
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follows the intention-to-treat principle. That is, PD, surgery or death is counted as event 
regardless of missed study visits or initiation of new anticancer therapy.  For the first 
sensitivity analysis, if the events (PD, surgery or death) are after the initiation of a new 
anticancer therapy for R/M disease, the data are censored at the last disease assessment prior 
to the initiation of a new anticancer therapy for R/M disease. The second sensitivity analysis 
considers initiation of a new anticancer treatment for R/M disease to be an EFS event for
subjects without a documented EFS event. The third sensitivity analysis is the same as the 
primary EFS analysis, with the exception that surgery is not counted as an EFS event. If a 
subject meets multiple criteria for censoring, the censoring criterion that occurs earliest will 
be applied. The censoring rules for primary and sensitivity analyses are summarized in 
Table 24.
Table 24
Censoring Rules for Primary and Sensitivity Analyses of EFS
Situation
Primary
Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
Sensitivity
Analysis 3
PD, surgery or death 
documented before 
new anticancer 
therapy* if any, or 
new anticancer 
therapy is not 
initiated
EFS event at 
date of 
documented
PD, surgery
or death
EFS event at date of 
documented PD, 
surgery, or death
EFS event at date of 
documented PD, 
surgery or death
EFS event at 
date of 
documented PD
or death.  If no 
PD and no 
death, censored
at last disease 
assessment.
PD, surgery or death 
documented after new 
anticancer therapy*
EFS event at 
date of 
documented
PD, surgery
or death
If the new anticancer 
therapy is for R/M 
disease, then censored at
last disease assessment 
before the initiation of a 
new anticancer therapy
for R/M disease; 
otherwise, EFS event at 
date of documented PD, 
surgery or death
EFS event at date of 
documented PD, 
surgery, death, 
initiation of a new 
anticancer therapy 
for R/M disease, 
whichever occurs 
first.
EFS event at 
date of 
documented PD
or death. If no 
PD and no 
death, censored
at last disease 
assessment.
No PD, no surgery 
and no death; new
anticancer therapy* is
not initiated
Censored at
last disease 
assessment
Censored at last disease
assessment
Censored at last
disease assessment 
Censored at last
disease 
assessment
No PD, no surgery
and no death; new
anticancer therapy* is
initiated
Censored at
last disease 
assessment
If the new anticancer 
therapy is for R/M 
disease, then censored at
last disease assessment 
before the initiation of a 
new anticancer therapy 
for R/M disease; 
otherwise, censored at 
last disease assessment
If the new anticancer 
therapy is for R/M 
disease, then EFS 
event at date of the 
initiation of a new 
anticancer therapy 
for R/M disease; 
otherwise, censored 
at last disease 
assessment
Censored at last
disease 
assessment
EFS= event free survival; PD=progressive disease; R/M=recurrent or metastatic.
* The new anticancer therapy in the sensitivity analyses 1 and 2 is defined as any new oncology drugs or 
radiation for R/M disease.
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Overall Survival 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The
hypothesis of a treatment difference in OS will be tested by the stratified log -rank test.
A stratified Cox proportional hazard model with Efron's method of tie handling will be used
to estimate the magnitude of the treatment difference (i.e., the HR) for OS. The HR and its
95% CI from the stratified Cox model with a single treatment covariate will be reported.
The stratification factors used for randomization will be applied.  In the event that there are a 
small number of events in one or more strata, for the purpose of analysis, strata will be 
combined to ensure sufficient number of events in each stratum.  Details regarding the 
combining of strata will be specified in the sSAP prior to database lock based on a blinded 
review of event counts by stratum.
Summary of Efficacy Analysis Methods
A summary of the analysis strategy for key efficacy endpoints is provided in Table 25.
Table 25
Analysis Strategy for Key Efficacy Endpoints
Endpoint/
Variable
Statistical Method†
Analysis 
Population
Missing Data
Approach
Primary Hypothesis 
EFS 
Test: Stratified Log-rank test 
Estimation: 
Stratified 
Cox 
model with Efron’s tie handling 
method
ITT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
Sensitivity analysis 3
Secondary Hypotheses 
OS
Test: Stratified Log-rank test 
Estimation: 
Stratified 
Cox 
model with Efron’s tie handling 
method
ITT
Censored at the last date the 
subject was known to be alive
EFS=event free survival; ITT=intention-to-treat; OS=overall survival.
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for
randomization (see Section 5.6) will be applied to the analysis model.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
AEs will be summarized overall and by the following time periods:

