Clinical trial NCT02358031
Conditions: Recurrent Head and Neck Cancer Metastatic Head and Neck Cancer
Keywords: Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death Receptor Ligand 1 (PDL1, PD-L1) Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2) chemotherapy, 5-fluorouracil, cisplatin, carboplatin
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-03-19; Completion date: 2023-07-19
Enrollment: 882 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Participants with recurrent or metastatic (R/M) squamous cell cancer of the head and neck (HNSCC) will be randomly assigned to receive pembrolizumab monotherapy \[pembro mono\], pembrolizumab plus chemotherapy with a platinum-based drug (cisplatin or carboplatin) and 5-Fluorouracil (5-FU) \[pembro combo\], or cetuximab plus a platinum-based drug (cisplatin or carboplatin) and 5-FU \[control\]. The overall primary study hypotheses are as follows in all participants and in participants with Programmed Cell Death Ligand 1 (PD-L1) positive expression defined by Combined Positive Score (CPS) ≥1 and CPS ≥20: 1) pembrolizumab monotherapy prolongs progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by Blinded Independent Central Review (BICR) and prolongs overall survival (OS) compared to standard treatment, and 2) pembrolizumab combination with chemotherapy prolongs PFS per RECIST 1.1 assessed by BICR and prolongs OS compared to standard treatment.

Detailed description:
The 12 primary superiority hypotheses will be evaluated by comparing the pembro mono arm or pembro combo arm separately to the control arm, for PFS and OS in all first line (1L) R/M HNSCC participants and in 1L R/M HNSCC participants with positive PD-L1 expression (PD-L1 CPS ≥1 and CPS ≥20).

Per protocol, response/progression or adverse events (AEs) that occur during the second pembrolizumab course will not be counted towards efficacy outcome measures or safety outcome measures, respectively.

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle for up to 35 cycles (up to \~2 years). arm 2: Participants receive pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to \~2 years); plus cisplatin 100 mg/m\^2 IV or carboplatin at a target area under the curve of 5 (AUC 5) IV, per Investigator's choice, on Day 1 of each 3-week cycle (6 cycle maximum \[up to \~4 months\]); plus 5-FU 1000 mg/m\^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum \[up to \~4 months\]). arm 3: Participants receive cetuximab on Day 1 at a dose of 400 mg/m\^2 IV, and then 250 mg/m\^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m\^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each 3-week cycle (6 cycle maximum \[up to \~4 months\] for platinum-based therapy); plus 5-FU 1000 mg/m\^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum \[up to \~4 months\]).
Interventions: intervention 1: Pembrolizumab intervention 2: Cisplatin intervention 3: Carboplatin intervention 4: 5-FU intervention 5: Cetuximab
Intervention descriptions: intervention 1: Pembrolizumab 200 mg IV on Day 1 of each 3-week cycle for up to 35 cycles (up to \~2 years). intervention 2: Cisplatin 100 mg/m\^2 IV on Day 1 of each 3-week cycle (6 cycle maximum \[up to \~4 months\]). intervention 3: Carboplatin at a target AUC 5 IV on Day 1 of each 3-week cycle (6 cycle maximum \[up to \~4 months\]). intervention 4: 5-FU 1000 mg/m\^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum \[up to \~4 months\]). intervention 5: Cetuximab on Day 1 at a dose of 400 mg/m\^2 IV, and then 250 mg/m\^2 IV on Day 1 of each subsequent week until disease progression or unacceptable toxicity