Period of treatment with pembrolizumab/placebo in combination with CRT

Period of maintenance with pembrolizumab/placebo 

Follow-up period with no treatment
The analysis of safety results will follow a tiered approach (Table 26).  The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) are either pre-specified as “Tier 1” endpoints or will be classified 
as belonging to "Tier 2" or "Tier 3" based on the number of events observed. 
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Tier 1 Events
Safety parameters or adverse events of interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance.  There 
are no Tier 1 events for this protocol as preliminary data from the MISP study [67] has 
demonstrated an acceptable and manageable safety/tolerability profile of pembrolizumab in 
combination with CRT for LA HNSCC.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of subjects with events.
Membership in Tier 2 requires that at least 10% of subjects in any treatment group exhibit the 
specific AE; all other AEs will belong to Tier 3. The threshold of at least 10% of subjects
was chosen for Tier 2 events because the population enrolled in this study is in critical 
condition and usually experiences various AEs of similar types regardless of treatment; 
events reported less frequently than 10% of subjects would obscure the assessment of the 
overall safety profile and add little to the interpretation of potentially meaningful treatment 
differences. In addition, 5% of subjects in any treatment group that exhibit a specific serious 
AE or a specific Grade 3-5 AE will be considered Tier 2 endpoints. Because many 95% CIs
for Tier 2 events may be provided without adjustment for multiplicity, the confidence 
intervals should be regarded as a helpful descriptive measure to be used in review, not a
formal method for assessing the statistical significance of the between-group differences in
AEs and laboratory values that meet predefined limits of change.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events.  The broad 
clinical and laboratory AE categories consisting of the proportion of subjects with any AE, 
any drug related AE, any Grade 3-5 AE, any SAE, any AE which is both drug-related and 
Grade 3-5, any AE which is both serious and drug-related, discontinuation due to an AE, and 
death that are not pre-specified as Tier 1 endpoints will be classified as belonging to “Tier 3.”  
Laboratory test toxicity grade shift from baseline is considered Tier 3 event. Only point 
estimates by treatment group are provided for Tier 3 safety parameters.
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Table 26
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific Grade 3-5 AE (incidence ≥5% of subjects in one of the 
treatment groups)
X
X
Specific serious AE (incidence ≥5% of subjects in one of the 
treatment groups)
X
X
Specific AEs, SOCs (incidence ≥10% of subjects in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any Serious AE 
X
Any Grade 3-5 AE
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
X
Any Grade 3-5 and Drug-Related AE
X 
Discontinuation due to AE
X
Any AE resulting in death
X
Specific AEs, surgical complications, SOCs (incidence >0% of 
subjects in one of the treatment groups)
X
Change from Baseline Results (lab toxicity grade)
X
AE = adverse event; CI=confidence interval; SOC = system organ class.
Statistical Methods for PRO Analyses: EORTC QLQ-C30 & QLQ-H&N35
The change from baseline in the following secondary QoL outcomes from the EORTC QLQ-
C30 and QLQ-H&N35 will be assessed:

EORTC QLQ-C30 Global health status/QoL score

EORTC QLQ-C30 physical functioning score 

QLQ- H&N35 Swallowing symptom score 

QLQ- H&N35 Speech symptom score 

QLQ-H&N35 Pain symptom score 
The time point for the mean change from baseline will be determined based on blinded data 
review prior to the database lock for any PRO analysis and documented in the sSAP. To 
assess the treatment effects on the quality-of-life outcomes, a constrained longitudinal data 
analysis (cLDA) model will be applied, with the PRO score as the response variable, and 
treatment, time, the treatment by time interaction and stratification factors as covariates.  The 
treatment difference in terms of least square (LS) mean change from baseline will be 
estimated from this model together with 95% CI.  Model-based LS mean with 95% CI will 
be provided by treatment group for PRO scores at baseline and post-baseline time point.
Details of PRO analyses will be described in the sSAP.
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Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.
No statistical hypothesis tests will be performed on
these characteristics. The number and percentage of subjects screened and randomized, and 
the
primary reasons for screening failure and discontinuation will be displayed.  
Demographic variables (e.g., age), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
Study enrollment is likely to be complete at the time of the efficacy interim analysis.  
Blinding to treatment assignment will be maintained at all investigational sites.  The results 
of interim analyses will not be shared with the investigators prior to the completion of the 
study.  Subject-level unblinding for the interim analysis will be restricted to an external 
unblinded statistician and scientific programmer performing the interim analysis, who will 
have no other responsibilities associated with the study.
The eDMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or modification to the executive 
oversight committee of the Sponsor. If the eDMC recommends modifications to the design of 
the protocol or discontinuation of the study, this executive oversight committee and 
potentially other limited Sponsor personnel may be unblinded to results at the treatment level 
in order to act on these recommendations. The extent to which individuals are unblinded with 
respect to results of interim analyses will be documented by the unblinded team. Additional 
logistic details will be provided in the eDMC Charter.  
Treatment-level results of the interim analysis will be provided by the unblinded statistician 
to the eDMC.  Prior to final study unblinding, the unblinded statistician will not be involved 
in any discussions regarding modifications to the protocol or statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
Efficacy Interim Analyses
A summary of interim and final analyses strategy for efficacy is provided in Table 27.
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Table 27
Summary of Interim and Final Analyses Strategy for Efficacy
Analyses
Key 
Endpoints
Timing†
Estimated Months 
after First Subject 
Randomized
Primary Purpose of Analysis
Efficacy 
IA
EFS
OS
At least 353 EFS 
events have been 
observed and all 
subjects have been 
followed up for at 
least 23 months
~48 months 
Demonstrate EFS superiority
Evaluate OS superiority
Efficacy 
FA
EFS 
OS
At least 410 EFS 
events have been 
observed and all 
subjects have been 
followed up for at 
least 35 months
~60 months 
Demonstrate EFS superiority 
(if not significant at IA)
Evaluate OS superiority
EFS = event-free survival; FA = final analysis; IA = interim analysis; OS = overall survival.
† Note: For efficacy IA and FA, if the EFS events accrue slower than expected, the analysis can be delayed up to 3 months 
after the projected timing, i.e., the Sponsor may conduct IA and FA with additional 3 months of follow-up, or the 
specified number of events is observed, whichever occurs first.
Decisions to stop the study early will be based on eDMC recommendations with review by 
the Executive Oversight Committee.  In the event that the study is stopped early for efficacy, 
the study will continue to follow subjects for survival update.
Type I error control for the efficacy analyses as well as efficacy bounds are described in 
Section 8.8 - Multiplicity.
Safety Interim Analyses
A summary of interim analysis strategy for safety is provided in Table 28.
Table 28
Summary of Interim Analyses Strategy for Safety
Key 
Endpoints 
Timing
Estimated Months after First 
Subject Randomized 
Primary Purpose of 
Analysis
AEs

First 30 subjects have completed 
Treatment 1 (concurrent CRT) 
phase
Every 4 months after the first 
planned safety IA for 1 year
Every 6 months thereafter and/or 
at the appropriate frequency as 
outlined by the eDMC.  Details 
will be included in the DMC 
charter.