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Clinical Trial of Pembrolizumab (MK-
3475) in First Line Treatment of
Recurrent/Metastatic Head and Neck
Squamous Cell Carcinoma
NCT02358031
09-Jun-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 Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of 
Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
IND NUMBER:  122,325
EudraCT NUMBER:  2014-003698-41
NCT NUMBER:  NCT02358031
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 12
SUMMARY OF CHANGES................................................................................................ 15
1.0
TRIAL SUMMARY.................................................................................................. 18
2.0
TRIAL DESIGN........................................................................................................ 19
Trial Design ........................................................................................................... 19
Trial Diagram........................................................................................................ 20
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es).............................................................. 20
Secondary Objective(s) & Hypothesis(es)........................................................... 22
Exploratory Objectives ....................................................................................... 22
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
Preclinical and Clinical Trials............................................................................. 24
Ongoing Clinical Trials....................................................................................... 25
Information on Other Trial-Related Therapy...................................................... 26
Rationale................................................................................................................ 27
Rationale for the Trial and Selected Subject Population .................................... 27
Rationale for Dose Selection/Regimen/Modification......................................... 28
4.2.2.1
Rationale for the Use of Comparator/Placebo ............................................. 28
Rationale for Endpoints ...................................................................................... 29
4.2.3.1
Efficacy Endpoints....................................................................................... 29
4.2.3.1.1
Primary.................................................................................................. 29
4.2.3.1.2
Secondary.............................................................................................. 29
4.2.3.2
Immune-related RECIST ............................................................................. 29
4.2.3.3
Rationale for Prospective Stratification and Evaluation of Biomarker 
Subpopulation.............................................................................................. 30
4.2.3.4
Safety ........................................................................................................... 31
4.2.3.5
Patient-reported Outcomes........................................................................... 31
4.2.3.5.1
eEORTC QLQ-C30 and eEORTC QLQ-H&N35 ................................ 31
4.2.3.5.2
Electronic EuroQol EQ-5D................................................................... 32
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4.2.3.5.3
Pain Medication Log............................................................................. 32
4.2.3.6
Planned Exploratory Biomarker Research................................................... 33
4.2.3.7
Future Biomedical Research........................................................................ 34
Benefit/Risk ........................................................................................................... 34
5.0
METHODOLOGY ................................................................................................... 35
Entry Criteria........................................................................................................ 35
Diagnosis/Condition for Entry into the Trial...................................................... 35
Subject Inclusion Criteria.................................................................................... 35
Subject Exclusion Criteria .................................................................................. 37
Study Intervention................................................................................................ 40
Dose Selection/Modification .............................................................................. 41
5.2.1.1
Dose Selection ............................................................................................. 41
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 41
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 43
5.2.1.2.2
Dose Modifications for Platinum.......................................................... 47
5.2.1.2.3
Dose Modifications for 5-Fluorouracil................................................. 48
5.2.1.2.4
Dose Modifications for Cetuximab....................................................... 50
Cetuximab Infusion Reactions ....................................................... 51
Dermatologic Toxicity ................................................................... 52
Respiratory Disorders..................................................................... 53
Timing of Dose Administration.......................................................................... 53
5.2.2.1
Pembrolizumab ............................................................................................ 54
5.2.2.2
Carboplatin................................................................................................... 54
5.2.2.3
Cisplatin....................................................................................................... 54
5.2.2.4
5-Fluorouracil .............................................................................................. 54
5.2.2.5
Cetuximab.................................................................................................... 54
Trial Blinding/Masking....................................................................................... 55
Randomization or Treatment Allocation............................................................ 55
Stratification.......................................................................................................... 55
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 56
Acceptable Concomitant Medications ................................................................ 56
Prohibited Concomitant Medications.................................................................. 56
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Rescue Medications & Supportive Care............................................................. 57
Supportive Care Guidelines for Pembrolizumab ................................................ 57
Supportive Care Guidelines for Cisplatin and Carboplatin ................................ 61
Supportive Care Guidelines for 5-FU................................................................. 61
Supportive Care Guidelines for Cetuximab........................................................ 61
Diet/Activity/Other Considerations..................................................................... 62
Diet...................................................................................................................... 62
Contraception...................................................................................................... 62
Use in Pregnancy ................................................................................................ 63
Use in Nursing Women....................................................................................... 64
5.7.4.1
Pembrolizumab ............................................................................................ 64
5.7.4.2
Cetuximab.................................................................................................... 64
5.7.4.3
Cisplatin....................................................................................................... 64
5.7.4.4
Carboplatin................................................................................................... 64
5.7.4.5
5-FU............................................................................................................. 64
Subject Withdrawal/Discontinuation Criteria................................................... 64
Discontinuation of Treatment ............................................................................. 64
5.8.1.1
Treatment After Initial Radiologic Progression........................................... 65
5.8.1.2
Discontinuation of Study Therapy After CR ............................................... 66
Withdrawal from the Trial .................................................................................. 67
Subject Replacement Strategy............................................................................. 67
Beginning and End of the Trial ........................................................................... 67
Clinical Criteria for Early Trial Termination ................................................... 67
6.0
TRIAL FLOW CHART ........................................................................................... 68
Initial Treatment Phase........................................................................................ 68
Pembrolizumab and Pembrolizumab Plus Chemotherapy Arms........................ 68
Standard Treatment Arm (Cetuximab plus Chemotherapy) ............................... 73
Second Course Phase – Retreatment With Pembrolizumab ............................ 79
7.0
TRIAL PROCEDURES ........................................................................................... 82
Trial Procedures ................................................................................................... 82
Administrative Procedures.................................................................................. 82
7.1.1.1
Informed Consent......................................................................................... 82
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7.1.1.1.1
General Informed Consent.................................................................... 82
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 82
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 83
7.1.1.3
Subject Identification Card .......................................................................... 83
7.1.1.4
Medical History ........................................................................................... 83
7.1.1.4.1
Disease Details...................................................................................... 83
7.1.1.5
Prior and Concomitant Medications Review............................................... 83
7.1.1.5.1
Prior Medications.................................................................................. 83
Prior Treatment Details for Head and Neck Cancer ...................... 83
7.1.1.5.2
Concomitant Medications..................................................................... 83
7.1.1.6
Assignment of Screening Number............................................................... 84
7.1.1.7
Assignment of Randomization Number....................................................... 84
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 84
Clinical Procedures/Assessments........................................................................ 84
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 84
7.1.2.2
Physical Exam.............................................................................................. 85
7.1.2.2.1
Full Physical Exam ............................................................................... 85
7.1.2.2.2
Directed Physical Exam........................................................................ 85
7.1.2.3
Vital Signs.................................................................................................... 85
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 85
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 85
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 85
7.1.2.6.1
Initial Tumor Imaging........................................................................... 86
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 86
7.1.2.6.3
Assessment of Disease.......................................................................... 87
irRECIST........................................................................................ 88
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling......................... 89
7.1.2.8
Patient-Reported Outcomes (PROs) and Pain Medication Log................... 89
Laboratory Procedures/Assessments .................................................................. 90
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 90
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 91
7.1.3.2.1
PK Blood Collection for Serum MK-3475........................................... 91
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7.1.3.2.2
Blood Collection for Anti-Pembrolizumab Antibodies........................ 91
7.1.3.3
Future Biomedical Research........................................................................ 91
Other Procedures................................................................................................. 92
7.1.4.1
Withdrawal/Discontinuation........................................................................ 92
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 92
7.1.4.2
Blinding/Unblinding .................................................................................... 92
7.1.4.3
Calibration of Critical Equipment................................................................ 92
Visit Requirements.............................................................................................. 93
7.1.5.1
Screening...................................................................................................... 93
7.1.5.2
Treatment Period.......................................................................................... 93
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 93
7.1.5.3
Posttreatment Visits ..................................................................................... 95
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 95
7.1.5.3.2
Follow-up Visits ................................................................................... 95
7.1.5.3.3
Survival Follow-up ............................................................................... 95
7.1.5.4
Survival Status ............................................................................................. 96
Assessing and Recording Adverse Events .......................................................... 96
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor ............................................................................................................... 97
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 98
Immediate Reporting of Adverse Events to the Sponsor.................................... 98
7.2.3.1
Serious Adverse Events ............................................................................... 98
7.2.3.2
Events of Clinical Interest............................................................................ 99
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 100
Evaluating Adverse Events............................................................................... 100
Sponsor Responsibility for Reporting Adverse Events .................................... 103
TRIAL GOVERNANCE AND OVERSIGHT................................................. 103
Scientific Advisory Committee......................................................................... 103
Executive Oversight Committee....................................................................... 103
Data Monitoring Committee............................................................................. 103
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 103
Statistical Analysis Plan Summary ................................................................... 104
Efficacy Analysis.............................................................................................. 104
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Safety Analyses................................................................................................. 104
Power and Sample Size..................................................................................... 104
Interim Analyses ............................................................................................... 106
8.1.4.1
Safety Interim Analyses............................................................................. 106
8.1.4.2
Efficacy Interim Analyses.......................................................................... 107
Statistical Analysis Plan ..................................................................................... 108
Responsibility for Analyses/In-House Blinding ............................................... 108
Hypotheses/Estimation ..................................................................................... 108
Analysis Endpoints ........................................................................................... 109
8.2.3.1
Efficacy Endpoints..................................................................................... 109
8.2.3.2
Safety Endpoints........................................................................................ 109
8.2.3.3
PRO Endpoints........................................................................................... 109
Analysis Populations......................................................................................... 110
8.2.4.1
Efficacy Analysis Populations................................................................... 110
8.2.4.2
Safety Analysis Populations ...................................................................... 110
8.2.4.3
PRO Analysis Population .......................................................................... 110
Statistical Methods............................................................................................ 110
8.2.5.1
Statistical Methods for Efficacy Analyses................................................. 111
8.2.5.1.1
Progression-Free Survival (PFS) ........................................................ 111
8.2.5.1.2
Overall Survival (OS) ......................................................................... 112
8.2.5.1.3
Proportion Progression Free at 6 Months and 12 Months .................. 113
8.2.5.1.4
Objective Response Rate (ORR) ........................................................ 113
8.2.5.1.5
Duration of Response (DOR) ............................................................. 113
8.2.5.1.6
Summary of Efficacy Analysis Methods............................................ 114
8.2.5.2
Statistical Methods for Safety Analyses .................................................... 115
8.2.5.3
Statistical Methods for PRO Analyses....................................................... 116
8.2.5.4
Summaries of Baseline Characteristics and Demographics....................... 116
Multiplicity ....................................................................................................... 117
Sample Size and Power Calculation ................................................................. 118
Subgroup Analyses and Effect of Baseline Factors.......................................... 120
Interim Analyses ............................................................................................... 121
8.2.9.1
Safety Interim Analyses............................................................................. 121
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8.2.9.2
Efficacy Interim Analyses.......................................................................... 122
Compliance (Medication Adherence)............................................................... 129
Extent of Exposure............................................................................................ 130
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 130
Investigational Product ...................................................................................... 130
Packaging and Labeling Information ............................................................... 130
Clinical Supplies Disclosure............................................................................... 131
Storage and Handling Requirements................................................................ 131
Returns and Reconciliation................................................................................ 131
Standard Policies................................................................................................. 131
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 131
Confidentiality..................................................................................................... 131
Confidentiality of Data ..................................................................................... 131
Confidentiality of Subject Records................................................................... 131
Confidentiality of Investigator Information...................................................... 132
Confidentiality of IRB/IEC Information........................................................... 132
Compliance with Financial Disclosure Requirements..................................... 132
Compliance with Law, Audit and Debarment ................................................. 133
Compliance with Trial Registration and Results Posting Requirements...... 134
Quality Management System............................................................................. 135
Data Management............................................................................................... 135
Publications ......................................................................................................... 135
11.0
LIST OF REFERENCES....................................................................................... 137
12.0
APPENDICES......................................................................................................... 143
Code of Conduct for Clinical Trials.................................................................. 143
Collection and Management of Specimens for Future Biomedical Research
.............................................................................................................................. 146
Understanding the Intent, Scope and Public Health Benefits of Exploratory 
Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff
.............................................................................................................................. 152
Abbreviations ...................................................................................................... 163
ECOG Performance Status................................................................................ 166
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 167
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RECIST 1.1 Criteria for Evaluating Response in Solid Tumors ................... 168
13.0
SIGNATURES......................................................................................................... 169
Sponsor's Representative ................................................................................... 169
Investigator.......................................................................................................... 169
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values...................................................... 36
Table 2
Trial Treatment ..................................................................................................... 40
Table 3
Dose Modifications for Trial Medications............................................................ 42
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations .................................................................... 44
Table 5
Dose Modification Guidelines for Febrile Neutropenia or Documented 
Infection................................................................................................................ 47
Table 6
Dose Modification Guidelines for Platinum Drug-Related Adverse Events........ 47
Table 7
Dose Modification Guidelines for Febrile Neutropenia or Documented 
Infection................................................................................................................ 48
Table 8
Dose Modification Guidelines for 5-Fluorouracil Drug-Related Adverse 
Events.................................................................................................................... 49
Table 9
Dose Modification Guidelines for Cetuximab Drug-Related Adverse Events..... 51
Table 10
Cetuximab Dose Modification for Infusion Reactions......................................... 52
Table 11
Cetuximab Dose Modification for Severe Acneiform Rash................................. 53
Table 12
Infusion Reaction Treatment Guidelines .............................................................. 60
Table 13
Imaging and Treatment After 1st Radiologic Evidence of PD............................. 88
Table 14
Laboratory Tests ................................................................................................... 90
Table 15
Evaluating Adverse Events................................................................................. 101
Table 16
Summary of Interim Safety Analysis Strategy ................................................... 107
Table 17
Summary of PFS and OS Analysis Strategies .................................................... 107
Table 18
Censoring Rules for Primary and Sensitivity Analyses of PFS.......................... 112
Table 19
Censoring Rules for DOR................................................................................... 113
Table 20
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints..... 114
Table 21
Analysis Strategy for Safety Parameters............................................................. 116
Table 22
Probability of Observing the Number (%) of Subjects who Require a Dose 
Modification........................................................................................................ 122
Table 23
Decision Guidance at Each Analysis.................................................................. 126
Table 24
Decision Guidance for PFS hypotheses at Each Analysis.................................. 129
Table 25
Product Descriptions........................................................................................... 130
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LIST OF FIGURES
Figure 1
Trial Diagram........................................................................................................ 20
Figure 2
Primary Hypotheses Schematic (Except for H9 and H13, All the Other 
Hypotheses are Tested for Superiority) ................................................................ 22
Figure 3
Multiplicity Strategy........................................................................................... 118
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 13/Global
09-JUN-2022
Added language to allow subjects to roll over to a pembrolizumab extension study.
Amendment 12/Global
20-MAY-2021
To update the pembrolizumab dose modification table and toxicity management 
guidelines for irAEs, in line with FDA request to harmonize the presentation of 
safety information across all FDA-approved PD-1/L-1 antibody prescribing 
information.
To align with the updated SmPC for cetuximab.
Amendment 11/Global
24-MAR-2020
The typographical error "co-primary" that appears at the end of the second 
paragraph in Section 4.2.3.1.1 has been corrected to "dual-primary" to indicate that 
the 2 primary endpoints in the study, OS and PFS, were "dual-primary" endpoints 
rather than "co-primary" endpoints. As a result, the study is considered positive if a 
statistically significant result is determined for either of these endpoints. This error 
has appeared in all versions of the protocol starting with amendment 048-05, dated 
05-AUG-2016.
Amendment 10/Global
11-JAN-2019
Modified to indicate the number of expected events, rather than required events, 
references to “event-driven” were removed, and text was modified to describe the 
timing of the final analysis to account for the scenario if the number of deaths for 
one hypothesis accumulates slower than expected to prevent the trial continuing for 
an unreasonable period for the final analysis.
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Document
Date of Issue
Overall Rationale
Amendment 9/Global
09-NOV-2017
Dose modification guidelines were updated per health authority feedback.
Hypotheses for PFS and OS superiority in biomarker positive subpopulation were 
added.
Follow-up time was increased at the second interim analysis and final analysis to 
allow adequate follow-up time to assess long-term effects of pembrolizumab.
Language was added to enable survival follow-up activities throughout the study at 
timepoints specified by the Sponsor.
Amendment 8/Global
24-AUG-2017
Follow-up time was increased at the interim and final analyses by 3 months to 
achieve data maturity at these timepoints.
Amendment 7/Global
17-MAR-2017
References to PD-L1 10% Combined Positive Score were removed; only the 20% 
and 1% cut points are planned to be analyzed.
Amendment 6/Sweden 
and Norway-specific 
amendment
16-AUG-2016
Updated to reflect changes in global amendment 5 and include information 
regarding benefit/risk assessment per country-specific requirements.
Amendment 5/Global
05-AUG-2016
OS was changed from a secondary objective to a primary objective, and biomarker 
population was updated to include PD-L1 ≥ 20% CPS, ≥ 10% CPS, ≥ 1% CPS. 
Sample size increased from 780 to 825 due to these changes.
The strongly positive PD-L1 enrichment population was removed.
Added QOL secondary objectives.
Changed ORR, DOR, and PFS per irRECIST from secondary to exploratory 
objectives.
Modified inclusion and exclusion criteria.
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Document
Date of Issue
Overall Rationale
Amendment 4/Sweden 
and Norway-specific 
amendment
06-AUG-2015
Added information regarding benefit/risk assessment per country-specific 
requirements.
Amendment 3/Norway-
specific amendment
31-MAR-2015
Added information regarding benefit/risk assessment and updated contraception 
language per country-specific requirements.
Amendment 2/Sweden-
specific amendment
12-MAR-2015
Added information regarding benefit/risk assessment and updated contraception 
language per country-specific requirements.
Amendment 1/Global
26-JUN-2015
Sample size increased from 750 to 780 based on prevalence of strongly positive PD-
L1 expression seen in data from the HNSCC cohorts in KEYNOTE-012.
Added PFS hypothesis for pembrolizumab in combination with chemotherapy vs. 
standard treatment in subjects with strongly positive PD-L1 expression.
Original Protocol
05-DEC-2014
Not applicable.
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
5.10
Trial Summary
Beginning and End of 
the Trial
Once subjects have achieved the trial 
objective or the trial has ended, subjects are 
discontinued from the trial and may be 
enrolled in an extension trial to continue 
protocol-defined assessments and treatment.
This trial has been selected to 
roll over into an extension 
trial.
2.2
Trial Diagram
Pembrolizumab extension trial after survival 
follow-up was added to the diagram.
This trial has been selected to 
roll over into an extension 
trial.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Title Page
12.1
Code of Conduct for 
Clinical Trials
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.
5.1
Entry Criteria
Added text regarding the collection and use of 
demographic data
To clarify the collection, use, 
and confidentiality of 
demographic data provided by 
the subjects
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2
Study Intervention
Added a column for IMP or NIMP/AxMP 
designation and updated terminology in the
‘Use’ column
To align with EU CTR
5.5.2
Prohibited Concomitant 
Medications
Added a note that any COVID-19 vaccine 
that is licensed in a given country is allowed 
in the study
To clarify the concomitant use 
of COVID-19 vaccines
7.1.1.1.2
12.2
Content and Collection 
of Specimens for Future 
Biomedical Research
Collection and 
Management of 
Specimens for Future 
Biomedical Research
Language was updated to clarify that Future 
Biomedical Research is not intended to be a 
sub-trial/sub-study.
Future Biomedical Research 
does not meet the definition of 
a sub-study per EU CTR.
12.1
Code of Conduct for 
Clinical Trials
Numerous edits throughout this section
To align with the current 
version of the Code of Conduct
12.4
Abbreviations
Deleted MSD from abbreviations list
MSD is now defined on the 
title page.
Throughout Document
Updated Sponsor name
To ensure that all references to 
the Sponsor reflect the 
corporate entity name change
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document
To ensure clarity and accurate 
interpretation of the intent of 
the protocol
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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab as First Line Treatment in Subjects with Recurrent/Metastatic 
HNSCC 
Trial Phase
Phase III
Clinical 
Indication
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Trial Type
Interventional
Type of control
Active control without placebo
Route 
of 
administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment 
Groups
(1) Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W); or
(2) Pembrolizumab (MK-3475) 200 mg Q3W + Platinum + 5-Fluorouracil (5-FU);
or
(3) Cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 (weekly) + Platinum 
+ 5-FU
(Platinum is either Cisplatin 100 mg/m2 Q3W or Carboplatin AUC 5 Q3W; 5-FU is 
1000 mg/m2/day continuous from Day 1 to Day 4 Q3W)
Number of trial 
subjects
Approximately 825 subjects will be enrolled.
Estimated 
duration of trial
The sponsor estimates that the trial will require approximately 60 months from the 
time the first subject provides documented informed consent until the last subject’s 
last visit.
Duration 
of 
Participation
Each subject will participate in the trial until death, drop out, or loss-to-follow-up 
from the time the subject provides documented informed consent through the final 
contact. After a screening phase of up to 28 days, each subject will receive treatment 
based on the arm to which they have been randomized.  Treatment on trial will 
continue until disease progression is verified by the central imaging vendor, 
unacceptable AEs, intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, noncompliance with trial 
treatment or procedures requirements, subject receives 24 months of study 
medication (pembrolizumab arms only), pregnancy, or administrative reasons. 
Subjects on either pembrolizumab arm who attain a CR may consider stopping trial 
treatment if they meet criteria for holding therapy. Subjects receiving 
pembrolizumab who stop trial treatment after receiving 24 months of study 
medication for reasons other than disease progression or intolerability, or subjects 
who attain a CR and stop trial treatment may be eligible for up to one year of 
retreatment upon experiencing centrally verified disease progression.  The decision 
to retreat will be at the discretion of the investigator only if the subject meets the 
criteria for retreatment and the trial is ongoing.  After the end of treatment, each 
subject will be followed for 30 days for AE monitoring (SAEs and ECIs will be 
collected for 90 days after the end of treatment).  Subjects who discontinue for 
reasons other than centrally verified disease progression will have posttreatment 
follow-up for disease status until disease progression is verified by the central 
imaging vendor, initiating a nonstudy cancer treatment, 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.
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Once the subject has achieved the trial objective or the trial has ended, the subject 
is discontinued from the trial and may be enrolled in an extension trial to continue 
protocol-defined assessments and treatment.
Randomization 
Ratio
1:1:1
A list of abbreviations used in this document can be found in Section 12.4.
2.0 TRIAL DESIGN
Trial Design
This is a randomized, active-controlled, multi-site, open-label trial of pembrolizumab, or 
pembrolizumab plus platinum plus 5-FU chemotherapies versus platinum plus 5-FU plus 
cetuximab in subjects with advanced head and neck cancer to be conducted in conformance 
with Good Clinical Practices (GCP). Approximately 825 subjects with first line recurrent or 
metastatic (R/M) head and neck cancer will be enrolled for examination of the efficacy and 
safety of pembrolizumab versus pembrolizumab plus chemotherapy versus standard of care 
with cetuximab and chemotherapy. Subjects will be randomized 1:1:1 between the 3 arms of 
the trial. 
The study will be stratified. Stratification factors are described in Section 5.4.