~5 months

~9, 13 months

~19, 25, etc. (every 6 
months and/or at the 
appropriate frequency as 
specified in the DMC 
charter) 
Safety evaluation
AE=Adverse Event; CRT=Chemoradiation therapy; DMC=Data Monitoring Committee; eDMC=external DMC; IA=interim 
analysis.
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Multiplicity
Multiplicity Control for Efficacy Analyses
The overall Type I error for testing the EFS and OS hypotheses is strongly controlled at 
=2.5% (1-sided) by using a fixed sequential testing procedure in the order of EFS and OS.
If the statistical criterion for success in the primary EFS hypothesis is met at the interim 
analysis or final analysis, the secondary OS hypothesis will be tested in all subjects. 
Figure 3 shows the initial one-sided α-allocation for each hypothesis in the ellipse 
representing the hypothesis. The weight for reallocation from the EFS hypothesis to OS is 
represented in the box on the line connecting hypotheses.  This is further explained below.
Figure 3
Multiplicity Schema
Event-Free Survival
The EFS hypothesis will be tested at α = 0.025.  Table 29 below shows the bounds and 
boundary properties for each analysis of EFS which were derived using a Lan-DeMets 
O'Brien-Fleming alpha-spending function.  Note that the final row of the table indicates the 
total power to reject the null hypothesis.  Also, note that the bounds and nominal alpha levels
provided in Table 29 are based on the assumption that the number of EFS events at IA and 
FA are 353 and 410, respectively. At the time of IA, the observed number of events may 
differ substantially from the expected.  To avoid overspending at the IA and leave reasonable 
alpha for the FA, the minimum alpha spending strategy will be adopted.  At the IA, the 
information fraction used in Lan-DeMets spending function to determine the alpha spending 
at the IA will be based on the minimum of the expected information fraction and the actual 
information fraction at the time of the analysis.  Specifically,  

In the scenario that the event accumulation is faster than expected, i.e., if the number 
of observed events exceeds the pre-specified number of events at IA, then the 
information fraction will be calculated as the pre-specified number of events at IA 
over the target number of events at FA, and hence the alpha spending at IA will not 
exceed the pre-specified level based on the pre-specified number of events, as shown 
in the table below.