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 a group-sequential design based on pre-specified criteria, using an 
independent, external DMC to monitor safety and efficacy. There will be 2 interim PFS/OS 
analyses, 1 final OS analysis, 1 planned interim safety analysis, and quarterly safety 
monitoring.  The interim safety analysis will be conducted when 10 subjects in the 
pembrolizumab plus chemotherapy arm have completed 2 cycles of treatment.  The interim 
PFS/OS analyses are time-driven.  More details are given in Section 8.2.9.
Results of the interim analyses will be reviewed by the DMC, which will make 
recommendations to the Sponsor to continue, modify, or end the trial according to the plan 
described briefly in Section 2.2 - Trial Diagram and in detail in Section 8.0 - Statistical 
Analysis Plan.
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Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
Choice of cisplatin or carboplatin will be made by the investigator before randomization.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
PD-L1 Positive Populations (Figure 2): subjects with PD-L1 positive expression defined by 
≥20 CPS and by ≥1 CPS; henceforth abbreviated as PD-L1 CPS 20 and PD-L1 CPS 1, 
respectively.
(1)
Objective: To compare the Progression Free Survival (PFS) per RECIST 1.1 as assessed 
by blinded independent central review (BICR) in first line recurrent/metastatic (R/M) 
HNSCC subjects, treated with pembrolizumab monotherapy versus standard treatment.
Hypothesis (H1):  Pembrolizumab monotherapy prolongs PFS by RECIST 1.1 
(BICR) in a subgroup of first line R/M HNSCC subjects with PD-L1 CPS 20
compared to standard treatment.
Hypothesis (H2):  Pembrolizumab monotherapy prolongs PFS by RECIST 1.1 
(BICR) in a subgroup of first line R/M HNSCC subjects with PD-L1 CPS 1 compared 
to standard treatment.
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Hypothesis (H3):  Pembrolizumab monotherapy prolongs PFS by RECIST 1.1 
(BICR) in all first line R/M HNSCC subjects compared to standard treatment.
(2)
Objective: To compare PFS per RECIST 1.1 as assessed by BICR in first line R/M 
HNSCC subjects, treated with pembrolizumab in combination with chemotherapy
versus standard treatment.
Hypothesis (H4):  Pembrolizumab in combination with chemotherapy prolongs PFS 
by RECIST 1.1 (BICR) in a subgroup of first line R/M HNSCC subjects with PD-L1 
CPS 20 compared to standard treatment.
Hypothesis (H5):  Pembrolizumab in combination with chemotherapy prolongs PFS 
by RECIST 1.1 (BICR) in a subgroup of first line R/M HNSCC subjects with PD-L1 
CPS 1 compared to standard treatment.
Hypothesis (H6):  Pembrolizumab in combination with chemotherapy prolongs PFS 
by RECIST 1.1 (BICR) in all first line R/M HNSCC subjects compared to standard
treatment.
(3)
Objective: To evaluate the overall survival (OS) in first line R/M HNSCC subjects,
treated with pembrolizumab monotherapy versus standard treatment.
Hypothesis (H7):  Pembrolizumab monotherapy prolongs OS in first line R/M 
HNSCC subjects with PD-L1 CPS 20 compared to standard treatment.
Hypothesis (H8):  Pembrolizumab monotherapy prolongs OS in first line R/M 
HNSCC subjects with PD-L1 CPS 1 compared to standard treatment.
Hypothesis (H9):  Pembrolizumab monotherapy is noninferior to standard treatment 
in terms of OS in all first line R/M HNSCC subjects.
Hypothesis (H10):  Pembrolizumab monotherapy prolongs OS in all first line R/M 
HNSCC subjects compared to standard treatment.
(4)
Objective: 
To evaluate OS in first line R/M HNSCC subjects, treated with 
pembrolizumab in combination with chemotherapy versus standard treatment.
Hypothesis (H11):  Pembrolizumab in combination with chemotherapy prolongs OS 
in first line R/M HNSCC subjects with PD-L1 CPS 20 compared to standard 
treatment.
Hypothesis (H12):  Pembrolizumab in combination with chemotherapy prolongs OS 
in first line R/M HNSCC subjects with PD-L1 CPS 1 compared to standard treatment.
Hypothesis (H13):  Pembrolizumab in combination with chemotherapy is 
noninferior to standard treatment in terms of OS in all first line R/M HNSCC subjects.
Hypothesis (H14):  Pembrolizumab in combination with chemotherapy prolongs OS 
in all first line R/M HNSCC subjects compared to standard treatment.
The statistical criterion for the success of H9 and H13 is that, if the upper bound of 
the confidence interval, based on the alpha level allocated to the analysis, for the 
hazard ratio is <1.2, then pembrolizumab experimental arm could be considered as
noninferior to the standard treatment arm in terms of OS.
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Figure 2
Primary Hypotheses Schematic (Except for H9 and H13, All the Other 
Hypotheses are Tested for Superiority)
Secondary Objective(s) & Hypothesis(es)
(1)
Objective:  To evaluate the safety and tolerability profile of pembrolizumab 
monotherapy or a combination of pembrolizumab with chemotherapy in all first line 
R/M HNSCC subjects.
The following secondary objectives will be evaluated in (1) PD-L1 CPS 20, (2) PD-L1 CPS 1
and (3) all subjects for both pembrolizumab in combination with chemotherapy and 
pembrolizumab monotherapy compared to standard treatment.
(2)
Objective:  To evaluate proportion progression free at 6 months and 12 months per 
RECIST 1.1 by BICR of first line R/M HNSCC subjects.
(3)
Objective:  To evaluate objective response rate (ORR) per RECIST 1.1 by BICR in 
first line R/M HNSCC subjects.
(4)
Objective:  To evaluate mean change from baseline in global health status/quality of 
life in first line R/M HNSCC subjects.
(5)
Objective: To evaluate TTD in global health status/quality of life, pain and swallowing 
in first line R/M HNSCC subjects.
Exploratory Objectives
(1)
Objective: To evaluate duration of response (DOR) per RECIST 1.1 by BICR in first 
line R/M HNSCC subjects.
(2)
Objective: 
To evaluate ORR, DOR and PFS using immune-related RECIST 
(irRECIST) as assessed by BICR in first line R/M HNSCC subjects.
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(3)
Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline in subjects with R/M HNSCC using the EORTC QLQ-C30 and EORTC QLQ-
H&N35.
(4)
Objective:  To characterize utilities in subjects with R/M HNSCC cancer using the 
EuroQol EQ-5D.
(5)
Objective:  To evaluate changes in opioid analgesic use from baseline in subjects with 
R/M HNSCC, based on reported concomitant medications, supplemented with a daily
Pain Medication Log.
(6)
Objective:  To investigate the relationship between pembrolizumab treatment and 
biomarkers predicting response (e.g., PD-L1, genetic variation, serum soluble PD-L1) 
utilizing archival tumor tissue and blood sampling.
(7)
Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study.  
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity 
for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies.  Keytruda™ 
(pembrolizumab) is indicated for the treatment of patients across a number of indications. 
Refer to the IB/approved labeling for detailed background information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (previously known as SCH 9000475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block 
the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation 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 [2; 3; 4; 5; 6]. In particular, the presence of CD8+ T cells and the ratio 
of CD8+ effector T cells / FoxP3+ regulatory T cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and Cytotoxic T-Lymphocyte-Associated Antigen-4 
(CTLA-4) which has been shown to negatively regulate antigen receptor signaling upon 
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engagement of its ligands (PD-L1 and/or PD-L2) [7; 8]. The structure of murine PD-1 has 
been resolved [9].  PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a 
cytoplasmic tail which is 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 (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  
Following T cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the 
ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules 
such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T cell signaling cascade [7; 
10; 11; 12].  The mechanism by which PD-1 down modulates T cell responses is similar to, 
but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins [13; 14].  PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T cells, B cells, T regs and Natural Killer cells [15; 16].  
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T cells as well as subsets of macrophages and dendritic cells [17]   The ligands for PD-1 (PD-
L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including nonhematopoietic tissues as well as in various tumors [13; 18; 19; 20].  Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T cell activation triggered through the T cell 
receptor.  PD-L1 is expressed at low levels on various nonhematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T cell function in peripheral tissues [13].  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels 
of this T cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T cell expansion 
in subjects with melanoma (MEL) [21].  This suggests that the PD-1/PD-L1 pathway plays a 
critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention.
Preclinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor
responses as a monotherapy in multiple models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T cell infiltration into the tumor and the presence of IFN-, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of
effector T cell function in vivo [22; 23; 24; 25; 26; 27; 28].  Experiments have confirmed the 
in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the IB).
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Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, nonsmall cell lung cancer
(NSCLC), a number of advanced solid tumor indications (including head and neck cancer) and 
hematologic malignancies.  For study details please refer to the IB.
Trials evaluating pembrolizumab in head and neck cancer have demonstrated clinical activity 
in patients with recurrent and/or metastatic disease.  KEYNOTE-012 is a Phase 1b study of 
pembrolizumab in 4 indications, one of which includes patients 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 recurrent and/or metastatic squamous cell 
carcinoma of the head and neck for treatment with single agent pembrolizumab.
The pooled data from Cohorts B and B2 were presented at ASCO 2016 and described efficacy 
and safety results after long-term follow-up [29]. 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 PS 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 patients who progress following first 
line treatment [30]. 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 [31].  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 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, 
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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 immunohistochemistry (IHC) scoring (combined positive scoring, CPS) improves the 
ability to predict response based on PD-L1 status compared to tumor cells alone (TPS) in 
subjects with R/M HNSCC. In addition, preliminary results from KEYNOTE-055 showed that 
using CPS 1 and 20 cutpoint demonstrates a positive predictive value (PPV) of 20.3% and 
26.8%, respectively, with negative predictive value (NPV) at 88.0% and 88.3%, respectively.  
The PFS survival curves are the most separated at CPS 20 [32].  The prevalence for CPS 1 and 
CPS 20 cutpoints are approximately 80% and 50%, respectively.
KEYNOTE-040 is a Phase 3, multicenter, international, randomized, open-label trial of single 
agent pembrolizumab (200 mg Q3W) versus standard of care in subjects with R/M HNSCC.  
Results from KEYNOTE-040 showed that pembrolizumab demonstrated a greater benefit in 
subjects with PD-L1 expressing tumors.  In the CPS 1 population, ORR was 17.3% for the
pembrolizumab arm compared to 9.9% for the standard of care arm (CI: 0.6%-14.6%). The 
median OS is 8.7 months for the pembrolizumab arm compared to 7.1 months for the standard 
of care arm (HR=0.75, CI: 0.59-0.95) [61].
Based on the evolving information obtained from further analysis of the KEYNOTE-012 study
as well as emerging biomarker data from KEYNOTE-055, we plan to evaluate PD-L1 
expression using a CPS 20 cutpoint, which balances all factors including PPV, prevalence, the 
biomarker specificity/sensitivity, in addition to the 50% TPS previously specified.  The CPS 1
cutpoint will also be evaluated.  We will continue the stratification of randomization according 
to the 50% TPS cutoff as already ongoing and will plan to correlate PD-L1 expression with 
clinical outcome according to both IHC criteria. All analysis of PD-L1 testing was based solely 
on the KEYNOTE-012, KEYNOTE-055, and KEYNOTE-040 clinical trials as the Sponsor
remains blinded to the ongoing KEYNOTE-048 database. Additionally, subject-level PD-L1 
biomarker results will continue to be masked in the database to the study team at the Sponsor 
including clinical, statistical, statistical programming, and data management personnel until 
the time of the planned efficacy analysis(es).
Information on Other Trial-Related Therapy
A variety of chemotherapies are used for patients with R/M, first line HNSCC. Early studies 
demonstrated small survival benefits after treatment with cisplatin or methotrexate or 
chemotherapy combinations [33]. In the 18 years following this early report from the Liverpool 
consortium, cisplatin, carboplatin, methotrexate, paclitaxel, 5-fluorouracil (5-FU), and their 
various combinations have been evaluated in several Phase 3 trials [34; 35; 36; 37; 38; 39]. 
The combination of cisplatin and 5-FU showed generally better results than other regimens 
with overall response rates ranging from 11 to 37% and OS ranging from 23 to 36 weeks. No 
Phase 3 randomized trial showed a significant advantage in OS for any regimen until 
cetuximab in combination with platinum and 5-FU was compared with platinum and 5-FU in 
the EXTREME trial. Addition of cetuximab to cisplatin-5-FU demonstrated the first significant 
increase in OS in first line head and neck cancer in EXTREME [40]. OS was increased from 
30 weeks for platinum-5-FU to 40 weeks with the platinum/5-FU/cetuximab regimen. In 
EXTREME, the corresponding ORR increased from 20 to 30% and the PFS increased from 13 
to 22 weeks. The EXTREME regimen is associated with an 82% frequency of Grade 3/4 
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toxicities. Paclitaxel or docetaxel-based regimens are used by many clinicians, but taxane-
containing regimens have yet to be directly compared with the EXTREME regimen in a 
randomized Phase 3 trial. Recent literature showed that the median OS of the EXTREME 
regimen may be prolonged (approximately 11 months) compared with original median OS 
published in 2008 (approximately 10 months) [58, 59, 60].
Since R/M first line patients have somewhat heterogeneous characteristics, National 
Comprehensive Cancer Network (NCCN) guidelines generally highlight the importance of 
considering individualized systemic therapies based on patient characteristics, given the 
toxicity of the EXTREME regimen. The only Category 1 evidence-supported combination 
regimen recommended by NCCN is the EXTREME regimen. NCCN guidelines offer 
consideration of the use of alternative combination regimens including platinum plus taxane, 
cisplatin plus cetuximab and cisplatin plus 5-FU, or the use of these agents as monotherapies.
Rationale
Rationale for the Trial and Selected Subject Population
Head and neck cancer describes a range of tumors that arise in the head and neck region, which 
includes the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, and salivary 
glands. The worldwide incidence of head and neck cancer exceeds half a million cases 
annually, ranking it as the fifth most common cancer worldwide [41], and accounts for 5% of 
all malignancies [42]. Although the head and neck region contains a wide diversity of 
structures and cell types, the vast majority of head and neck cancers arise from the mucosa of 
the upper aerodigestive tract and are predominantly squamous cell in origin.
A large number of patients with head and neck cancer initially present with locally advanced, 
Stage III/IV disease that is initially treated with combinations of chemotherapy, radiation 
and/or surgery. This initial treatment is generally designated as “definitive” therapy, which 
typically combines chemoradiation and surgery and can result in disease control rates ranging 
between 33 and 86% of patients. Patients who progress after initial definitive therapy require 
subsequent treatment for recurrent (R) disease. Patients who initially present with metastatic 
(M) disease generally receive the same therapy as those with recurrent disease after definitive 
treatment. Together, patients with recurrent or metastatic (R/M) disease receive the first line 
chemotherapies outlined above (Section 4.1.4).
In this trial, subjects with oropharynx cancer will be stratified by HPV status (positive or 
negative).  The favorable prognostic significance of HPV-positive head and neck cancers in 
the oropharynx has been increasingly established [43].  Preliminary data of single agent 
pembrolizumab in head and neck cancer patients in KEYNOTE-012 demonstrate efficacy in 
both HPV-positive and HPV-negative patients. Investigator site assessment of HPV using IHC 
staining for the p16 protein will be used for the subjects with oropharyngeal cancer prior to 
randomization.
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Rationale for Dose Selection/Regimen/Modification
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)
• Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg Q3W 
across multiple indications
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled with 
melanoma and nonsmall 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 vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 3
studies compared 10 mg/kg Q3W vs. 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 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.
4.2.2.1
Rationale for the Use of Comparator/Placebo
See Section 4.1.4.
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Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary
OS is the gold standard endpoint to demonstrate efficacy of antineoplastic therapy.  Achieving 
superiority in OS, however, is likely to be limited by dilution of benefit with multiple post-
progression therapies as well as disproportionate crossover in the control arm to available PD-
1/PD-L1 axis of therapies.  Therefore, overall survival of pembrolizumab treatment is 
evaluated as noninferior before superior to standard of care treatment in the analysis. In 
addition, pembrolizumab monotherapy has shown OS benefit in previously treated HNSCC 
patient population (Section 4.1.3).
Progression-free survival is an acceptable measure of clinical benefit for a randomized Phase 
3 trial that demonstrates superiority of a new antineoplastic therapy, especially if the magnitude 
of effect is large and the therapy has a favorable risk-benefit profile. The substantial toxicity 
of the EXTREME regimen contributes to a comparative lack of acceptance by patients and 
physicians, arguing for a critical need to establish an effective alternative regimen. The 
available trials of PD-1/PD-L1 therapies in later lines of therapy as well as their potential 
approval in previously treated patients will lead to substantial crossover of patients receiving 
the EXTREME comparator for the duration of this trial. Taken together, these factors support 
the use of PFS as a dual-primary endpoint in this trial.
RECIST 1.1 will be used to determine the dates of progression as this methodology is accepted 
by regulatory authorities.  Because the treatment assignment is unblinded, images will be read 
by independent radiologists blinded to treatment assignment to minimize bias in the response 
assessments.  In addition, final determination of radiologic progression will be based on the 
central assessment of progression, rather than site assessment.  Real-time determination of 
radiologic progression as determined by central review will be communicated to the site. 
4.2.3.1.2 Secondary
ORR by RECIST 1.1 criteria as assessed by blinded independent central radiology review will 
serve as an additional measure of efficacy.
4.2.3.2
Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses.  The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST may not 
provide an accurate
response assessment of immunotherapeutic agents such as 
pembrolizumab.  Therefore, RECIST 1.1 will be used with the following adaptations:
If radiologic imaging by central imaging vendor verifies initial PD, tumor assessment should 
be repeated ≥4 weeks later in order to confirm PD with the option of continuing treatment per 
below while awaiting radiologic confirmation of progression.  If repeat imaging shows a 
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reduction in the tumor burden compared to the initial scan demonstrating PD, treatment may 
be continued / resumed.  If repeat imaging confirms PD, subjects will be discontinued from 
study therapy (exception noted in Section 7.1.2.6.3).  In determining whether or not the tumor 
burden has increased or decreased, investigators should consider all target lesions as well as 
nontarget lesions (please refer to the Site Imaging Manual).
In subjects who have initial evidence of radiological PD verified by central imaging vendor, it 
is at the discretion of the treating physician whether to continue a subject on study treatment 
until repeat imaging is obtained.  This clinical judgment decision should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive pembrolizumab treatment while waiting for 
confirmation of PD if they are clinically stable as defined by the following criteria:
•
Absence of signs and symptoms indicating disease progression
•
No decline in ECOG PS
•
Absence of rapid progression of disease
•
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of PD.
Subjects randomized to the standard treatment arm will not have irRECIST assessments.
4.2.3.3
Rationale for Prospective Stratification and Evaluation of Biomarker 
Subpopulation
Late line R/M HNSCC subjects evaluated in KEYNOTE-012 were enrolled if their tumor PD-
L1 immunohistochemistry (IHC) showed any evidence of ligand expression. KEYNOTE-012 
sought to evaluate responses in a population of subjects likely to demonstrate higher ORRs
than anticipated for subjects with PD-L1 negative tumors. Studies to date in additional 
indications (melanoma and lung) suggest that subjects may respond to pembrolizumab even if 
their tumors show little or no PD-L1 by IHC, although potentially at a lower rate of response. 
KEYNOTE-012 was amended to include subjects that are both positive and negative by IHC, 
and response rates are being determined and evaluated for various expression levels of PD-L1.
Data from epidemiology studies suggest that PD-L1 expression in a subject’s tumor(s) varies 
with the circumstances of testing. Overall, the evaluation of tumor PD-L1 status likely most 
accurately reflects expression in the tumor to be treated using tumor biopsies nearest the time 
of treatment initiation, and at times after any previous cancer therapies were administered. 
Consequently, subjects enrolled in KEYNOTE-048 will preferably have a biopsy of their 
tumor evaluated either using initial diagnostic specimens or from newly obtained biopsies if 
subjects received cancer treatment after their diagnostic biopsy. IHC will be used to evaluate 
the PD-L1 status of the tumor specimen. Further details of the statistical approach to evaluating 
this population are described in Section 8.2.
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4.2.3.4
Safety
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with R/M HNSCC. The primary safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE criteria. Safety will be assessed by 
quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab, including SAEs and ECIs. Safety will be assessed by reported adverse 
experiences using CTCAE, Version 4.0. The attribution to drug, time of onset, duration of the 
event, its resolution, and any concomitant medications administered will be recorded. AEs will 
be analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. 
Furthermore, specific irAEs will be collected and designated as immune-related ECIs as 
described in Section 7.2.3.2. The mandatory Safety Follow-Up Visit should be conducted 
approximately 30 days after the last dose of trial treatment or before the initiation of a new 
antineoplastic treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-
Up Visit should be recorded.  Subjects with an AE of Grade >1 will be followed until the 
resolution of the AE to Grade 0-1 or until the beginning of a new antineoplastic therapy, 
whichever occurs first.  SAEs and ECIs that occur within 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, should be followed and recorded.
4.2.3.5
Patient-reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-H&N35 and EQ-5D are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability. A 
Pain Medication Log will collect information on daily prescription medication use, which may 
indicate changes in pain either affected by disease progression and/or treatment tolerability.
4.2.3.5.1 eEORTC QLQ-C30 and eEORTC QLQ-H&N35
The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which 
contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive 
and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, 
sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global 
health and quality-of-life scale [44].
The EORTC QLQ-H&N35 is in use worldwide as one of the standard instruments for 
measuring quality of life in head and neck cancer subjects [45; 46] and consists of 7 multi-item 
scales measuring pain in the mouth, problems with swallowing, senses, speech, social eating 
and social contact, and 11 single-item scales assessing 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 [47].  The EORTC QLQ-C30 and EORTC 
QLQ-H&N35 are psychometrically and clinically validated instruments appropriate for 
assessing quality of life in subjects with head and neck cancer. These instruments were used 
in the EXTREME registration trial comparing platin-5-fluorouracil alone versus combined 
with cetuximab as first line treatment in recurrent or R/M HNSCC, which led to the FDA 
approval of cetuximab monotherapy in subjects with recurrent or metastatic SCCHN refractory 
to cisplatin [48; 49].  They were also used in the Phase III trial of subjects with locoregionally 
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advanced head and neck cancer receiving radiotherapy alone with radiotherapy plus cetuximab 
[46].
For the global health status/quality of life and function scales, a higher value indicates a better 
level of function; for symptom scales and items, a higher value indicates increased severity of 
symptoms. Prior literature indicates that head and neck pain and the ability to swallow are 
clinically relevant symptom measures in the R/M HNSCC population [48; 49; 50; 51]. Thus, 
TTD in the pain and swallowing multi-item scales of the EORTC QLQ-H&N35, in addition to 
TTD and mean change from baseline in global health status/quality-of-life scale of the EORTC 
QLQ-C30, will be evaluated as secondary objectives.
The EORTC QLQ-C30 and EORTC QLQ-H&N35 are to be completed at various time points 
as specified in the study Flow Chart, beginning with Cycle 1 until 30 days posttreatment
discontinuation.
4.2.3.5.2 Electronic EuroQol EQ-5D
The electronic EuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of 
health outcome.  The eEQ-5D will provide data for use in economic models and analyses 
including developing health utilities or quality adjusted life-years.  The 5 health state 
dimensions in this instrument include the following: mobility, selfcare, usual activities, 
pain/discomfort, and anxiety/depression (5).  Each dimension is rated on a 3-point scale from 
1 (extreme problem) to 3 (no problem).  The eEQ-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.  The eEQ-5D will always be completed by subjects first before completing the 
electronic EORTC QLQ-C30 and EORTC QLQ-H&N35 and is to be completed at various 
time points as specified in the Trial Flow Chart, beginning with Cycle 1 until 30 days 
posttreatment discontinuation.
4.2.3.5.3 Pain Medication Log
The Pain Medication Log is a paper-based pamphlet that will be completed daily by subjects 
to document the use of prescription pain medications.  The objective of the Pain Medication 
Log is to provide data to assess changes in opioid analgesic use from baseline.  The Pain 
Medication Log will record the use of prescription pain medication by the subject, the name of 
each pain medication, and the dose of each tablet taken or patch used.  For each prescription 
pain medication tablet, subjects will indicate number of tablets taken. For each prescription 
pain medication patch, subjects will indicate the days the patch was used. 
It is recommended that subjects complete the log starting from the Screening Visit.  The Pain 
Medication Log is to be completed by subjects daily and submitted to site personnel at each 
scheduled visit as specified in the study Flow Chart, beginning with Screening until 30 days 
posttreatment discontinuation. At each study visit, study personnel will verify the information 
with the subject.  Site personnel will determine the use and the total daily dose of prescription 
pain medication(s) and enter these data on the concomitant medication form of the case report 
form (CRF).
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4.2.3.6
Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab therapy may 
also be pursued.  For example, tumor and blood samples (including serum and plasma) from 
this study may undergo proteomic, genomic, metabolomic and transcriptional analyses.  
Additional research may evaluate factors important for predicting responsiveness or resistance 
to pembrolizumab therapy and other immunologic targets.
Assays may include but are not limited to:
Immunohistochemistry
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab.  Other biomarkers contributing to the PD-1/PD-L1 axis may also be explored.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material will be completed to assess 
expression of approximately 700 genes and attempt to define a gene set critical for clinical 
response to pembrolizumab.  The hypothesis to be tested is that pembrolizumab induces 
responses in tumors that reflect an inflamed/ immune phenotype based on gene expression 
signatures capturing PD-L1 and interferon-gamma transcriptional programs.  Global profiling 
will also be pursued.  Expression of individual genes related to the immune system may also 
be evaluated such as immune signatures and critical cytokines (eg, IL-10).  MicroRNA 
profiling may also be pursued in serum samples.
Proteomic Analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released into 
the blood.  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab therapy, as well as levels of PD-L1 IHC or protein 
in the tumor.  Blood would be a less invasive compartment compared to tumor from which to 
measure PD-L1 protein biomarker.  In addition to this specific protein biomarker, both tissue 
and blood derivatives can be subjected to proteomic profiling studies using a variety of 
platforms that could include but are not limited to immunoassay, liquid chromatography/mass 
spectrometry.  This approach could identify novel protein biomarkers that could aid in patient 
selection for pembrolizumab therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or it can detect the presence of specific T cell clones within the tumor 
microenvironment.  There is a potential that this hypermutated state and the detection of 
increased T cell clonality may correlate with response to pembrolizumab therapy, and/or that 
the converse, ‘hypomutated’ state or lack of T cells clones may correlate with nonresponse. 
Understanding genetic determinants of drug response is an important endeavor during medical 
research.  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 AEs, the data might inform optimal use of therapies in the patient 
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population. This research contributes to understanding genetic determinants of efficacy and 
safety associated with the treatments in this study.
4.2.3.7
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens routinely and specifically 
collected 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.
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 specimens for FBR is to explore 
and identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. For instance, exploratory PGt studies may be performed if significant 
PK/Pharmacodynamic relationships are observed or AEs are identified.  Genomic markers of 
disease may also be investigated.  Such retrospective pharmacogenetic studies will be 
conducted with appropriate biostatistical design and analysis and compared to 
PK/Pharmacodynamic results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. 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 this FBR 
are presented in Section 12.2 - Collection and Management of Specimens for Future 
Biomedical Research.  Additional informational material for IRBs/ERCs and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from pembrolizumab 
during participation, as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this clinical 
trial may be found in the accompanying IB and Informed Consent documents.
Pembrolizumab has a positive benefit-risk profile and is well tolerated in the approved 
indications.  Publications of a significantly positive benefit/risk ratio have been reported for 
melanoma in a single arm study encompassing nearly 1000 patients (KEYNOTE-001), which 
led to US FDA approval in September 2014. Pembrolizumab has subsequently received 
approval for the treatment of patients with nonsmall cell lung cancer (NSCLC) and for the 
treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma 
(HNSCC).  The Investigator Brochure provides additional details about these approvals.  The 
US FDA approval to treat patients with R/M HNSCC with disease progression on or after 
platinum-containing chemotherapy was based on the favorable tumor response rate and 
durability of responses seen in KEYNOTE-012 and KEYNOTE-055. The potential benefits 
for patients with HNSCC are addressed in Section 4.1.3, which details responses of subjects 
with HNSCC in KEYNOTE-012 and KEYNOTE-055.
The most common pembrolizumab adverse reactions (reported in ≥20% of patients) include 
pruritus, diarrhea, and cough. In the pembrolizumab monotherapy trials, the incidence of Grade 
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3-5 drug-related AEs across studies is 13.8%.  Pembrolizumab immune-mediated Adverse 
Events of Special Interest (AEOSIs) are relatively uncommon. The most frequently reported 
AEOSI is hypothyroidism, with an overall incidence of 8.5%. Furthermore, most AEOSIs are 
mild to moderate in severity, and are generally readily manageable with appropriate care in the 
clinical setting. The AEs associated with pembrolizumab are milder and less frequent than 
events reported for the cetuximab, platinum, 5-FU comparator in this trial. For the cetuximab-
platinum-5-FU comparator, Grade 4 events are seen in 31% of patients, including neutropenia 
as the most frequent Grade 4 event (4%). For the cetuximab-platinum-5FU arm, 82% of 
patients experienced a Grade 3 or 4 AE including 22% with neutropenia, 13% with anemia and 
11 % with thrombocytopenia.
The safety profile of the KEYNOTE-048 pembrolizumab combination arm (pembrolizumab 
plus platinum plus 5-FU), together with the pembrolizumab monotherapy arm and standard 
treatment arm (cetuximab plus chemotherapy) has been evaluated by an external DMC at an 
early interim safety analysis in the initial stage of this trial, and continues to be evaluated on a 
quarterly basis.  Following DMC review of the unblinded safety data (including the recent 
DMC meeting in February 2017), the DMC recommended to continue the trial with no 
changes.   
The durability of immunotherapeutic responses, together with the tolerability advantage of 
pembrolizumab argues strongly for a direct comparison of the current approved cetuximab-
platinum-5-FU regimen both with pembrolizumab monotherapy and with a pembrolizumab-
platinum-5-FU combination as proposed in this trial. As noted, this clinical trial is designed to 
provide a direct comparison between the current regimen and the investigational arms 
proposed in this trial.
5.0 METHODOLOGY
Entry Criteria
As stated in the Code of Conduct for Clinical Trials (Section 12.1), our studies include people 
of varying age, race, ethnicity, and sex. The collection and use of these demographic data is to 
follow all local laws and guidelines in keeping with the needs for subject confidentiality while 
supporting the study of the disease, its related factors, and the IMP under investigation.
Diagnosis/Condition for Entry into the Trial
Male and female subjects HNSCC of at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Have histologically or cytologically-confirmed R/M HNSCC that is considered 
incurable by local therapies. 