In the scenario that the event accumulation is slower than expected and the number of 
events is less than the pre-specified number of events in the table when IA is 
conducted, the bounds will be adjusted using the spending functions accordingly, 
with information fraction calculated as the actual number of events at IA over the 
target number of events at FA.  
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The final EFS analysis will use the remaining Type I error not spent at an earlier analysis, 
regardless of the number of events observed at the final analysis. The nominal alpha level at 
the final analysis will be calculated by considering the correlation between the test statistics,
as determined by the actual number of EFS events at IA and FA.
If the EFS hypothesis is rejected at any analysis, the α = 0.025 (one-sided) will be rolled over 
to the OS test.
Table 29
Efficacy Boundaries and Properties for EFS Analyses
Analysis†
Value
Efficacy
IA: 86% 
Z 
2.1517 
N: 780
p (1-sided) 
0.0157 
Events: 353
~HR at bound 
0.7952
Month: 48 
P(Cross) if HR=1 
0.0157 
P(Cross) if HR=0.7 
0.8841
Final Analysis 
Z 
2.0422
N: 780
p (1-sided) 
0.0206
Events: 410
~HR at bound 
0.8172
Month: 60 
P(Cross) if HR=1 
0.0250
P(Cross) if HR=0.7 
0.9463
EFS=event-free survival; HR=hazard ratio; IA=interim analysis
† This column displays the number (Events) and percentage (%) of needed EFS events, the expected sample size (N) and 
the estimated months (Month) after first subject is randomized for each analysis.
p (1-sided): nominal α for group sequential testing.  
~HR at bound: the approximate hazard ratio required to reach an efficacy bound.
P(Cross if HR=1): the probability of crossing a bound under the null hypothesis.
P(Cross if HR=0.7): the probability of crossing a bound under the alternative hypothesis.
Of note, while the information fraction used for alpha spending calculation will be the 
minimum of the actual information fraction and the expected information fraction, the 
correlations required for deriving the bounds will still be computed using the actual 
information fraction based on the observed number of events at the IA over the target number 
of events at FA.
The minimum spending approach assumes timing is not based on any observed Z-value and 
thus the Z test statistics used for testing conditioned on timing are multivariate normal.  
Given the probabilities derived with the proposed spending method, the correlations based on 
actual event counts are used to compute bounds that control the Type I error at the specified 
alpha level for a given hypothesis conditioned on the interim analysis timing.  Since this is 
true regardless of what is conditioned on, the overall Type I error for a given hypothesis 
unconditionally is controlled at the specified level.  By using more conservative spending 
early in the study, power can be retained to detect situations where the treatment effect may 
be delayed.
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Overall Survival
Overall survival will be tested only if EFS superiority is demonstrated and will be tested at 
α = 0.025.  Table 30 below shows the bounds and boundary properties for OS testing which 
were derived using a Lan-DeMets O'Brien-Fleming alpha spending function.  Note that the 
bounds and nominal alpha levels provided in Table 30 are based on the assumption that the 
number of OS events at IA and FA are 220 and 268, respectively. If the actual number of 
events at the OS analyses differs from those specified in the table, the same minimum 
spending approach as used for EFS will be implemented and the bounds will be adjusted 
accordingly. The final OS analysis will occur at the same time as the final EFS analysis, and 
the final OS analysis will use the remaining Type I error not spent at an earlier analysis, 
regardless of the number of events observed at the final analysis. 
Table 30
Efficacy Boundaries and Properties for OS Analyses
Analysis†
Value
Efficacy
IA: 82% 
Z 
2.2169
N: 780
p (1-sided) 
0.0133
Events: 220
~HR at bound 
0.7412
Month: 48 
P(Cross) if HR=1 
0.0133
P(Cross) if HR=0.71 
0.6239
Final Analysis 
Z 
2.0305
N: 780
p (1-sided) 
0.0212
Events: 268
~HR at bound 
0.78
Month: 60 
P(Cross) if HR=1 
0.025
P(Cross) if HR=0.71 
0.79
HR=hazard ratio; IA=interim analysis; OS=overall survival.
† This column displays the number (Events) and percentage (%) of needed OS events, the expected sample size (N) and the 
estimated months (Month) after first subject is randomized for each analysis.
p (1-sided): nominal α for group sequential testing.
~HR at bound: the approximate hazard ratio required to reach an efficacy bound.
P(Cross if HR=1): the probability of crossing a bound under the null hypothesis.
P(Cross if HR=0.71): the probability of crossing a bound under the alternative hypothesis.
Multiplicity Control for Safety Analyses
There are multiple safety interim analyses planned in this study.  The eDMC has 
responsibility for assessment of overall risk/benefit.  When prompted by safety concerns, the 
eDMC can request corresponding efficacy data.  eDMC review of efficacy data to assess the 
overall risk/benefit to study subjects will not require a multiplicity adjustment typically 
associated with a planned efficacy IA.  However, to account for any multiplicity concerns
raised by the eDMC review of unplanned efficacy data when prompted by safety concerns, a 
sensitivity analysis for OS adopting a conservative multiplicity adjustment will be 
pre-specified in the sSAP.
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Sample Size and Power Calculations
The study will randomize approximately 780 subjects in a 1:1 ratio into the experimental arm 
of pembrolizumab in combination with CRT and the control arm of placebo in combination 
with CRT.  
Power and IA calculations for EFS and OS were performed using the gsDesign R package,
Event-Free-Survival
The EFS hypothesis testing strategy was designed for α=0.025 (one-sided) and power of 
94.6% to detect a HR of 0.7 with 410 EFS events at the final analysis. The sample size was 
estimated based on the following assumptions: 
(1) true HR of 0.7; 
(2) the duration of EFS in the placebo in combination with CRT group is assumed to follow a 
piece-wise constant hazard exponential distribution with a cumulative EFS rate of 70% at 
12 months, and 40% at 36 months; 
(3) an enrollment of 25 months, with accrual rates of 2 subjects per month for the first 
2 months, 10 subjects per month for the next 2 months, ~24 subjects per month for the next 
2 months, and ~38 subjects per month thereafter; and 
(4) a 10% cumulative dropout rate at 12 months in both treatment groups.
Overall Survival
At α=0.025 (one-sided), the final OS hypothesis test yields 79% power to detect a HR of 0.71
with 268 deaths observed.  The power was estimated based on the following assumptions: 
(1) true HR of 0.71; 
(2) the duration of OS in the placebo in combination with CRT group is assumed to follow a 
piece-wise constant hazard exponential distribution with a cumulative OS rate of 85% at 
12 months, 65% at 36 months and 48% at 96 months;
(3) the same enrollment assumption as used for EFS; and 
(4) a 3% cumulative dropout rate at 12 months in both treatment groups.
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of the following classification 
variables:

Geographic region (North America vs. European Union vs. Rest of the World)

RT regimen (AFX vs. SFX)

HPV status (Positive vs. Negative)

ECOG Performance Score (0 vs. 1)

Disease stage at baseline (Stage III vs. Stage IV)
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
PD-L1 status (Combined Positive Score [CPS]≥1 vs. CPS<1)

Age (<65 vs. ≥65)

Sex (Female vs. Male)

Race (White vs. All Others)

Primary tumor location (Hypopharynx vs. Larynx vs. Oral cavity vs. Oropharynx)
A Forest plot will be produced, which provides the estimated point estimates and confidence 
intervals for the treatment effect across the categories of subgroups listed above.  If the 
number of subjects in a category of a subgroup variable is less than 10% of the ITT 
population, the subgroup analysis will not be performed for this category of the subgroup 
variable, and this subgroup variable will not be displayed in the forest plot. The subgroup 
analysis will be conducted using an unstratified Cox model.
Country-specific populations may also be analyzed per local regulatory requirements, and the
primary endpoint may be estimated and plotted within each category of the above
classification variables in country-specific populations.
Compliance
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Summary 
statistics will be provided on extent of exposure for the ASaT population.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
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Table 31
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab 
(MK-3475), 100 mg/4 mL
Injection
Provided centrally by the Sponsor.
Cisplatin, 1 mg/mL
Injection
Provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee.
Note: Cisplatin will be provided locally in 
some countries by the trial site, subsidiary or 
designee, 
depending 
on 
local 
country 
operational or regulatory requirements.
All supplies indicated in Table 31 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 31 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial 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. 
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Study sites will receive open label pembrolizumab kits and open label cisplatin kits.
Clinical Supplies Disclosure
This trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial site personnel will be used to blind supplies. Treatment identity (name, 
strength or potency) is included in the label text; random code/disclosure envelopes or lists 
are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask trial treatment identity. The emergency unblinding 
call center should only be used in cases of emergency (see Section 7.1.7.2). In the event that 
the emergency unblinding call center is not available for a given site in this trial, the central 
electronic treatment allocation/randomization system (IVRS/IWRS) should be used in order 
to unblind subjects and to unmask treatment/vaccine identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
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Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
     