Subjects should not have had prior systemic therapy administered in the 
recurrent or metastatic setting.  Systemic therapy which was completed more 
than 6 months prior to providing documented informed consent if given as part 
of multimodal treatment for locally advanced disease is allowed.
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
The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, 
and larynx.

Subjects may not have a primary tumor site of nasopharynx (any histology).
2. Be willing and able to provide documented informed consent for the trial.  The subject 
may also provide consent for FBR.  However, the subject may participate in the main 
trial without participating in FBR.
3. Be 18 years of age on day of signing informed consent.
4. Have measurable disease based on RECIST 1.1 as determined by the site.  Tumor 
lesions situated in a previously irradiated area are considered measurable if progression 
has been demonstrated in such lesions.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500/μL (1.5 x 109/L)
Platelets
≥100,000/μL (100 x 109/L)
Hemoglobin
≥9 g/dL (90 g/L) or ≥5.6 mmol/L 
Renal
Creatinine OR
Measured or calculateda creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5xULN OR
≥60 mL/min for subject with
creatinine levels >1.5x institutional ULN
Hepatic
Total bilirubin
≤1.5xULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULN OR
≤5xULN for subjects with liver metastases
Coagulation
International 
Normalized 
Ratio 
(INR) 
or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT) or 
Partial Thromboplastin Time PTTb
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants
a Creatinine clearance should be calculated per institutional standard.
b PTT may be performed if the local lab is unable to perform aPTT.
7. Have results from 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 
7.1.2.7 for details). If HPV status was previously tested using this method, no additional 
testing is required.
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Note:  Tumor p16 expression must be evaluated by assessment of IHC analysis 
with CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson 
AZ) using ‘Benchmark Ultra’ autostainer (Ventana, Tucson, AZ) and 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 patients with oropharynx cancer using the specified method.
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, 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.
8. Have provided tissue for PD-L1 biomarker analysis from a core or excisional biopsy 
(FNA is not adequate).  Repeat samples may be required if adequate tissue is not 
provided.  A newly obtained biopsy (within 90 days prior to start of study treatment) is 
strongly preferred, but an archival sample is acceptable.
Note: Refer to Section 7.1.2.7 for more information on tissue sample 
requirements.
9. Female subjects of childbearing potential should have a negative blood pregnancy test 
within 72 hours prior to receiving the first dose of study medication.  A urine test can 
be considered if a blood test is not appropriate.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 180 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for >1 year.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred method 
of contraception for the subject.
11. Male subjects should agree to use an adequate method of 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 method 
of contraception for the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent.
2. Has PD within 6 months of completion of curatively intended systemic treatment for 
locoregionally advanced HNSCC. 
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3. Has had radiation therapy (or other nonsystemic therapy) within 2 weeks prior to 
randomization or subject has not fully recovered (i.e., ≤Grade 1 or at baseline) from 
AEs due to a previously administered treatment.
Note: Subjects with ≤Grade 2 neuropathy, ≤Grade 2 alopecia, or laboratory 
values on Table 1 are an exception to this criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.
4. Is currently participating and receiving study therapy, or has participated in a study of 
an investigational agent and received study therapy, or used an investigational device, 
any of which occurred within 4 weeks of the first dose of treatment.
Note: Participation in the follow-up phase (receiving no study treatment) of a 
prior study is allowed.
5. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (e.g. 
tumor bleeding, uncontrolled tumor pain) in the opinion of the treating investigator.
6. 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 premedication for allergic reactions (e.g. IV contrast), 
or as a prophylactic management of AEs related to the chemotherapies specified in the 
protocol is allowed. The use of physiologic doses of corticosteroids may be approved 
after consultation with the Sponsor. 
7. Has a diagnosed and/or treated additional malignancy within 5 years prior to 
randomization with the exception of: curatively treated basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, curatively resected in situ cervical cancer, and 
curatively resected in situ breast cancer. Other exceptions may be considered with 
Sponsor consultation.
Note: The time requirement for no malignancy for 5 years does not apply to the 
cancer for which a subject is enrolled in the trial.
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. 
Note: Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging (using the 
identical imaging modality for each assessment, either MRI or CT scan) for at 
least 4 weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment.  This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability.
9. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
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replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.
10. Has had an allogeneic tissue/solid organ transplant.
11. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
12. Has an active infection requiring systemic therapy.
13. 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. 
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 180 days after 
the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if 
the patient has previously participated in MSD MK-3475 clinical trials.
17. Has a known history of HIV (HIV 1/2 antibodies).
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
19. Has received a live vaccine within 30 days of planned start of study therapy.
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Study Intervention
The treatment(s) to be used in this trial are outlined below in Table 2.  
Table 2
Trial Treatment
Drug
Dose/ Potency
Dose 
Frequency
Route of 
Adminis-
tration
Regimen
Use
IMP or
NIMP/
AxMP
Pembrolizumab
200 mg
Every 3 
weeks
Intravenous
Day 1 of 
each cycle 
(3-week 
cycles)
Test Product
IMP
Cisplatin
100 mg/m2
Every 3 
weeks
Intravenous
Day 1 of 
each cycle 
(3-week 
cycles) for 
6 cycles
Test Product
IMP
Carboplatin
AUC 5
Every 3 
weeks
Intravenous
Day 1 of 
each cycle 
(3-week 
cycles) for 
6 cycles
Test Product
IMP
5-FU
1000 
mg/m2/day 
continuous 
from day 1-4 
of each cycle
Every 3 
weeks
Intravenous
Day 1 of 
each cycle 
(3-week 
cycles) for 
6 cycles
Test Product
IMP
Cetuximab
Initial dose on 
day 1 is 
400 mg/m2
over 2 hours 
followed by 
weekly doses 
of 250 mg/m2
over 1 hour.
Every week
Intravenous
Days 1, 8, 
and 15 of 
each cycle 
(3-week 
cycles)
Comparator
IMP
EEA = European Economic Area; IMP = investigational medicinal product; NIMP/AxMP = 
noninvestigational/auxiliary medicinal product.
Subjects may receive a maximum of 6 cycles (infusions) of platinum and 5-FU
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European 
Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is 
followed. 
Trial treatment should begin on the day of randomization or within 5 days of the date on which 
the subject is allocated/assigned.
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.
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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 to record 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
5.2.1.1
Dose Selection
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 are provided in the Pharmacy Manual.
Treatment on the standard treatment arm will be prepared and administered as per the approved 
product label.  The body surface area (BSA) in m2 should be calculated per local guidance.
Carboplatin will be administered at an AUC/time curve of 5 mg/mL/min as an IV infusion on 
Cycle Day 1 of a 3-week cycle.  Pursuant to the NCI Cancer Therapy Evaluation Program
Information Letter Regarding the AUC-Based Dosing of Carboplatin, the maximum 
carboplatin dose should not exceed the target AUC (mg*min/mL)*150 mL/min, but it may be 
less. As well, the GFR used in the Calvert formula to AUC-based dosing should not exceed 
125 mL/min. For this trial, the maximum dose of carboplatin cannot exceed a total dose of 
750 mg.  Alterations in renal function may require a recalculation of the carboplatin dose.
Cisplatin will be administered at a dose of 100 mg per square meter of BSA as an IV infusion 
on Cycle Day 1 of a 3-week cycle.
5-FU will be administered at a dose of 1000 mg per square meter of BSA per day as a
continuous infusion for 4 days on Cycle Days 1-4 of a 3-week cycle.
Cetuximab will be administered at a dose of 400 mg per square meter of BSA as an IV infusion 
on Day 1 of the study followed by subsequent weekly doses of 250 mg per square meter as IV 
infusions.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
The CTCAE version 4.0 (CTCAE 4.0) must be used to grade the severity of AEs.  If 
appropriate, the Investigator may attribute each toxicity event to cisplatin or carboplatin, 5-
FU, cetuximab or pembrolizumab alone in the combination arms and use a stepwise dose 
reduction according to Table 3.  If a dose reduction for toxicity occurs with any agent, the dose 
may not be re-escalated. Dose modifications are always based on the previous cycle.
Subjects can have 2 levels of dose reductions per agent to cisplatin, carboplatin, 5-FU, and
cetuximab throughout the course of the study for toxicities as described in Table 3.  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. For pembrolizumab 
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toxicities refer to Table 4, platinum toxicities refer to Table 5 and Table 6, 5-FU toxicities refer 
to Table 7 and Table 8, and cetuximab toxicities refer to Table 9, Table 10, and Table 11.  If a 
subject experiences several toxicities and there are conflicting recommendations, follow the 
most conservative dose adjustment recommended (dose reduction appropriate to the most 
severe toxicity).
Reduction or holding of one agent and not the other agents is appropriate if, in the opinion of 
the Investigator, the toxicity is clearly related to one of the study drugs. If, in the opinion of 
the Investigator, the toxicity is related to the combination of 2 agents, both drugs should be 
reduced or held according to recommended dose modifications. If the toxicity is related to the 
combination of 3 agents, all 3 agents should be reduced or held according to the recommended 
dose modifications. If one or more study agent(s) are held for toxicity, the schedule for 
restarting the agent(s) should correspond with the next treatment cycle once the toxicity has 
resolved according to the recommended guidelines. Subjects who require more than 2 levels 
of dose reductions as outlined in Table 3 below to any particular component of the regimen for 
toxicities will have that agent discontinued.
Exceptional circumstances to following the dose modification tables below may be considered 
after consultation with the Sponsor.
Table 3
Dose Modifications for Trial Medications
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Cisplatin
100 mg/m2
80 mg/m2
(20% decrease)
64 mg/m2
(20% decrease)
Discontinue
Carboplatin
AUC 5
AUC 4
(20% decrease)
AUC 3
(20% decrease)
Discontinue
5-FU
1000 mg/m2/day
800 mg/m2/day
(20% decrease)
640 mg/m2/day
(20% decrease)
Discontinue
Cetuximab
400 mg/m2 then 
250 mg/m2
200 mg/m2
(20% decrease)
150 mg/m2
(20% decrease)
Discontinue
Note: Pembrolizumab dose should not be modified for toxicity.  See Table 4 for modification of 
Pembrolizumab dosing schedule for drug-related AEs.
Investigators may follow the local label for dose modifications. If a toxicity is not otherwise 
specified, investigators should refer to the label or local standard of care for dose adjustments. 
Dose modification according to Table 3 is allowable for intolerable Grade 2-3 toxicities not 
specified in the tables below at the Investigator’s discretion.  These dose modification 
decisions must be documented in the subject’s study records and in the case report form.
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5.2.1.2.1 Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included 
as part of the evaluation. 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 monotherapy, coformulations, or IO combinations are provided in Table 4. 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms of 
pneumonitis
•
Evaluate participants with suspected pneumonitis 
with 
radiographic 
imaging 
and 
initiate 
corticosteroid treatment
•
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
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 participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
•
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
•
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring 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
T1DM 
or 
Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure
Withhold a
•
Initiate insulin replacement 
therapy 
for 
participants 
with T1DM
•
Administer 
anti-
hyperglycemic 
in 
participants 
with 
hyperglycemia
•
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
•
Administer corticosteroids 
and 
initiate 
hormonal 
replacements as clinically 
indicated
•
Monitor for signs and symptoms of hypophysitis 
(including 
hypopituitarism 
and 
adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
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 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
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 
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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5.2.1.2.2 Dose Modifications for Platinum 
Investigators may switch subjects from cisplatin to carboplatin during the course of the study 
if toxicities occur.  If the cisplatin dose was modified prior to switching, the subject may start 
at a carboplatin dose of AUC 5 and will be eligible to receive an additional 2 dose 
modifications of carboplatin.  
Table 5
Dose Modification Guidelines for Febrile Neutropenia or Documented Infection
Adverse Event
Number of 
Occurrences
Treatment Modification
Febrile neutropeniaa
Documented infection
1
Reduce by 1 DL
The use of growth factors and antibiotics should be 
considered per local standards.
2
Reduce by 1 DL
Consider prophylactic antibiotics for subsequent cycles.
The use of growth factors should be strongly considered per 
local standards.
3
Discontinue platinum
ANC=absolute neutrophil count; DL=dose level.
a.
ANC <1000/mm3 (1.0 x 109/L) and a single temperature >38.3C or sustained temperature ≥38C for >1 
hour.
Table 6
Dose Modification Guidelines for Platinum Drug-Related Adverse Events
Category
Toxicity
Hold 
Platinum 
Treatment 
for Grade
Timing for 
Restarting 
Platinum 
Treatment
Dose for 
Restarting 
Platinum 
Treatment
Discontinue Platinum
Hematologic
Neutropenia
31
Neutrophil count 
resolves to 
>1,000/mm3 (1.0 x 
109/L)
No Reduction
*consider G-CSF
Toxicity does not resolve 
within 12 weeks of last 
infusion or if >2 Dose 
Level reductions 
exceeded
41
Neutrophil count 
resolves to 
>1,000/mm3 (1.0 x 
109/L)
Reduce by 1 DL
*consider G-CSF 
Toxicity does not resolve 
within 12 weeks of last 
infusion or if >2 Dose 
Level reductions 
exceeded
Thrombocytopenia
2
Platelet count 
resolves to 
≥75,000/mm3 (75 
x 109/L) or 
baseline
No reduction
Toxicity does not resolve 
within 12 weeks of last 
infusion or if >2 Dose 
Level reductions 
exceeded
3-41
Platelet count 
resolves to 
≥75,000/mm3 (75 
x 109/L) or 
baseline 
Reduce by 1 DL
Toxicity does not resolve 
within 12 weeks of last 
infusion or if >2 Dose 
Level reductions 
exceeded
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Category
Toxicity
Hold 
Platinum 
Treatment 
for Grade
Timing for 
Restarting 
Platinum 
Treatment
Dose for 
Restarting 
Platinum 
Treatment
Discontinue Platinum
Non-
hematologic
Creatinine 
Increased
2-41
Toxicity resolves 
to Grade 0-1 
For subjects taking 
Carboplatin, 
reduce by 1 DL
For subjects taking 
Cisplatin, change 
Cisplatin to 
Carboplatin
Toxicity does not resolve 
within 12 weeks of last 
infusion or if >2 Dose 
Level reductions 
exceeded
Ototoxicity or 
Sensory 
neuropathy
2
Change Cisplatin to Carboplatin
May continue treatment with Carboplatin
3-4
May switch Cisplatin to Carboplatin if resolved to Grade ≤2 within 12 
weeks of last infusion
If already using carboplatin, then discontinue
All other non-
hematologic 
toxicities2
3-41
Toxicity resolves 
to Grade 0-1 
Reduce by 1 DL
Toxicity does not resolve 
within 12 weeks of last 
infusion 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 
within 12 weeks of last 
infusion or if >2 Dose 
Level reductions 
exceeded
1Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment 
after Grade 4 drug-related AE
2Patients with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.  Permanently discontinue from agent 
for persistent Grade 2 adverse reactions for which treatment has been held, and did not recover to Grade 0-1 within 12 weeks of the last 
dose.  With investigator and Sponsor agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue in 
the trial only if asymptomatic and controlled.
5.2.1.2.3 Dose Modifications for 5-Fluorouracil
Table 7
Dose Modification Guidelines for Febrile Neutropenia or Documented Infection
Adverse Event
Number of 
Occurrences
Treatment Modification
Febrile neutropeniaa
Documented infection
1
Reduce by 1 DL
The use of growth factors and antibiotics should be 
considered per local standards.
2
Reduce by 1 DL.
Consider prophylactic antibiotics for subsequent 
cycles.
The use of growth factors should be strongly 
considered per local standards.
3
Discontinue 5-FU
a.
ANC <1000/mm3 and a single temperature >38.3C or sustained temperature ≥38C for >1 hour.
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Table 8
Dose Modification Guidelines for 5-Fluorouracil Drug-Related Adverse Events
Category
Toxicity
Hold 5-FU 
Treatment 
for Grade
Timing for 
Restarting 
5-FU 
Treatment
Dose for 
Restarting 
5-FU 
Treatment
Discontinue 5-FU
Hematologic
Neutropenia
31
Neutrophil 
count resolves 
to >1,000/mm3
(1.0 x 109/L)
No 
Reduction
*consider 
G-CSF
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
41
Neutrophil 
count resolves 
to >1,000/mm3
(1.0 x 109/L)
Reduce by 
1 DL
*consider 
G-CSF 
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
Thrombocytopenia
2
Platelet count 
resolves to 
≥75,000/mm3
(75 x 109/L) or 
baseline
No 
reduction
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
3-41
Platelet count 
resolves to 
≥75,000/mm3
(75 x 109/L) or 
baseline 
Reduce by 
1 DL
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
Non-
hematologic
Creatinine 
Increased
2-41
Toxicity 
resolves to 
Grade 0-1
No 
reduction
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
Mucositis
Diarrhea
2-41
Toxicity 
resolves to 
Grade 0-1
Reduce by 
1 DL
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
Hand-foot 
syndrome
2
Toxicity 
resolves to 
Grade 0-1
No 
reduction
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
3-41
Toxicity 
resolves to 
Grade 0-1
Reduce by 
1 DL
Toxicity does not 
resolve within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
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Category
Toxicity
Hold 5-FU 
Treatment 
for Grade
Timing for 
Restarting 
5-FU 
Treatment
Dose for 
Restarting 
5-FU 
Treatment
Discontinue 5-FU
All other non-
hematologic 
toxicities2
3-41
Toxicity 
resolves to 
Grade 0-1 
Reduce by 
1 DL
Toxicity does not 
resolve within 12 
weeks of last 
infusion 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 within 12 
weeks of last 
infusion or if >2 
Dose Level 
reductions exceeded
1Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment 
after Grade 4 drug-related AE
2Patients with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.  Permanently discontinue from agent 
for persistent Grade 2 adverse reactions for which treatment has been held, and did not recover to Grade 0-1 within 12 weeks of the last 
dose.  With investigator and Sponsor agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue 
in the trial only if asymptomatic and controlled.
5.2.1.2.4 Dose Modifications for Cetuximab
The first dose should be administered slowly and the speed must not exceed 5 mg/min while
all vital signs are closely monitored for at least 2 hours.  For any delayed cetuximab treatment, 
do not repeat the initial dose of 400 mg/m².  At the restart of cetuximab treatment, all 
subsequent infusions will be at the appropriate dose level according to Table 9, Table 10, and 
Table 11. If a subject develops a toxicity that mandates interruption of therapy, the toxicity 
must resolve within 12 weeks from the last dose of cetuximab or the drug should be 
discontinued with the exception of a subject who is clinically benefiting from cetuximab 
treatment.  In this case, the investigator may request the Sponsor to allow the subject to 
continue to receive cetuximab.
Cetuximab therapy will not be delayed for chemotherapy-related toxicity.  If chemotherapy 
administration is delayed, the subject may continue to receive weekly infusions of cetuximab. 
After resolution of toxicity, platinum and/or 5-FU may be restarted at any weekly visit when 
cetuximab is given (ie, Day 8 or Day 15 of a cycle). The interval between platinum and/or 5-
FU infusions will continue as every 3 weeks from the time of the restart. If subjects on the 
cetuximab + platinum + 5-FU arm are required to have the platinum and/or 5-FU discontinued 
for toxicity, the subject may continue to receive cetuximab alone. In the case of cetuximab 
toxicity, subjects may continue on chemotherapy alone.
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Table 9
Dose Modification Guidelines for Cetuximab Drug-Related Adverse Events
Category
Toxicity
Hold 
Cetuximab 
Treatment 
for Grade
Timing for 
Restarting 
Cetuximab 
Treatment
Dose for 
Restarting 
Cetuximab 
Treatment
Discontinue 
Cetuximab
Non-
Hematologic
Infusion 
Reaction
2-4
See Section 5.2.1.2.4.1 and Table 10
Rash
3-4
See Section 5.2.1.2.4.2 and Table 11
Respiratory 
Disorders
See Section 5.2.1.2.4.3
All other non-
hematologic 
toxicities1
3-4
Toxicity 
resolves to 
Grade 0-1
Reduce by 1 
DL2
Toxicity does not 
resolve within 12 
weeks of last infusion 
or if >-2 Dose Level 
reductions exceeded
Laboratory 
Adverse 
Events3
4
Toxicity 
resolves to 
Grade 2 or 
less
Reduce by 1 
DL2
Toxicity does not 
resolve within 12 
weeks of last infusion 
or if >-2 Dose Level 
reductions exceeded
Note: Permanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment 
after Grade 4 drug-related AE.
1 Patients with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.  Permanently discontinue from agent for 
persistent Grade 2 adverse reactions for which treatment has been held and did not recover to Grade 0-1 within 12 weeks of the last dose. 
2 See Table 3
3.With investigator and Sponsor agreement, subjects with a laboratory AE still at Grade 2 after 12 weeks may continue in the trial only if 
asymptomatic and controlled.
Cetuximab Infusion Reactions
If during the first infusion, a subject experiences an infusion-related reaction, the infusion 
should be stopped. Subjects who experience cetuximab-related infusion reactions should have 
cetuximab reduced/discontinued according to Table 10 and continue to receive antihistamine 
premedication prior to further administration.  Once the cetuximab infusion rate has been 
decreased due to an allergic/hypersensitivity reaction, it should remain decreased for all 
subsequent infusions. A careful benefit-risk assessment should be undertaken including 
consideration whether the subject may have preformed IgE antibodies before a subsequent 
infusion is given.
If the subject experiences a second infusion reaction at the decreased rate, cetuximab must be 
discontinued.  If any Grade 3-4 infusion reaction occurs, cetuximab treatment must be 
discontinued immediately. Subjects who experience serious infusion reactions will be 
discontinued from cetuximab. The subject may continue to receive chemotherapy as scheduled.
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Table 10
Cetuximab Dose Modification for Infusion Reactions
CTCAE 
Grade
Hold Treatment (Y/N)
Dose for Restarting Treatment
1
See Note
Decrease the cetuximab infusion rate by 50% and monitor 
closely for any worsening.
Note: If during the first infusion, an infusion-related reaction 
occurs within the first 15 minutes, the infusion should be 
stopped. The total infusion time for cetuximab should not 
exceed 4 hours.
2
Y
Stop cetuximab infusion and 
administer bronchodilators, 
oxygen, etc. as medically 
indicated.
Resume infusion at 50% of previous rate once
allergic/hypersensitivity reaction has resolved or decreased to 
Grade 1 in severity, and monitor closely for any worsening
3-4
Y
Stop the cetuximab infusion 
immediately and disconnect 
infusion tubing from the subject
Stop the cetuximab infusion immediately and disconnect 
infusion tubing from the subject. Administer epinephrine, 
bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc., as medically 
indicated.
Subjects must discontinue treatment with cetuximab 
permanently. 
Dermatologic Toxicity
Skin reactions to cetuximab are very common and often may require dose interruptions or 
discontinuation. The dosing of cetuximab must be withheld for 1 to 2 weeks in the case of 
severe (Grade 3 or 4) acneiform rash.  According to clinical practice guidelines, prophylactic 
use of oral tetracyclines (6 to 8 weeks) and topical application of 1% hydrocortisone cream 
with moisturizer should be considered.  If acneiform rash improves during this time to ≤Grade 
2, then the dose of cetuximab should be reduced as indicated in Table 11.  The dose 
modification guidelines in Table 9 should be followed for dermatologic toxicities other than 
acneiform rash.
For intolerable and severe skin reactions (≥Grade 3), cetuximab must be interrupted. If 
acneiform rash does not improve to ≤Grade 2 during this time, cetuximab will be permanently 
discontinued. 
Subjects who have held cetuximab therapy for more than 2 consecutive infusions due to 
acneiform rash, and upon resolution of the toxicity are still felt to be benefiting from cetuximab 
treatment may resume cetuximab with Sponsor approval. 
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Table 11
Cetuximab Dose Modification for Severe Acneiform Rash
Severe Acneiform 
Rash (Grade 3)
Dose 
Interruption
Outcome
Dose Modification
1st occurrence
Omit 1-2 doses
Improveda
None, continue at same dose
2nd occurrence
Omit 1-2 weeks
Improveda
Permanently reduce by 1 dose level b
3rd occurrence
Omit 1-2 weeks
Improveda
Permanently reduce by another dose 
level b
4th occurrence
Permanently
Discontinue
N/A
a.
If rash does not improve to ≤Grade 2, then discontinue cetuximab.
b.
See Table 3. Discontinue cetuximab if dose is less than 150 mg/m2
Respiratory Disorders
Cases of interstitial lung disease (including fatal cases) have been reported. Confounding and 
contributing factors in patients, such as preexisting pulmonary diseases, and use of 
concomitant chemotherapy known to be associated with interstitial lung disease, may be fatal 
and requires close monitoring.  In the event of symptoms (such as dyspnea, cough, fever) or 
radiographic findings suggestive of interstitial lung disease, prompt diagnostic investigation 
should occur.
If interstitial lung disease is diagnosed, cetuximab must be permanently discontinued and the 
subject managed appropriately.
Timing of Dose Administration
Trial treatment of pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons (up to 5 days after randomization 
is permitted).
Trial treatment of cisplatin, carboplatin, 5-FU, or cetuximab may be administered up to 3 days 
before or after the scheduled dosing date for administrative reasons per the investigator’s 
judgment (up to 5 days after randomization is permitted).  The ±3-day window for cetuximab 
generally applies to restarting cetuximab after a treatment delay; administering cetuximab with 
less than 7 days between doses is not recommended.
Subjects may receive a maximum of 6 cycles (infusions) of the chemotherapy agents 
(carboplatin, cisplatin, and 5-FU).
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
(e.g., elective surgery, unrelated medical events, subject vacation, and holidays) not related to 
study therapy. Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the subject's study record.
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5.2.2.1
Pembrolizumab
Trial treatment of pembrolizumab will be administered on Day 1 of each 3-week treatment 
cycle after all procedures and assessments have been completed as detailed on the Trial Flow 
Chart (Section 6.0). 
Pembrolizumab will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window 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 preparation of the pembrolizumab
infusion and administration of infusion solution.
For subjects randomized to the pembrolizumab plus chemotherapy arm, the pembrolizumab
infusion is administered first followed by the platinum and 5-FU infusions.
5.2.2.2
Carboplatin
Carboplatin will be administered on Day 1 of each treatment cycle after completion of all 
procedures and assessments are completed according to the Trial Flow Chart in Section 6.0.
Carboplatin is given as a dose of AUC 5 using infusion duration of 60 minutes (or infusion 
duration according to local practice).
5.2.2.3
Cisplatin
Cisplatin will be administered on Day 1 of each treatment cycle after completion of 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 infusion duration of 60 minutes (or infusion 
duration according to local practice).
5.2.2.4
5-Fluorouracil
5-FU will be administered as a dose of 1000 mg/m2/day as a continuous infusion from Day 1
to Day 4 of each treatment cycle.
On Day 1 of each treatment cycle, the 5-FU infusion should be started after completion of all 
procedures and assessments according to the Trial Flow Chart in Section 6.0.
5.2.2.5
Cetuximab
Trial treatment with cetuximab should be administered on Days 1, 8 and 15 of each 3-week 
cycle after all procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0). 
Cetuximab will be given as an initial loading dose on Cycle 1 Day 1 of 400 mg/m2 with infusion 
time of 120 minutes (maximum infusion rate 5 mg/min). For subsequent infusions, the 
cetuximab dose is 250 mg/m2 with infusion duration of 60 minutes (maximum infusion rate 
10 mg/min) for all doses starting with the Cycle 1 Day 8 administration.
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For subjects in the Standard Treatment Arm (cetuximab plus chemotherapy), the cetuximab 
infusion is administered followed by the platinum and 5-FU infusions. After platinum and 5-
FU are discontinued, for subjects with at least stable disease, cetuximab monotherapy may 
continue until disease progression or unacceptable toxicity occurs.
Trial Blinding/Masking
This is an open-label trial; therefore the Sponsor, investigator and subject will know the 
treatment administered to an individual subject.  Imaging data for the primary analysis will be 
centrally reviewed by independent radiologist(s) without knowledge of subject treatment 
assignment or PD-L1 biomarker results.
The subject-level PD-L1 biomarker results will be masked in the database to the study team at 
the Sponsor including clinical, statistical, statistical programming, and data management 
personnel. Access to the PD-L1 subject-level biomarker results will be limited to an unblinded 
Sponsor clinical scientist, unblinded data manager, unblinded Sponsor statistician, and 
unblinded Sponsor statistical programmer who will be responsible for data review to ensure 
validity of results but who will have no other responsibilities associated with the study.
See Section 7.1.4.2, 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 IVRS/IWRS.
There are 3 treatment arms.  
Subjects will be assigned randomly in a 1:1:1 ratio to the treatment arms as follows:
1. Pembrolizumab Monotherapy Arm:
Pembrolizumab (200 mg Q3W)
2. Pembrolizumab plus Chemotherapy Arm:
Pembrolizumab (200 mg Q3W) + [Cisplatin (100 mg/m2 Q3W) or Carboplatin (AUC 5 
Q3W)] + 5-FU (1000 mg/m2/day 4-day infusion Q3W)
3. Cetuximab plus Chemotherapy Arm:
Cetuximab 400 mg/m2 then 250 mg/m2 QW + [Cisplatin (100 mg/m2 Q3W) or 
Carboplatin (AUC 5 Q3W)] + 5-FU (1000 mg/m2/day 4-day infusion Q3W)
Stratification
Randomization will be stratified according to the following factors:
1. PD-L1 tumor expression as determined by PD-L1 immunohistochemistry (strongly 
positive vs. not strongly positive)
Note: Strongly positive includes those subjects whose tumor expression levels are
≥50%. Not strongly positive includes those subjects whose tumor expression levels are
<50%, or are not able to be determined for any reason.
2. HPV status for oropharynx cancer as determined by p16 immunohistochemistry (IHC) 
(positive vs. negative); HPV status for subjects without oropharynx cancer (e.g. cancers 
of the oral cavity, hypopharynx and larynx) is considered HPV negative.
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3. Eastern Cooperative Oncology Group (ECOG) Performance Scale (0 vs. 1)
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 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 may also be included on the CRF.
Prescription pain medications should be entered into the CRF using the information recorded 
by the subject on the Pain Medication Log. For prescription pain medications recorded on the 
Pain Medication Log, changes in drug dosage, total daily dose, route, and dates should be 
documented on the CRF.
All concomitant medications received from first dose of trial treatment through 30 days after 
the last dose of trial treatment should be recorded in the CRF.  Medications administered more 
than 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 (including retreatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be considered on an exceptional case by case basis after consultation with 
Sponsor.  The subject must have clear measurable disease outside the radiated 
field.  Administration of palliative radiation therapy will be considered clinical 
progression for the purposes of determining PFS.
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
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 (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.
o
Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines.  These vaccines will 
be treated just as any other concomitant therapy.
Investigational vaccines (i.e., those not licensed or approved for Emergency 
Use) are not allowed.
o
Note:  It is acceptable for subjects receiving the cetuximab + platinum + 5-FU
therapy to receive live vaccines while participating in the trial.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE.  The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.  Additionally, a short, limited course of steroids may be used to treat 
medical conditions and/or AEs during the study after Sponsor notification and 
consultation.
o
Note:  For subjects randomized to the standard treatment arm (cetuximab plus 
chemotherapy) the use of systemic glucocorticoids on trial treatment is 
acceptable and may be required for premedication.
o
Note:  Inhaled steroids are allowed for management of asthma/ COPD.
o
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to 
IV contract dye) or
use of corticosteroids as premedication
for 
chemotherapeutic agents specified in the protocol is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
treatment.  Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies during the Posttreatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab
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. Where appropriate, these guidelines include the 
use of oral or intravenous 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 
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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: Refer to Section 5.2.1 for dose modification.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.

Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). 
o
All subjects who experience 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.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high-dose oral steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or
≥Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.

Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.
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
Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, nonselective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
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
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.
Table 12 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 12
Infusion Reaction 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 
infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(e.g., 
antihistamines, NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic medications 
indicated for < =24 hrs.
Stop Infusion and monitor symptoms.
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 one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (e.g., 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 trial treatment 
administration.
Subject 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic).
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)
Stop Infusion.
Additional appropriate medical therapy may include 
but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
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.
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Subject is permanently discontinued from 
further trial treatment administration.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
Supportive Care Guidelines for Cisplatin and Carboplatin
The following guidelines may be used for subjects in the pembrolizumab plus chemotherapy 
arm.
Prevention and/or treatment of nausea and vomiting should be managed with:
1. Emend (aprepitant) 150 mg IV or Emend 3 day pack 125 mg day 1, 80 mg day 2, 80 mg 
day 3
2. Plus Aloxi (palonosetron) 0.25 mg IV
Additionally, nausea may be managed with:
1. Zofran (ondansetron) 8 mg twice a day; or
2. Compazine (prochlorperazine) 10 mg 3-4 times per day
For subjects randomized to the standard treatment arm (cetuximab plus chemotherapy) the use 
of systemic glucocorticoids during trial treatment is acceptable and may be required for 
premedication.
Initial use of dexamethasone is limited to no more than 8 mg administered on Day 1 of a 
treatment cycle before study treatment. Need for additional dexamethasone must be discussed 
with the Sponsor. Dexamethasone should be administered prior to study treatment.
Please refer to the product label or local standards of care for additional cisplatin and 
carboplatin supportive measures.
Supportive Care Guidelines for 5-FU
Please refer to the product label or local standards of care for 5-FU supportive measures.
Supportive Care Guidelines for Cetuximab
Subjects receiving cetuximab should be premedicated with an H1 antagonist (e.g., 50 mg of 
diphenhydramine) intravenously 30-60 minutes prior to the first dose.  Premedication for 
subsequent doses of cetuximab should be given per medical judgment and history of prior 
infusion reactions.
Guidelines for medical therapy for infusion reactions detailed in Table 12 above are also 
recommended for reactions due to cetuximab.
Refer to the approved product label for additional supportive care guidance.
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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.
Contraception
Pembrolizumab, carboplatin, cisplatin, 5-FU and cetuximab may have adverse effects on a 
fetus in utero.  Furthermore, it is not known if carboplatin, cisplatin, 5-FU and cetuximab have
transient adverse effects on the composition of sperm.  Therefore, nonpregnant, 
nonbreastfeeding women may only be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not 
had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The 2 birth control methods can be either 
2 barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects 
should start using birth control from study Visit 1 throughout the study period up to 180 days 
after the last dose of study therapy.
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide as per local regulations or 
guidelines.  Appropriate hormonal contraceptives will include any registered and marketed 
contraceptive agent that contains an estrogen and/or a progestational agent (including oral, 
subcutaneous, intrauterine, or intramuscular agents).
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 they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in Section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor.  If there is any question that a subject will not reliably comply 
with the requirements for contraception, that subject should not be entered into the study.
For countries (e.g., Sweden and Norway) or sites that follow the Clinical Trial Facilitation 
Group (CTFG) guidance, please use the following:
Pembrolizumab, carboplatin, cisplatin, 5-FU and cetuximab may have adverse effects on a 
fetus in utero.  Furthermore, it is not known if carboplatin, cisplatin, 5-FU and cetuximab have
transient adverse effects on the composition of sperm.  Therefore, nonpregnant, 
nonbreastfeeding women may only be enrolled if they are willing to follow the CTFG 
Guidance (Final Version 2014-09-15, Sections 4.1 and 4.2) for highly effective birth control 
as outlined below, or are considered to be highly unlikely to conceive. Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year will be considered postmenopausal), 
or 3) not heterosexually active for the duration of the study.
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Subjects should use birth control methods 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

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner

Sexual abstinence
Subjects should start using birth control from study Visit 1 throughout the study period up to 
180 days after the last dose of study therapy.
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 they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in Section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor.  If there is any question that a subject 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 any 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 7.2.2.
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Use in Nursing Women
Since many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, subjects who are breastfeeding are not eligible for enrollment. 
Specific additional information follows for individual agents used in this trial.
5.7.4.1
Pembrolizumab
It is unknown whether pembrolizumab is excreted in human milk. 
5.7.4.2
Cetuximab
It is not known whether cetuximab is secreted in human milk. IgG antibodies, such as 
cetuximab, can be excreted in human milk.  It is recommended that women do not breastfeed 
during treatment with cetuximab and for 2 months after the last dose.
5.7.4.3
Cisplatin
Cisplatin has been reported to be found in human milk; subjects receiving cisplatin injection 
should not breastfeed.
5.7.4.4
Carboplatin
It is not known whether carboplatin is excreted in human milk. Because there is a possibility 
of toxicity in nursing infants secondary to carboplatin treatment of the mother, it is 
recommended that breastfeeding be discontinued if the mother is treated with carboplatin 
injection.
5.7.4.5
5-FU
It is not known whether 5-FU is excreted in human milk. Because 5-FU inhibits DNA, RNA 
and protein synthesis, mothers should not nurse while receiving this drug.
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 7.1.5.3 – Posttreatment 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 7.1.4 – Other Procedures.
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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
Note: For unconfirmed radiographic disease progression, please see Section 5.8.1.
o
Unacceptable adverse experiences as described in Section 5.2.1.2
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
The subject is lost to follow-up
o
Completed 24 months of treatment with pembrolizumab
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.5.2.1.  
o
Administrative reasons
The End of Treatment and Follow-up Visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end 
of treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons other than 
PD will have posttreatment follow-up for disease status until centrally verified disease 
progression, initiating a nonstudy cancer treatment, 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.
5.8.1.1
Treatment After Initial Radiologic Progression
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions.
Pembrolizumab Monotherapy and Pembrolizumab Plus Chemotherapy Arms
If radiologic imaging by the central imaging vendor shows PD, tumor assessment may be 
repeated by the site 4 weeks later in order to confirm PD with the option of continuing 
treatment per below while awaiting radiologic confirmation of progression. If repeat imaging 
shows a reduction in the tumor burden compared to the initial scan demonstrating PD, 
treatment may be continued as per treatment calendar. If repeat imaging confirms PD, subjects 
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will be discontinued from study therapy. In determining whether or not the tumor burden has 
increased or decreased, investigators should consider all target lesions as well as nontarget 
lesions.
The decision to continue study treatment after the first evidence of disease progression 
determined by the central imaging vendor is at the Investigator’s discretion based on the 
clinical status of the subject as described in Table 13 in Section 7.1.2.6.3.1.
Subjects may receive study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG PS

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Standard Treatment Arm
Confirmation of progression does not apply to subjects randomized to the standard treatment 
arm. Subjects on the standard treatment arm should discontinue treatment with study 
medication after radiologic PD is verified by the central imaging vendor.
5.8.1.2
Discontinuation of Study Therapy After CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least 2 
treatments with pembrolizumab beyond the date when the initial CR was declared. Subjects 
who then experience centrally verified radiographic disease progression may be eligible for up 
to 1 year of additional treatment with pembrolizumab at the discretion of the investigator if:

No cancer treatment was administered since the last dose of pembrolizumab

The subject meets the safety parameters listed in the Inclusion/Exclusion criteria