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  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.
Compliance with Financial Disclosure Requirements
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.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
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 Section 12.1 -
MSD Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
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The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, MSD, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial 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 trial, 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 subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial 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 trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
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Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. MSD will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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11.0 LIST OF REFERENCES
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N Engl J Med 2006;354:567-78.
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Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 
5-year survival data from a phase 3 randomised trial, and relation between 
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in: Lancet Oncol. 2010 Jan;11(1):14.
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Ang KK, Zhang QE, Rosenthal DI, Nguyen-Tan P, Sherman EJ, Weber RS, et al. 
A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation 
plus cisplatin with or without cetuximab for stage III-IV head and neck squamous 
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2011 Jun 3-7; Chicago, IL: ASCO; 2011. p. 2.
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Ang K, Zhang Q, Wheeler RH, Rosenthal DI, Nguyen-Tan F, Kim H, et al. A 
phase III trial (RTOG 0129) of two radiation-cisplatin regimens for head and neck 
carcinomas (HNC): impact of radiation and cisplatin intensity on outcome 
[abstract]. Abstracts of the 2010 ASCO Annual Meeting; 2010 Jun 4-8; Chicago:  
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chemoradiotherapy versus acceleration of radiotherapy with or without 
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(GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012 
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Joint Committee on Cancer/Union for International Cancer Control TNM stage 
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Molecular classification identifies a subset of human papillomavirus-associated 
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10;24(5):736-47.
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12.0 APPENDICES
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
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, conducts clinical trials worldwide to 
evaluate the safety and effectiveness of our products. As such, we are committed to designing, planning, 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 MSD’s global standards, local and/or national regulations 
(including all applicable data protection laws and regulations), and International Council for Harmonisation Good 
Clinical Practice (ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, and 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 (eg, 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 (ie, 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. Input may be considered from a broad range of stakeholders, including patient advocacy groups/patients 
representing the trial population, caregivers, and healthcare providers to ensure operational feasibility. Trial design 
also includes proactive identification of critical to quality factors using a risk-based approach. Plans are then 
developed to assess and mitigate risks to those factors as appropriate during the trial. All trial protocols are and 
will be assessed for the need and capability to enroll underrepresented groups. Participants must meet protocol 
entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with their role prior to their 
becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified 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 and ICH Guidelines. 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. 
Trial designs include procedures and systems for the identification, monitoring, and reporting of safety concerns. 
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.
During trial planning, the need for an independent Data Monitoring Committee (DMC) is assessed. DMC review of 
data accumulated during the conduct of the trial is integral to the well-being of trial participants.
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 
medical record 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 (eg, 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.
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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 trial as outlined in Section 7.1.3.7 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
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.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all subjects or legal guardians, at a trial visit by 
the investigator or his or her designate.  Informed consent for Future Biomedical 
Research should be presented to the subjects on the visit designated in the trial flow chart.  
If delayed, present consent at next possible Subject Visit.  Consent forms signed by the 
subject will be kept at the clinical trial site under secure storage for regulatory reasons.  
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A template of each trial 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 subject consent for Future Biomedical Research will be captured in the 
electronic Case Report Forms (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 trial flow chart. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the subject is 
having blood drawn for other trial purposes.
4. Confidential Subject 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 subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment 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 trial 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 subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., 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
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@MSD.com). 
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Subsequently, the subject'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 
subject 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 trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’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 trial 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 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial 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 Subjects3,4