The trial is ongoing.
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Additional details are provided in Section 7.1.5.2.1. Response or progression 
in this Second Course Phase will not count towards the ORR and PFS of the primary endpoint 
in this trial.
For subjects who are discontinued from treatment but continue to be monitored in the trial, see 
Section 6.0 – Trial Flow Chart, and Section 7.1.5.3 – Posttreatment Visits for those procedures 
to be completed at each specified visit.
Subjects may be allowed to begin treatment again if deemed medically appropriate, and 
provided the subject meets the criteria specified in Section 7.1.5.2.1 – Second Course Phase 
(Retreatment Period).
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Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are outlined 
in Section 7.1.4 – Other Procedures.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject provides documented informed consent form.  
The overall trial ends when the last subject completes the last study-related phone call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Upon study completion, subjects are discontinued and may be enrolled in a pembrolizumab 
extension study.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. The trial may be stopped early for safety at the recommendation of the Data Monitoring 
Committee (DMC). Section 7.3.3 describes the DMC and its responsibilities.
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6.0 TRIAL FLOW CHART
Initial Treatment Phase
Pembrolizumab and Pembrolizumab Plus Chemotherapy Arms
Trial Period: Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discontinuation
Safety 
Follow-up
Follow-Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
-28 to -1
+5d
± 3
± 3
± 3
± 3
± 3
At time of 
treatment discon
30 days after 
last dose of 
study 
medication 
(± 3 days)
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
(± 14 
days)
Administrative Procedures
Informed Consent
Xe
Informed Consent for Future Biomedical 
Research
Xf
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Reviewg
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
Prior Treatment for Head and Neck Cancer
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
< ----------------------------------------------------------------------------------------------------------------------- >
X
Clinical Procedures/Assessments
Disease Details
X
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discontinuation
Safety 
Follow-up
Follow-Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
-28 to -1
+5d
± 3
± 3
± 3
± 3
± 3
At time of 
treatment discon
30 days after 
last dose of 
study 
medication 
(± 3 days)
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
(± 14 
days)
Review Adverse Eventsh
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead ECG (Local)
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs, Weight, and Heightk
X
X
X
X
X
X
X
X
ECOG Performance Statusn
X
X
X
X
X
X
X
X
Laboratory 
Procedures/Assessments:  
analysis performed by LOCAL laboratory
Pregnancy Test – Serum or Urinel
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
Xp
Chemistry Panelo
Xn
X
X
X
X
X
X
Xp
Urinalysiso
Xn
X
X
Xj
Xp
T3 (total or free), FT4 and TSHo
Xn
X
X
Xj
Xp
Laboratory 
Procedures/Assessments: 
analysis 
performed 
by 
CENTRAL 
laboratory
Pharmacokineticsq
Xq
Xq
Xq
Anti-pembrolizumab Antibodiesq
Xq
Xq
Xq
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discontinuation
Safety 
Follow-up
Follow-Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
-28 to -1
+5d
± 3
± 3
± 3
± 3
± 3
At time of 
treatment discon
30 days after 
last dose of 
study 
medication 
(± 3 days)
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
(± 14 
days)
Blood for Geneticsr,y
X
Correlative Blood Samples for DNAs
X
X
X
X
Correlative Blood Samples for RNAs
X
X
X
X
Correlative Blood Samples for plasmas
X
Correlative Blood Samples for serums
X
Efficacy Measurements
Tumor Imaging and RECIST Assessment
Xt
Xu
Xu
Xb,v
Xb
Tumor Tissue Collection
Archival or Newly Obtained Tissue Collection 
for Subjects with Oropharynx Cancer Tested 
Locally for HPV Status for Stratification 
(newly obtained may be obtained 90 days prior 
to treatment initiation)
Xw
Newly 
Obtained 
Tissue 
Collection 
for 
Biomarker Analysis (Tested Centrally) on All 
Subjects 
Prior 
to 
Randomization 
for 
Stratification (may be obtained 90 days prior to 
treatment initiation). Tissue sample for FBR.
Xw
Patient-Reported Outcomes
EuroQol EQ-5Dx
X
X
X
Xj
Xj
X
Xx
EORTC QLQ-C30x
X
X
X
Xj
Xj
X
Xx
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated 
beyond 6 cycles
Discontinuation
Safety 
Follow-up
Follow-Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
-28 to -1
+5d
± 3
± 3
± 3
± 3
± 3
At time of 
treatment discon
30 days after 
last dose of 
study 
medication 
(± 3 days)
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
(± 14 
days)
EORTC QLQ-H&N 35x
X
X
X
Xj
Xj
X
Xx
Pain Medication Logx
X
X
X
X
X
X
X
X
X
a.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 
weeks.   For subjects in the pembrolizumab plus chemotherapy arm, subjects may receive a maximum of 6 cycles (infusions) of platinum and 5-FU. Pembrolizumab treatment 
may continue after discontinuation of chemotherapy. Imaging should be performed at 9 weeks after randomization and every 6 weeks thereafter (42 days ±7 days) regardless 
of any treatment delays. 
b
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (±7 days) (or every 9 weeks ±7 days after the first year) until (1) the start of new anticancer treatment, (2) disease progression as assessed by the 
central imaging vendor, (3) death, or (4) the end of the study, whichever occurs first.  The first follow-up imaging assessment should occur 6 weeks (±7 days) from the last 
scheduled on-treatment imaging timepoint (or 9 weeks ±7 days from the last scheduled on-treatment imaging timepoint after the first year).
c.
After the start of new anticancer treatment or documented disease progression by the central imaging vendor, whichever occurs first, the subject enters the Survival Follow-
Up Phase and should be contacted by telephone approximately every 12 weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any 
time during the course of the study. 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 death event previously recorded).
d.
In general, the window for each visit is ±3 days unless otherwise noted.  Cycle 1 treatment should be given within 5 days of randomization.
e.
Documented informed consent must be obtained prior to performing any protocol-specified procedure.  Results of a test performed prior to the subject signing consent as part 
of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial 
treatment).  Screening number will be assigned when the study informed consent is documented.
f.
Providing documented informed consent for the FBR sample is optional.  Detailed instructions for the collection and management of specimens for FBR are provided in the 
Procedures Manual and Section 12.2.  
g.
Prior medications – Record all medications taken within 28 days before the first dose of trial treatment. Concomitant medications – Enter new medications started from the 
first dose of trial treatment through 30 days after the last dose of trial treatment.  Record all medications taken for AEs as defined in Section 7.2.
h.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days
following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever comes first.  Afterwards, report only 
SAEs and ECIs that are related to trial treatment.
j.
To be repeated every 2 cycles after Cycle 4. ePROs will continue up to 1 year.
k.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.
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l.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A urine test can be considered if serum 
is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
m.
Coagulation factors (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 factors monitored closely throughout the trial.
n.
ECOG and laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. Screening labs must be collected and assessed prior to 
randomizing the subject.  ECOG must be 0 or 1 on the first day of dosing.  See Section 7.1.3 for details regarding laboratory tests.
o.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests. T3 or FT3 can be assayed 
based on local standards.
p.
Unresolved abnormal labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
q.
For subjects in the pembrolizumab and pembrolizumab plus chemotherapy arms, pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 
1, 2, 4, 8 and every 4 cycles thereafter. All pre-dose trough samples should be drawn within 24 hours before infusion of pembrolizumab.  Additional postdose peak PK 
samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8.
r.
This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless
the IRB/IEC does not approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future biomedical 
research if the subject signs the FBR consent.  Detailed instructions for the collection and management of specimens are provided in the Procedures Manual.
s.
See Section 7.1.2.7 and the Study Procedures Manual for correlative blood sample information. Detailed instructions are provided in the Procedures Manual.
t.
The initial tumor imaging will be performed within 28 days prior to randomization.  Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to randomization. Local reading (investigator assessment with site radiology reading) will 
be used to determine eligibility and for subject management.  The Sponsor will collect radiological assessments for analysis by a central imaging vendor.  The processes for 
image collection and transmission to the central vendor are in the Site Imaging Manual.
u.
The first on-study imaging time point will be performed at 9 weeks (±7 days) after the date of randomization and then every 6 weeks (±7 days) thereafter or more frequently 
if clinically indicated. After 1 year, imaging time point will occur every 9 weeks (±7 days).  Imaging timing should follow calendar days and should not be adjusted for delays 
in cycle starts or extension of pembrolizumab cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  On-study scans should be 
submitted immediately to the central imaging vendor and progressive disease should be verified by the central imaging vendor prior to subject discontinuation from treatment.  
Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management.  The Sponsor will collect radiological 
assessments for analysis by a central imaging vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual.
v.
In subjects who discontinue study therapy without centrally verified disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., date of discontinue ±4-week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is
not mandatory.
w.
Baseline tumor tissue from an archival tissue sample or newly obtained 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 PD-L1 
biomarker testing prior to randomization for stratification. Refer to Section 7.1.2.7 for additional information about tissue requirements. Detailed instructions for tissue 
collection, process and shipment are provided in the Procedures Manual.  If the subject signs the FBR consent, any leftover tissue that would ordinarily be discarded at the 
end of the main study will be retained for FBR. 
x.
It is a best practice and strongly recommended that ePROs are administered to randomized subjects prior to drug administration, AE evaluation, and disease status notification.  
All ePROs are to be performed prior to dosing at Cycle 1, Cycle 2, Cycle 3, Cycle 4 and every 2 cycles thereafter (e.g., Cycle 6, Cycle 8, Cycle 10) up to 1 year from treatment 
initiation or End of Treatment, whichever occurs first, and at the 30-day Safety Follow-up Visit.  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. The Pain Medication Log should be collected at all scheduled visits from Screening through 
the Safety Follow-up Visit (see Section 4.2.3.5.3).
y.
This sample should be drawn for planned, exploratory genetic analysis of DNA unless there is either a documented law or regulation prohibiting collection, or unless the
IRB/IEC does not approve of the collection.
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Standard Treatment Arm (Cetuximab plus Chemotherapy)
Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated beyond 
6 cycles
5
6
Discon
Safety 
Follow-up
Follow-
Up 
Visitsb
Survival 
Follow-
upc
Treatment Day
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window 
(Days)d:
-28 to -1
+5d
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
At time of 
treatment
discon
30 days 
after last 
dose of 
study 
medication 
(± 3 days)
Every 6 
weeks 
post 
discon
or per 
footnote
Every 
12 
weeks
(± 14 
days)
Administrative 
Procedures
Informed Consente
X
Informed 
Consent 
for 
Future 
Biomedical 
Researchf
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Prior 
and 
Concomitant 
Medication Reviewg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior treatment for head and 
neck cancer
X
Trial 
Treatment 
Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Post-study 
Anticancer 
Therapy Status
X
X
Survival Statusc
< ------------------------------------------------------------------------------------------------------------------------------------------------ >
X
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated beyond 
6 cycles
5
6
Discon
Safety 
Follow-up
Follow-
Up 
Visitsb
Survival 
Follow-
upc
Treatment Day
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window 
(Days)d:
-28 to -1
+5d
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
At time of 
treatment
discon
30 days 
after last 
dose of 
study 
medication 
(± 3 days)
Every 6 
weeks 
post 
discon
or per 
footnote
Every 
12 
weeks
(± 14 
days)
Clinical 
Procedures/Assessments
Disease details
X
Review Adverse Eventsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead Electrocardiogram 
(Local)
X
Full Physical Examination
X
X
Directed 
Physical 
Examination
X
X
X
X
X
X
Vital Signs, Weight, and 
Heightk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Statusn
X
X
X
X
X
X
X
X
Laboratory 
Procedures/Assessments: 
analysis 
performed 
by 
LOCAL laboratory
Pregnancy Test – Serum or 
Urine l
X
PT/INR and aPTTm
X
CBC with Differentialo
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
Chemistry Panelo
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated beyond 
6 cycles
5
6
Discon
Safety 
Follow-up
Follow-
Up 
Visitsb
Survival 
Follow-
upc
Treatment Day
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window 
(Days)d:
-28 to -1
+5d
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
At time of 
treatment
discon
30 days 
after last 
dose of 
study 
medication 
(± 3 days)
Every 6 
weeks 
post 
discon
or per 
footnote
Every 
12 
weeks
(± 14 
days)
Urinalysiso
Xn
X
X
Xj
Xp
T3 (total or free), FT4 and 
TSHo
Xn
X
X
Xj
Xp
Laboratory 
Procedures/Assessments: 
analysis 
performed 
by 
CENTRAL laboratory
Blood for Geneticsw
X
Correlative Blood Samples
for DNAq
X
X
X
X
Correlative Blood Samples 
for RNAq
X
X
X
X
Correlative Blood Samples 
for plasmaq
X
Correlative Blood Samples 
for serumq
X
Efficacy Measurements
Tumor 
Imaging 
and 
RECIST assessment
Xr
Xs
Xs
Xb,t
Xb
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Trial Period:
Screening 
Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
To be repeated beyond 
6 cycles
5
6
Discon
Safety 
Follow-up
Follow-
Up 
Visitsb
Survival 
Follow-
upc
Treatment Day
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Scheduling Window 
(Days)d:
-28 to -1
+5d
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 
3
± 
3
At time of 
treatment
discon
30 days 
after last 
dose of 
study 
medication 
(± 3 days)
Every 6 
weeks 
post 
discon
or per 
footnote
Every 
12 
weeks
(± 14 
days)
Tumor Tissue Collection
Archival or Newly Obtained 
Tissue 
Collection 
for 
Subjects with Oropharynx 
Cancer Tested Locally for 
HPV 
Status 
for 
Stratification 
(newly 
obtained may be obtained 90 
days prior to treatment 
initiation)u
Xu
Newly 
Obtained 
Tissue 
Collection for Biomarker 
Analysis (tested centrally) 
On all Subjects Prior to 
Randomization 
for 
Stratification 
(may 
be 
obtained 90 days prior to 
treatment initiation)u. Tissue 
sample for FBR.
Xu
Patient-Reported 
Outcomes (ePROs)
EuroQol EQ-5D
Xv
Xv
Xv
Xj,v
Xj,v
Xv
Xv
EORTC QLQ-C30
Xv
Xv
Xv
Xj,v
Xj,v
Xv
Xv
EORTC QLQ-H&N 35
Xv
Xv
Xv
Xj,v
Xj,v
Xv
Xv
Pain Medication Logv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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a. In general, assessments/procedures are to be performed prior to the treatment dose.  Carboplatin and cisplatin will be dosed on Day 1 of each 3-week cycle. 5-FU will be dosed 
continuously on Days 1-4 of each 3-week cycle. Subjects may receive a maximum of 6 cycles of platinum and 5-FU. Cetuximab will be dosed on Days 1, 8 and 15 of each 3-
week cycle. After discontinuing chemotherapy, cetuximab treatment may continue until disease progression or unacceptable toxicity occurs.  Imaging should be performed at 
9 weeks after randomization and every 6 weeks thereafter (42 days ±7 days) regardless of any treatment delays. 
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (±7 days) (or every 9 weeks ±7 days after the first year) until (1) the start of new anticancer treatment, (2) disease progression as assessed by the central 
imaging vendor, (3) death, or (4) the end of the study, whichever occurs first. The first follow-up imaging assessment should occur 6 weeks (±7 days) from the last scheduled 
on-treatment imaging timepoint (or 9 weeks ±7 days from the last scheduled on-treatment imaging timepoint after the first year).
c. After the start of new anticancer treatment or documented disease progression by the central imaging vendor, whichever occurs first, the subject enters the Survival Follow-Up 
Phase and should be contacted by telephone approximately every 12 weeks to assess for survival status. Updated survival status may be requested by the Sponsor at any time 
during the course of the study. 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 death event previously recorded).
d. In general, the window for each visit is ±3 days unless otherwise noted.  Cycle 1 treatment should be given within 5 days of randomization.
e. Documented informed consent must be obtained prior to performing any protocol-specified procedure.  Results of a test performed prior to the subject signing consent as part 
of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial 
treatment).  Screening number will be assigned when the study informed consent is documented.
f.
Providing documented informed consent for the FBR sample is optional.  Detailed instructions for the collection and management of specimens for FBR are provided in the 
Procedures Manual and Section 12.2. 
g. Prior medications – Record all medications taken within 28 days before the first dose of trial treatment. Concomitant medications – Enter new started from the first dose of 
trial treatment through 30 days after the last dose of trial treatment.  Record all medications taken for AEs as defined in Section 7.2.
h. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever comes first.  Afterwards, report only 
SAEs and ECIs that are related to trial treatment.
j.
To be repeated every 2 cycles after Cycle 4. For subjects who remain on treatment for greater than 1 year, ePROs will continue up to 1 year only.
k. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.
l.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A urine test can be considered if serum 
is not appropriate.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
m. Coagulation factors (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 factors monitored closely throughout the trial.
n. ECOG and laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. Screening labs must be collected and assessed prior to 
randomizing the subject.  ECOG must be 0 or 1 on the first day of dosing.  See Section 7.1.3 for details regarding laboratory tests.
o. After screening, labs should be taken on day of treatment or labs may be drawn up to 72 hours prior to dosing if acceptable per local standard of care.  See Section 7.1.3 for 
details regarding laboratory tests.  T3 or FT3 can be assayed based on local standards.
p. Unresolved abnormal labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
q. See Section 7.1.2.7 correlative blood sample information. Detailed instructions with specific timepoints per sample are provided in the Procedures Manual.
r.
The initial tumor imaging will be performed within 28 days prior to randomization.  Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to randomization.  Local reading (investigator assessment with site radiology reading) will 
be used to determine eligibility and for subject management.  The Sponsor will collect radiological assessments for analysis by a central imaging vendor.  The processes for 
image collection and transmission to the central vendor are in the Site Imaging Manual.
s.
The first on-study imaging time point will be performed at 9 weeks (±7 days) after the date of randomization, and then every 6 weeks (±7 days) thereafter, or more frequently 
if clinically indicated. After 1 year, imaging time point will resume every 9 weeks (±7 days).  Imaging timing should follow calendar days and should not be adjusted for delays 
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in cycle starts.  The same imaging technique should be used in a subject throughout the trial.  On-study scans showing progression should be submitted immediately to the 
central imaging vendor and progressive disease should be verified by the central imaging vendor prior to subject discontinuation from treatment.  Local reading (investigator 
assessment with site radiology reading) will be used to determine eligibility and for subject management.  The Sponsor will collect radiological assessments for analysis by a 
central imaging vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual.
t.
In subjects who discontinue study therapy without centrally verified disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., date of discontinue ±4-week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory.
u. Baseline tumor tissue from an archival tissue sample or newly obtained 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 from a newly obtained sample must also be provided to the 
central vendor for PD-L1 biomarker testing prior to randomization for stratification. Refer to Section 7.1.2.7 for additional information about tissue requirements. Detailed 
instructions for tissue collection, process and shipment are provided in the Procedures Manual.  If the subject signs the FBR 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 ePROs are administered to randomized subjects prior to drug administration, AE evaluation, and disease status 
notification.  All ePROs are to be performed prior to dosing at Cycle 1, Cycle 2, Cycle 3, Cycle 4 and every 2 cycles thereafter (e.g., Cycle 6, Cycle 8, Cycle 10) up to 1 year 
from treatment initiation or End of Treatment, whichever occurs first, and at the 30-day Safety Follow-up Visit.  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. The Pain Medication Log should be collected at all scheduled visits from 
Screening through the Safety Follow-up Visit (see Section 4.2.3.5.3).
w. This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the
IRB/IEC does not approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future biomedical research 
if the subject signs the FBR consent.  Detailed instructions for the collection and management of specimens are provided in the Procedures Manual.
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Second Course Phase – Retreatment With Pembrolizumab
Trial Period:
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety Follow-
up
Follow-Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
Second Course 
treatment discon
30 days after 
last dose of 
study 
medication
(± 3 days)
Every 6 weeks 
post discon or 
per footnote
Every 12 
weeks
(± 14 days)
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
Pembrolizumab Administrationg
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
< ----------------------------------------------------------------------------------------------------------------------------------
>
X
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X
X
X
X
Xi
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
Vital Signs and Weightk
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  analysis 
performed by LOCAL laboratory
Pregnancy Test – Serum or Urinel
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
Xr
Chemistry Panelo
Xn
X
X
X
X
X
X
Xr
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Trial Period:
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Posttreatment
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety Follow-
up
Follow-Up 
Visitsb
Survival 
Follow-upc
5
6
Scheduling Window (Days)d:
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
Second Course 
treatment discon
30 days after 
last dose of 
study 
medication
(± 3 days)
Every 6 weeks 
post discon or 
per footnote
Every 12 
weeks
(± 14 days)
T3, FT4 and TSHo
Xn
Xj
Xj
Xr
Efficacy Measurements
Tumor Imaging and RECIST assessment
Xp
Xp
Xp
Xq
Xp
a.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 
weeks; however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 5.2.1.2.  If the interval is 
increased, all procedures except imaging should be performed based on the new dosing schedule.  Imaging should always be performed every 6 weeks (42 days ±7 days) 
regardless of any treatment delays. 
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (±7 days) until (1) the start of new anticancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs first. The 
first follow-up imaging assessment should occur 6 weeks (±7 days) from the last scheduled on-treatment imaging timepoint.
c.
After the start of new anticancer treatment or documented disease progression by the central imaging vendor, whichever occurs first, the subject enters the Survival Follow-
Up Phase and should be contacted by telephone approximately every 12 weeks to assess for survival status. Updated survival status may be requested by the Sponsor at any 
time during the course of the study. 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 death event previously recorded).
d.
In general, the window for each visit is ±3 days unless otherwise noted.
e.
Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on pembrolizumab for reasons other than disease progression or 
intolerability may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1. 
f.
Concomitant medications – Enter new medications started from the first dose of Second Course treatment through 30 days after the last dose of Second Course treatment.  
Record all medications taken for AEs as defined in Section 7.2.
g.
Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
h.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever comes first.  Afterwards, report only 
SAEs and ECIs that are related to trial treatment.
j.
To be repeated every 2 cycles after Cycle 5.
k.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.
l.
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of retreatment. A urine test can be considered if serum 
is not appropriate. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
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m.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy. PTT may be performed if the local 
lab is unable to perform aPTT.
n.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab.  See Section 7.1.3 for 
details regarding laboratory tests.
o.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests. T3 or FT3 can be 
assayed based on local standards.
p.
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab.  Imaging should continue to be performed every 6 weeks (42 ±7 days) from the 
first dose of Second Course trial treatment or more frequently if clinically indicated. The same imaging technique should be used in a subject throughout the trial.  Local 
reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management.  The Sponsor will collect radiological 
assessments for analysis by a central imaging vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual.
q.
In subjects who discontinue study therapy, a radiologic evaluation should be performed at the time of treatment discontinuation (i.e., date of discontinue ±4-week window).  
If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory.
r.
Unresolved labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of trial treatment if labs are within normal 
range.
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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
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’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 dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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, answer all of his/her questions, and obtain written informed consent before 
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performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
7.1.1.2
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.
7.1.1.3
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 written informed consent.
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.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinical significant by the Investigator. The subject’s history of tobacco 
use will also be collected.  Details regarding the subject’s head and neck cancer will be 
recorded separately and not listed as medical history.
7.1.1.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s head and neck cancer.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before the first dose of trial treatment.  Prior treatment for head and neck cancer 
will be recorded separately and not listed as a prior medication.
Prior Treatment Details for Head and Neck Cancer
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record concomitant medication, if any, taken by the 
subject from the first dose of trial treatment through 30 days after the last dose of trial 
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treatment.  All medications related to reportable SAEs and ECIs should be recorded as defined 
in Section 7.2.
7.1.1.6
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 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 7.1.5.1.  
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  The 
randomization number identifies the subject for all procedures occurring after randomization.  
Once a 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 randomization number.
For subjects randomized to either the pembrolizumab plus chemotherapy or standard treatment 
arm, investigators must choose which platinum drug will be used (carboplatin or cisplatin)
prior to randomization. The selection will be documented in the trial database via IVRS/IWRS 
(See Data Entry Guidelines).
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
pembrolizumab doses on the pembrolizumab treatment arm require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Administration of trial medication will be monitored by the investigator and/or institution staff.  
The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered. 
The instructions for preparing and administering pembrolizumab are provided in the Pharmacy 
Manual.  Treatment with standard therapies will be prepared and administered as per the 
approved product label.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
AEs will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 4.0 (see Section 12.6).  Toxicities will be characterized in 
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terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
For subjects in all treatment arms, all AEs of unknown etiology should be evaluated to 
determine if it is possibly an ECI of a potentially immunologic etiology (termed immune-
related adverse events, or irAEs); see Section 5.6.1 regarding the identification, evaluation and 
management of potential irAEs.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical exam 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.
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to dosing 
on Day 1 of each treatment cycle.  New clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart.  Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only.  
7.1.2.4
12-Lead Electrocardiogram (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.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.5) at screening, 
prior to dosing on Day 1 of each treatment cycle and at discontinuation of trial treatment as 
specified in the Trial Flow Chart.
7.1.2.6
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central vendor can be found in the 
Site Imaging Manual.  Tumor imaging may be performed by CT scan (preferred) or MRI, but 
the same imaging technique should be used in a subject throughout the trial.  CT scan is the 
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more commonly used modality and is preferred for the majority of subjects.  An MRI can be 
utilized if clinically appropriate.  
Imaging should include the head, neck, chest, and abdomen at all timepoints specified in the 
Study Flow Chart. Imaging of the pelvis is optional. A CT from the vertex of the head to the 
thoracic inlet or a brain CT is strongly preferred. For an individual subject, imaging should 
be consistent at all timepoints, (i.e., follow-up scans should image the same areas as the 
baseline area, using the same imaging modality).
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1 will 
be used to determine subject eligibility.  Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, MSD allows maximum of 10 target lesions in total and 
5 per organ. All scheduled images for all study subjects from the sites will be submitted to the 
central imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at an unscheduled time point to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the 
central imaging vendor as well.  
The central imaging vendor will receive radiologic images for a retrospective analysis of 
subject eligibility and treatment response. In addition, radiologic progression will be based 
on the independent central assessment of progression, rather than site assessment. The 
central imaging vendor will verify PD following first radiologic evidence of PD assessed 
by the local site investigator.  Verification of radiologic progression applies to all 3 
treatment arms.
Expedited verification of radiologic progression as determined by 
central review (following site assessment of progression) will be communicated to the site 
(See Section 7.1.2.6.3 below).
7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to the date of randomization.  
The site study team must review pre-trial images to confirm the subject has measurable disease 
per RECIST 1.1.  
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days prior to the date of 
randomization.  
7.1.2.6.2 Tumor Imaging During Trial
The first imaging assessment should be performed at 9 weeks (63 days ±7 days) from the date 
of randomization.  Subsequent imaging should be performed every 6 weeks (42 days ±7 days)
or more frequently if clinically indicated.  After 1 year, subjects who remain on treatment will 
have imaging performed every 9 weeks (±7 days).  Imaging should not be delayed for delays 
in cycle starts.  
Per RECIST 1.1, PR or CR should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (i.e. 6 weeks later), whichever is clinically indicated.  Imaging should 
then return to the original schedule beginning with the next protocol-specified timepoint. 
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Subjects who obtain a confirmation scan at 4 weeks do not need to undergo the next scheduled 
imaging assessment if it is due <4 weeks later; imaging may resume at the subsequent 
scheduled timepoint. (e.g. If a subject obtains a scan at Week 13 to confirm a Week 9 response, 
they will not be required to complete the scheduled Week 15 scan.  The next imaging would 
then occur at Week 21 as usual).
Continue to perform imaging until whichever of the following occurs first:

Initial site-assessed disease progression is verified by the central imaging vendor and 
confirmed by a repeat assessment ≥4 weeks later.
Note: a repeat assessment is not required for subjects on the standard treatment arm.

The start of new anticancer treatment

Withdrawal of consent

Death 

The end of the study
Note:  For subjects on the pembrolizumab monotherapy or pembrolizumab plus 
chemotherapy arm, if the site-assessed disease progression is verified by the central 
imaging vendor and the subject is clinically stable as per section 7.1.2.6.3.1, it is the 
discretion of the PI to continue to treat and image the subject at least 4 weeks after the first 
scan indicating PD.  irRECIST would then be followed by the site to determine if the 
follow-up scan confirms PD.  
For subjects on the pembrolizumab monotherapy or pembrolizumab plus chemotherapy arms, 
confirmatory scans (at least 4 weeks after the first scan) will be submitted to the central imaging 
vendor; however the confirmatory scans do not need to be submitted for expedited Verification 
of Progression (VOP) unless progression was not verified on the scans showing initial site-
assessed PD.
Subjects randomized to the standard treatment arm will not have irRECIST assessments.
Subjects who have unconfirmed disease progression may continue on treatment and follow the 
regular imaging schedule intervals until progression is confirmed provided they have met the 
conditions detailed in Section 7.1.2.6.3.
7.1.2.6.3 Assessment of Disease
RECIST 1.1 will be applied by the central imaging vendor as the primary measure for 
assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status (e.g., discontinuation of study therapy).  Scans showing 
site-assessed PD should be submitted to the central imaging vendor immediately. The site will 
be notified if the imaging vendor verifies disease progression using RECIST 1.1.  
During the follow-up period, imaging will be repeated every 6 weeks (±7 days) during the first 
year of study participation and then every 9 weeks (±7 days) after 1 year. See the Trial Flow 
Charts in Section 6 and Section 7.1.5.3.2 for information about the Follow-up Visits.
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irRECIST
As noted above for subjects on the pembrolizumab monotherapy or pembrolizumab plus 
chemotherapy arm, if site-assessed PD has been verified by the central imaging vendor, the 
site may elect to continue treatment, repeat imaging ≥4 weeks later and assess tumor response 
or progression per irRECIST:

If imaging shows PD, tumor assessment may be repeated by the site at least 4 weeks 
later in order to confirm PD with the option of continuing treatment for clinically stable 
subjects (see Table 13).  Clinically stable is defined by the following criteria:

Absence of signs and symptoms indicating disease progression

No decline in ECOG PS

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Table 13
Imaging and Treatment After 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic
evidence of PD
Repeat imaging at >4
weeks at site 
to confirm PD
May continue study
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory scan by 
site
Repeat imaging at > 4
weeks to confirm PD 
per 
physician 
discretion only
Discontinue 
treatment
Repeat scan 
confirms
PD
No additional 
imaging
Required*
Discontinue treatment
No additional imaging
required
N/A
Repeat scan shows
SD, PR or CR
Continue regularly
scheduled 
imaging 
assessments
Continue study
treatment at the 
Investigator’s 
discretion
Continue regularly
scheduled imaging 
assessments
May restart study
treatment if 
condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion
Abbreviations: N/A = not applicable; PD = progressive disease; PR = partial response; SD = stable disease.

In determining whether or not the tumor burden has increased or decreased, 
investigators should consider all target lesions as well as nontarget lesions.  Subjects 
that are deemed clinically unstable are not required to have repeat imaging for 
confirmation.  If radiologic progression is confirmed by subsequent scan then the 
subject will be discontinued from trial treatment (exception noted in Section 7.1.2.6.3).  
If radiologic progression is not confirmed, then the subject should resume or continue 
trial treatment and have their next scan according to the protocol schedule of every 6 
weeks (42 ± 7 days).  
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Note: If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 
weeks apart demonstrating PD) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, an exception to continue treatment may be 
considered following consultation with the Sponsor.
irRECIST data will be collected in the clinical database for subjects on the pembrolizumab 
monotherapy arm or the pembrolizumab plus chemotherapy arm.
irRECIST criteria are not applied to subjects on the standard treatment arm. After initial PD is 
verified by the central imaging vendor, subjects on the standard treatment arm will enter the 
Survival Follow-Up Phase.
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling
Subjects with oropharynx cancer 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 
‘Benchmark 
Ultra’ 
autostainer 
(Ventana, 
Tucson, 
AZ) 
and 
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.
All subjects will submit either a newly obtained (within 90 days prior to start of study 
treatment) or archival core or excisional biopsy (FNA is not adequate) to a central lab for 
characterization of PD-L1 status.  A newly obtained biopsy is strongly preferred, but an 
archival sample is acceptable.
This specimen may be the diagnostic sample for subjects with a new diagnosis of metastatic 
HNSCC.
Tumor lesions used for newly obtained biopsies should not be the same lesions used as 
RECIST target lesions, unless there are no other lesions suitable for biopsy and following 
Sponsor consultation.
Blood for correlative studies (includes blood for DNA, RNA, and exploratory biomarkers) 
should be collected pre-dose at Cycle 1, Cycle 2, Cycle 3, and at treatment discontinuation. 
Blood for correlative samples (plasma and serum) will be collected pre-dose at Cycle 1.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
7.1.2.8
Patient-Reported Outcomes (PROs) and Pain Medication Log
The EuroQol EQ-5D, EORTC QLQ-C30, and EORTC QLQ-H&N35 questionnaires will be 
administered by trained site personnel and completed electronically by subjects in the 
following order: EuroQol 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 
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recommended that ePROs are administered to randomized subjects prior to drug 
administration, AE evaluation, and disease status notification.
Subjects should complete the Pain Medication Log daily and return it to site personnel at each 
scheduled study visit as shown in the Trial Flow Chart. Site personnel will provide new Pain 
Medication Logs to the subjects as needed.
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 Procedures Manual 
Section 2.3.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 14.
Table 14
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum 
human 
chorionic 
gonadotropina
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase (ALT) Protein
aPTTe
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3) 
or Free T3b
Red Blood Cell 
Count
Microscopic exam, if 
abnormal 
results 
are 
noted
Free thyroxine (T4)
Absolute 
Neutrophil Count
Calciumc
Urine pregnancy testa
Thyroid-stimulating 
hormone (TSH)
Absolute 
Lymphocyte 
Count
Chloride
Blood for correlative studies
Creatinine
PK (for subjects on the 
pembrolizumab arms)
Glucose
Anti-pembrolizumab 
Antibodies (for subjects on 
the pembrolizumab arms)
Magnesium
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
A measure of carbon dioxide 
(CO2 or bicarbonate)b
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Hematology
Chemistry
Urinalysis
Other
Uric acid
Uread
a. Perform on women of childbearing potential only.  Serum pregnancy test is preferred but urine test can be 
considered if serum not appropriate.
b. If available as standard of care in your region. The carbon dioxide may be either a measurement of CO2 or 
bicarbonate as an electrolyte.
c. Corrected calcium should be checked for subjects with hypoalbuminemia.
d. Blood Urea Nitrogen is preferred; if not available urea may be tested.
e.   PTT may be performed if the local lab is unable to perform aPTT.
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment. Screening labs should be collected and assessed prior to randomizing the 
subject.  After Cycle 1, predose laboratory procedures can be conducted up to 72 hours prior 
to dosing.  Results must be reviewed by the investigator or qualified designee and found to be 
acceptable prior to each dose of trial treatment.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently planned 
as shown in the Trial Flow Chart (Section 6.1). Blood samples for PK and ADA collected may 
be stored only at this time. Further sample analysis may be performed if required. If ongoing 
PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
7.1.3.2.1 PK Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum PK samples will be provided 
in the Procedures Manual.  PK samples should be drawn from subjects in the pembrolizumab 
and pembrolizumab plus chemotherapy arms.
7.1.3.2.2 Blood Collection for Anti-Pembrolizumab Antibodies
Sample collection, storage and shipment instructions for anti-pembrolizumab antibody 
samples will be provided in the Procedures Manual.  Anti-pembrolizumab antibody samples 
should be drawn from subjects in the pembrolizumab and pembrolizumab plus chemotherapy 
arms.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future use

Leftover tumor tissue
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Other Procedures
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the End of Treatment 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. After discontinuing treatment following assessment of CR or 24 
months of treatment, these subjects should return to the site for a Safety Follow-up Visit 
(described in Section 7.1.5.3.1) and then proceed to the Follow-up Period of the study 
(described in Section 7.1.5.3.2). 
Subjects on the pembrolizumab monotherapy arm or 
pembrolizumab plus chemotherapy arm who discontinue treatment after they a) attain a CR or 
b) complete 24 months of treatment with pembrolizumab have the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.2.1.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their specimens 
and all derivatives destroyed.   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), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the subject's 
specimens will be removed from the biorepository and be destroyed.  A letter will be sent from 
the Sponsor to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction.  Any analyses in progress at 
the time of request for 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 specimen 
destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open-label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and 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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Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives

Drug administration equipment – as required for storing, preparing, and administering 
study treatment
See protocol-specified guidance in the Administrative Binder, Procedures Manual and Site 
Imaging Manual.
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.
7.1.5.1
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 performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  Screening procedures are to be completed within 28 days prior to the first dose trial 
treatment except for the following:

Laboratory tests and ECOG PS are to be performed within 10 days prior to the first 
dose of trial treatment. ECOG 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.

Tumor sample collection is not required to be obtained within 28 days prior to the first 
dose of trial treatment. Newly obtained tumor tissue may be obtained within 90 days 
of treatment initiation.
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 is met.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. 
7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects on the pembrolizumab monotherapy arm or pembrolizumab plus chemotherapy arm
who stop pembrolizumab with SD or better may be eligible for up to one year of additional 
pembrolizumab therapy if they progress after stopping study treatment.  This retreatment is 
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termed the Second Course Phase of this study and is only available if the study remains open 
and the subject meets the following conditions:

Either
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1

Was treated for at least 24 weeks with pembrolizumab before 
discontinuing therapy

Received at least 2 treatments with pembrolizumab beyond the date 
when the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined and centrally verified radiographic disease 
progression after stopping their initial treatment with pembrolizumab

Did not receive any anticancer treatment since the last dose of pembrolizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 5.1.2

Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication. 

Female subject of childbearing potential should be willing to use 2 methods of birth 
control, or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 180 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have been free from menses for >1 year.

Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 180 days after the last dose of study therapy. 