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject 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 subjects.  Subjects will not be identified by 
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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 subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject 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. Questions3,4
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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Abbreviations
Abbreviation/Term
Definition
5-FU
5-fluorouracil
ADA
Anti-drug Antibodies
AE
Adverse Event
AFX
Accelerated Fractionation
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve, or
Area under the concentration-time curve
BCG
Bacillus Calmette–Guérin
BICR
Blinded Independent Central Review
BID
Twice (two times) a Day
BSA
Body Surface Area
CBC
Complete Blood Count
CD28
Cluster of Differentiation 28
CD3ζ
CD3 zeta
CI
Confidence Interval
CNS
Central Nervous System
CPS
Combined Positive Score
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CRT 
Chemoradiation Therapy
CRU
Clinical Research Unit
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
CTV
Clinical Target Volume
DAHANCA
Danish Head and Neck Cancer group
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSMB
Date and Safety Monitoring Board
DOR
Duration of Response
ECE
Extracapsular Extension
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
eDMC
External Data Monitoring Committee
EEA
European Economic Area
EFS
Event Free Survival
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of Cancer
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Abbreviation/Term
Definition
EQ-5D
European Quality of Life-5 Dimension
ERC
Ethics Review Committee
ESMO
European Society for Medical Oncology
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDG-PET
Fludeoxyglucose Positron Emission Tomography
FFPE
Formalin-fixed Paraffin Embedded
FNA
Fine Needle Aspirate
FSH
Follicle Stimulating Hormone
FSR
First Site Ready
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GTV
Gross Tumor Volume
GTVn
Gross Nodal Tumor Volume 
GTVp
Gross Primary Tumor Volume
Gy
Gray
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HNC
Head and Neck Cancer
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICRU
International Commission on Radiation Units & Measurements
IFN γ
Interferon gamma
Ig
Immunoglobulin
IgG4
Immunoglobulin
IGRT
Image-Guided Radiation Therapy
IgV
Ig-variable 
IHC
Immunohistochemistry
IL-2
Interleukin-2
IL-10
Interleukin-10
IMRT
Intensity Modulated Radiation Therapy
INR
International Normalized Ratio
irAE
Immune-related AEs
IRB
Institutional Review Board
ITFB
Investigator Trial File Binder
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention-To-Treat
IV
Intravenous
IVD
In vitro diagnostic
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
kg
Kilogram
JV
Kilo voltage
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Abbreviation/Term
Definition
LA HNSCC
Locally Advanced Head and Neck Squamous Cell Carcinoma
LRC
Local Regional Control
LS
Least square
mAb
Monoclonal Antibody
MASCC
Multinational Association of Supportive Care in Cancer
mcL
Microliters
MDT
Multidisciplinary Team
MEL
Melanoma 
mg
Milligram
mg/kg
Milligram per Kilogram
MSD ISP
Merck Sharpe & Dohme Investigator Studies Program
mL
Milliliter
MRI
Magnetic Resonance Imaging
mRNA
messenger RNA
MSI
Microsatellite instability (MSI) 
MTD
Maximum Tolerated Dose
MV
Megavolt
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
OAR
Organ(s) at Risk
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PBPK
Physiologically Based Pharmacokinetics
PCL
Protocol Clarification Letter
PD
Progressive Disease
PD-1
Programmed Cell Death Receptor 1 
PD-L1
Programmed Cell Death Receptor Ligand 1
PD-L2
Programmed Cell Death Receptor Ligand 2
PEG
Percutaneous Gastrostomy
PET
Positron Emission Tomography
PFS
Progression Free Survival
PIN
Personal Identification Number
PK
Pharmacokinetic
PKCθ
Protein kinase C-theta
PO
Per oral
PR
Partial Response
PRO
Patient Reported Outcome
PRV
Planning Organ at Risk Volume
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
PTV
Planning Target Volume
QART
Quality Assurance in Radiotherapy
QLQ-C30
Quality of Life Questionnaire C-30
QLQ-H&N35
Quality of Life Questionnaire Head and Neck 35
QoL
Quality of Life
QW
Every Week
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
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Abbreviation/Term
Definition
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RP
Retropharyngeal
RT
Radiotherapy or Radiation Therapy
RT QA
Radiation Therapy Quality Assurance
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SFU
Survival Follow-Up
SFX
Standard Fractionation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SIB-IMRT
Simultaneous Integrated Boost Intensity Modulated Radiation Therapy
SITC
Society for Immunotherapy of Cancer
SNP
Single Nucleotide Polymorphisms
SOC
Standard of Care
sSAP
Supplemental Statistical Analysis Plan
t½
Terminal half-life 
T1DM
Type 1 Diabetes
TCR
T-cell Receptor
TIL
Tumor-infiltrating Lymphocytes
TMDD
Target-mediated Drug Disposition
TNBC
Triple Negative Breast Cancer
TNFα
Tumor Necrosis Factor Alpha
TPS
Tumor Proportion Score
TRAE
Treatment Related Adverse Event
Tregs
Regulatory T-cells
TSH
Thyroid Stimulating Hormone
UICC
Union for International Cancer Control
ULN
Upper Limit of Normal
USA
United States of America
VOP
Verification of Progression
WBC
White Blood Cell
ZAP70
Zeta-chain–associated Protein Kinase
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house-work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
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Calculation of the Glomerular Filtration Rate (GFR)
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
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Cisplatin Market Authorization (for sites conducting study in France only)
See website http://base-donnees-publique.medicaments.gouv.fr for the most recent version of 
the medicines SmPC.
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Technical Note for the Piecewise Constant Hazard Exponential Survival
Given a set of time points, 
the piecewise constant hazard 
function is defined as
The exponential survival function is
The survival function Si (t), for a given interval
, simplifies to
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Country-specific Requirements
France-specific Requirements
Subjects should be permanently discontinued from study treatment if any of the following 
AEs occur:

Stevens-Johnson Syndrome

Toxic-epidermal necrolysis

Recurrent Grade 3 colitis
Japan-specific Requirements
Section 5.2 Trial Treatment(s)
Table 2 Trial Treatments: Intravenous solution, not provided by the Sponsor, as Placebo for 
MK-3475 in this protocol is not categorized as “product(s) used in the clinical trial” in Japan.
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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