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might 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.
Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab.  Treatment will be administered for up to one additional year.
Visit requirements for the Second Course Phase are outlined in Section 6.2 – Trial Flow Chart
– Second Course Phase – Retreatment with Pembrolizumab.
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7.1.5.3
Posttreatment Visits
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 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 Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anticancer therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anticancer treatment should 
also be followed and recorded. 
Subjects who are eligible for retreatment with pembrolizumab (as described in Section 
7.1.5.2.1) may have up to 2 safety follow-up visits, 1 after the Treatment Period and 1 after the 
Second Course Phase.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than centrally verified disease 
progression will move into the Follow-Up Phase and should be assessed every 6 weeks (42 ±7 
days) by radiologic imaging to monitor disease status. 
After 1 year, the imaging time point will occur every 9 weeks (±7 days). The Sponsor may 
request survival status to be assessed at additional time points during the course of the study 
(not to exceed approximately 12 weeks).  Every effort should be made to collect information
regarding disease status until the start of new anticancer therapy, disease progression 
determined by the central imaging vendor, death, end of study, or if the subject begins 
retreatment with pembrolizumab as detailed in Section 7.1.5.2.1.  Information regarding post-
study anticancer treatment will be collected if new treatment is initiated.
For subjects who stopped treatment prior to the maximum time of 24 months due to confirmed 
CR or who completed 24 months of treatment, a less frequent imaging schedule of 12 weeks 
can be considered with Sponsor approval; this applies only to subjects prior to initiation of 
Second Course (retreatment).
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.2.1 will move from the Follow-Up Phase to the Second Course Phase when 
they experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart 
for Retreatment with pembrolizumab.
7.1.5.3.3 Survival Follow-up
Once a subject experiences disease progression by site assessment which is verified by central 
review, and confirmed by the second radiologic assessment (confirmation scan applies to 
pembrolizumab arms only), or starts a new anticancer therapy, whichever occurs first, the 
subject enters the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first.
The Sponsor may request survival status to be assessed at additional time points during the 
course of the study. For example, these additional assessments may be requested prior to an 
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external DMC safety review, efficacy interim analysis, and/or final analysis. All subjects who 
do not have a death reported will be contacted at the time of the Sponsor’s request.
7.1.5.4
Survival Status
To ensure current and complete survival data is available at the time of database locks, updated 
survival status may be requested during the course of the study by the Sponsor. For example, 
updated survival status may be requested prior to but not limited to an external DMC 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 previously recorded a death 
event in the collection tool).
Assessing and Recording Adverse Events
An AE 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 AE 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 AE.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs.  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.
AEs 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 AE.
All AEs that occur after the consent form is signed but before 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 randomization through 30 days following cessation of treatment, all AEs 
must be reported by the investigator. Such events will be recorded at each examination on the 
AE CRFs/worksheets.  The reporting timeframe for AEs meeting any serious criteria is 
described in Section 7.2.3.1. The investigator will make every attempt to follow all subjects 
with nonserious AEs for outcome.
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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).
AEs will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified 
procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the 
subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.
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 standard 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.
Cetuximab Overdose
There is no available information for the treatment of a cetuximab overdose. In cases of greater 
than recommended doses, the AEs were similar to the known safety profile. Appropriate 
supportive treatment should be provided if clinically indicated.
Otherwise, overdose should be managed according to local label and practice.
Carboplatin Overdose
There is no known antidote for carboplatin overdose. The anticipated complications of 
overdose may include myelosuppression and impairment of hepatic and renal function.
Otherwise, overdose should be managed according to local label and practice.
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.
5-FU Overdose
Signs and symptoms of 5-FU overdose are similar to the adverse reactions associated with the 
drug and should be managed according to local label and practice. Subjects who have a 5-FU 
overdose should be closely monitored for 4 weeks.
Otherwise, overdose should be managed according to local label and practice.
If an AE(s) is associated with (“results from”) the overdose of Sponsor's product or vaccine, 
the AE(s) is reported as an SAE, 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 nonserious ECI, using the terminology “accidental or intentional overdose 
without adverse effect.”
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All reports of overdose with and without an AE must be reported within 24 hours to the 
Sponsor either by electronic media or paper.  Sponsor Contact information 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 AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 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 that occur from the time of randomization through 120 days 
following cessation of Sponsor’s product, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  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
7.2.3.1
Serious Adverse Events
A SAE is any AE 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, AEs 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.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
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Refer to Table 15 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until randomization, any SAE, 
or follow up to a SAE, including death due to any cause other than progression of the cancer 
under study (reference Section 7.2.3.3 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 randomization through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any SAE, or follow up to a SAE, including death due to any cause
other than progression of the cancer under study (reference Section 7.2.3.3 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)
Additionally, any SAE, 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.  
All subjects with SAEs must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECI and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until 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 randomization through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, 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).
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 
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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).
ECIs (both nonserious and SAEs) from the date of first dose through 90 days following 
cessation of treatment, or 30 days after the initiation of a new anticancer therapy, whichever is 
earlier, need to be reported to the Sponsor within 24 hours of the event, regardless of attribution 
to study treatment, consistent with standard SAE reporting guidelines and either by electronic 
media or paper.  Sponsor contact information can be found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.
7.2.3.3
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 - Immediate Reporting of Adverse Events to the Sponsor. Any such event will 
be submitted to the Sponsor within 24 hours either by electronic or paper media.
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 aggregate 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 AEs according to the NCI 
CTCAE, version 4. Any AE which changes CTCAE grade over the course of a given episode 
will have each change of grade recorded on the AE CRFs/worksheets.
All AEs 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 AE causality to the combination regimen or to a single agent 
of the combination.  In general, causality attribution should be assigned to the combination 
regimen (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 15
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all AEs as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 selfcare ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A SAE is any AE 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 AE
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 preexisting condition that has not 
worsened is not a SAE.  A preexisting condition is a clinical condition that is diagnosed prior to the use of an 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 AE associated with an overdose is considered a SAE for collection purposes. An overdose that is not associated 
with an AE is considered a nonserious 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 SAE 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 AE. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the AE cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the AE? The determination of the likelihood that the Sponsor’s product caused the AE will be provided by an investigator who is a 
qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the AE based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the AE:
Exposure
Is there evidence that the 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 CRFs/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 AEs will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations.
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 nonSponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The EOC comprises members of Sponsor Senior Management.  The EOC will receive and 
decide upon any recommendations made by the DMC regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external 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 8.1.4 - 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 
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.
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 nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any interim analysis for 
efficacy, will be documented in an sSAP and referenced in the CSR for the study.  Post hoc 
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exploratory analyses will be clearly identified in the CSR.  The PRO analysis plan will also be 
included in the sSAP.
In addition, a separate analysis plan document will be issued prior to the conduct of any interim 
analysis for efficacy for the following:

Pharmacokinetics and pharmacodynamics evaluation (detailed in Section 7.1.3.2).
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the SAP (Section 8.2).
Efficacy Analysis
The primary and key secondary or exploratory endpoints, primary analysis population, and 
statistical methods that will be employed for the efficacy analyses are presented in Table 20.
The intention-to-treat (ITT) population that includes all randomized subjects will serve as the 
primary population for the analyses of efficacy data in this trial. Regular safety monitoring is 
planned in this trial (Section 8.2.9). If, upon the recommendation of DMC, the enrollment in 
pembrolizumab in combination with chemotherapy arm is paused and re-opened, subjects 
randomized during the pause will be excluded from the efficacy analysis population of 
pembrolizumab in combination with chemotherapy vs. standard treatment comparisons.
The primary efficacy endpoints are:

PFS per RECIST 1.1 (i.e., time from randomization to documented progressive disease 
or death due to any cause, whichever occurs first)

OS (i.e., time from randomization to death due to any cause)
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, multiple 
comparisons, multiple populations and interim analyses is described in Section 8.2.9 Interim 
Analyses and in Section 8.2.6 Multiplicity.
Safety Analyses
The All-Subjects-as-Treated population will be employed for safety analyses.  For this study, 
there are no pre-specified events of interest, i.e., no Tier 1 events.
Power and Sample Size
The study plans to randomize approximately 825 subjects with 1:1:1 ratio into the treatment 
groups of pembrolizumab monotherapy, a combination of pembrolizumab with chemotherapy
and standard treatment, stratified by PD-L1 expression (strongly positive vs. not strongly 
positive as defined by TPS 50% cutpoint), HPV status (HPV+ vs. HPV-), and ECOG 
performance status (0 vs. 1). The prevalence of the PD-L1 positive subpopulation is projected 
to be 50% for PD-L1 CPS 20 and 80% for PD-L1 CPS 1 subpopulation.
Two interim efficacy analyses are planned in this study.  A Hwang-Shih-DeCani 
alpha-spending function with gamma parameter (-4) is constructed to implement group-
sequential efficacy boundaries to control the Type I error for each PFS and each OS hypothesis.
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PFS
Two PFS analyses are planned at interim analyses 1 and 2.  The PFS hypotheses will be tested 
at interim analysis 1, and a second test of PFS, which will be the final PFS analyses, may occur 
at interim analysis 2 only if superior PFS is not declared at interim analysis 1.  At the time of 
final PFS analysis,
H1, H4: for subjects with PD-L1 CPS 20, it is expected that approximately 237 PFS events 
will have been observed between one experimental treatment and standard treatment.  
The study has 90% power with each experimental treatment (pembrolizumab 
monotherapy [H1] or pembrolizumab in combination with chemotherapy [H4]) to 
detect a hazard ratio of 0.58 vs. standard treatment at alpha = 0.19% (one-sided).
H2, H5: for subjects with PD-L1 CPS 1, it is expected that approximately 378 PFS events 
will have been observed between one experimental treatment and standard treatment.  
The study has 98.6% power with each experimental treatment (pembrolizumab 
monotherapy [H2] or pembrolizumab in combination with chemotherapy [H5]) to 
detect a hazard ratio of 0.59 vs. standard treatment at alpha = 0.19% (one-sided).  (Note 
that H2 will be tested only if H1 is rejected and H5 will be tested only if H4 is rejected)
H3: for all subjects, it is expected that approximately 474 PFS events will have been 
observed between pembrolizumab monotherapy and standard treatment.  The study has 
99.6% power with pembrolizumab monotherapy to detect a hazard ratio of 0.6 vs. 
standard treatment at alpha = 0.19% (one-sided).  (Note that H3 will be tested only if 
H1 and H2 are rejected under the multiplicity strategy.)
H6: for all subjects, it is expected that approximately 474 PFS events will have been 
observed between pembrolizumab in combination with chemotherapy and standard 
treatment.  The study has 97.7% power with pembrolizumab in combination with 
chemotherapy to detect a hazard ratio of 0.6 vs. standard treatment at alpha = 0.02% 
(one-sided). 
The PFS sample size calculation is based on the following assumptions: 1) progression-free 
survival follows an exponential distribution with a median of 6 months in the standard 
treatment arm; 2) hazard ratios are 0.58 for subjects with PD-L1 CPS 20, 0.59 for subjects with 
PD-L1 CPS 1 and 0.6 for all subjects; 3) an enrollment period of 21 months; 4) at least 9
months follow-up at interim analysis 1, and 17 months follow-up at interim analysis 2; and 5) 
a yearly dropout rate of 5%.
OS
Three OS analyses are planned at interim analyses 1, 2 and the final analysis.  At the time of 
the final analysis:
H7, H11: for subjects with PD-L1 CPS 20, it is expected that approximately 222 deaths 
will have been observed between one experimental treatment and standard treatment.  
The study has 90.5% power with each experimental treatment (pembrolizumab 
monotherapy [H7] or pembrolizumab in combination with chemotherapy [H11]) to 
detect a hazard ratio of 0.6 vs. standard treatment at alpha = 0.7% (one-sided). 
H8, H12: for subjects with PD-L1 CPS 1, it is expected that approximately 359 deaths will 
have been observed between one experimental treatment and standard treatment.  The 
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study has 94.3% power
with each experimental treatment (pembrolizumab 
monotherapy [H8] or pembrolizumab in combination with chemotherapy [H12]) to 
detect a hazard ratio of 0.65 vs. standard treatment at alpha = 0.7% (one-sided). (Note 
that H8 will be tested only if H7 is rejected and H12 will be tested only if H11 is 
rejected.)
H9, H13: for all subjects, it is expected that approximately 455 deaths will have been 
observed between one experimental treatment and standard treatment.  The study has 
87.85% power with a hazard ratio of 0.85 to establish noninferiority (NI margin = 1.2) 
for each experimental treatment (pembrolizumab monotherapy [H9] or pembrolizumab 
in combination with chemotherapy [H13]) vs. standard treatment at alpha = 0.7% (one-
sided).  (Note that H9 will be tested only if H7 and H8 are rejected under the 
multiplicity strategy.)
H10, H14: for all subjects, it is expected that approximately 455 deaths will have been 
observed between one experimental treatment and standard treatment.  The study has 
90.4% power with each experimental treatment (pembrolizumab monotherapy [H10]
or pembrolizumab in combination with chemotherapy [H14]) to detect a hazard ratio
of 0.7 vs. standard treatment at alpha = 0.7% (one-sided).  (Note that H10 will be tested 
only if H7 through H9 are rejected under the multiplicity strategy and H14 will be 
tested only if noninferiority is established for H13.)
The OS sample size calculation is based on the following assumptions: 1) overall survival
follows an exponential distribution with a median of 10 months in the standard treatment arm;
2) the hazard ratios are 0.6 for subjects with PD-L1 CPS 20, 0.65 for subjects with PD-L1 CPS
1, 0.7 for all subjects for the superiority hypotheses, and 0.85 for all subjects for the
noninferiority hypotheses; 3) an enrollment period of 21 months; 4) at least 23 months follow-
up; and 5) a yearly dropout rate of 2%.
The assumptions for median PFS of 6 months and median OS of 10 months in the standard 
treatment arm is based on the median PFS and median OS estimates from the EXTREME trial
[40; 54].  The assumptions do not take into account potential prognostic implications in a 
biomarker selected population.  As such, the median of the standard treatment arm for the PD-
L1 positive subgroups may be more or less than 6 months for PFS and more or less than 10 
months for OS. 
Interim Analyses
Two efficacy interim analyses, one formal safety interim analysis and quarterly safety 
monitoring will be performed in this study.  Results will be reviewed by an external DMC. 
These interim analyses are summarized below.  Details are provided in Section 8.2.9.
8.1.4.1
Safety Interim Analyses
The endpoints, timing and purpose of the safety interim analysis are summarized in Table 16
below. The decision rule and other statistical details are further described in Section 8.2.9.
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Table 16
Summary of Interim Safety Analysis Strategy
Key Endpoints for Interim 
Analysis
Timing of Interim Analysis
Purpose of Interim Analysis
Percentage of subjects who 
require a dose modification
AE data
10 subjects in the 
pembrolizumab in 
combination with 
chemotherapy arm have 
completed 2 cycles of
treatment
quarterly
Safety evaluation
8.1.4.2
Efficacy Interim Analyses
There will be 2 interim analyses for efficacy.  Table 17 below summarizes the analysis 
strategies.  Further details of interim analyses are provided in Section 8.2.9 as well as in the 
DMC charter.
Table 17
Summary of PFS and OS Analysis Strategies
PFS and OS 
Analyses
Key 
Endpoints
Timing of 
Analysis
Expected Number of Events at the 
Time of Analysis
Primary Purpose of 
Analysis
Interim 
analysis 1
PFS
OS
30 months 
from 
study start
~423 
PFS 
events 
between 
pembrolizumab in combination 
with chemotherapy and standard 
treatment in all subjects
Demonstrate PFS and 
OS superiority
Interim 
analysis 2
OS
38 months 
from 
study start
~421 
deaths 
between 
pembrolizumab in combination 
with chemotherapy and standard 
treatment in all subjects
Demonstrate PFS (if 
not significant at IA1) 
and OS superiority
Final 
analysis
OS 
~44
months 
from 
study start
≥ 
222 
deaths 
between 
one 
experimental 
treatment 
and 
standard treatment in PD-L1 CPS 
20
≥ 
359 
deaths 
between 
one 
experimental 
treatment
and 
standard treatment in PD-L1 CPS 1
≥ 
455
deaths
between 
one 
experimental 
treatment
and 
standard treatment in all subjects
Demonstrate 
OS 
superiority
For the interim analyses, the actual timing is determined by the minimum follow-up; and for the final 
analysis, the actual timing is determined by both the expected event numbers and minimum follow-up. The 
table only lists the timing and the expected event numbers of the hypotheses that drive the analysis.  The 
event numbers of other hypotheses are provided in Section 8.2.9.2.
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Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The randomized allocation schedule will be generated and implemented by the vendor of the 
study IVRS.
Although this trial is being conducted as an open-label study, analyses or summaries generated 
by randomized treatment assignment, actual treatment received, and/or PD-L1 biomarker 
status will be limited and documented. Further documentation will be provided in the sSAP.  
In addition, the independent radiologist(s) will perform the central imaging review without 
knowledge of treatment group assignment.
The investigator and study team at the Sponsor consisting of clinical, statistical, statistical 
programming and data management personnel, will be blinded to subject-level PD-L1 
biomarker results. An unblinded Sponsor clinical scientist, unblinded Sponsor statistician,
unblinded Sponsor statistical programmer, and unblinded data manager will have access to the 
subject-level PD-L1 results for the purpose of data review and will have no other 
responsibilities associated with the study. A summary of PD-L1 biomarker prevalence may 
be provided to the study team at the Sponsor by the IVRS vendor or the unblinded Sponsor 
statistician. Key enrollment metrics and study data will also be monitored by the unblinded 
Sponsor statistician and unblinded Sponsor statistical programmer to inform the timing of each 
analysis.
Planned interim analyses are described in Section 8.2.9.  The PFS analyses, described in 
Section 8.2.9, occurs prior to the final OS analysis. Treatment-level results at the interim 
analyses will be provided by the external unblinded statistician to the eDMC. The DMC 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 Sponsor Executive
Oversight Committee.  Depending on the recommendation of the external DMC, the Sponsor 
may prepare a regulatory submission.  Participant-level unblinding to support regulatory filing 
will be restricted to a designate team in the Sponsor, who will have no other responsibilities 
associated with the study.  If the DMC recommends modifications to the design of the protocol 
or discontinuation of the study, the executive oversight committee may be unblinded to results 
at the treatment level in order to act on these recommendations.  Additional logistical details, 
revisions to the above plan, and data monitoring guidance will be provided in the DMC 
Charter.  Key aspects of the interim analyses are described in Section 8.2.9.
Prior to final study unblinding, the Sponsor and external unblinded statisticians will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
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Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
8.2.3.1
Efficacy Endpoints
Primary
Progression-free survival (PFS) – RECIST 1.1 by BICR
Progression-free-survival is defined as the time from randomization to the first documented 
disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever 
occurs first. See Section 8.2.5.1.1 for definition of censoring.
OS
OS is defined as the time from randomization to death due to any cause. Subjects without 
documented death at the time of the final analysis will be censored at the date of the last follow-
up.
Secondary
Proportion progression free at 6 months and 12 months – RECIST 1.1 by BICR
The proportion progression free at 6 months and at 12 months is defined as the Kaplan-Meier 
estimate of the survival function for PFS at 6 months and 12 months, respectively.  The 
progression-free status is based upon BICR per RECIST 1.1.
Objective Response Rate (ORR) – RECIST 1.1 by BICR
ORR is defined as the proportion of the subjects in the analysis population who have a CR or 
PR. Responses are based upon BICR per RECIST 1.1.
Exploratory
Duration of Response (DOR) – RECIST 1.1 by BICR
For subjects who demonstrated CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death, whichever occurs first.
Details of other exploratory endpoints will be provided in the sSAP.
8.2.3.2
Safety Endpoints
Safety measurements are described in Section 7 Trial Procedures.
8.2.3.3
PRO Endpoints
Global health status/quality-of-life assessment is based on the global health status/quality-of-
life scales of the QLQ-C30 (items 29 and 30); pain is based on the pain multi-item scales of 
the EORTC QLQ-H&N35 (items 31-34), and TTD in swallowing is based on the swallowing 
multi-item scales of the EORTC QLQ-H&N35 (items 35-38).
TTD is defined as the time from baseline to first onset of PRO deterioration with confirmation 
(true deterioration). Here, true deterioration in the global health status/quality of life, pain, and 
swallowing endpoints is defined as a 10 points or greater worsening from baseline for each 
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multi-item scale [48; 52; 53] and confirmed by a second adjacent 10 or more deterioration from 
baseline under a right-censoring rule.
Analysis Populations
8.2.4.1
Efficacy Analysis Populations
The analysis of primary efficacy endpoints are based on the ITT population, i.e., subjects will 
be included in the treatment group to which they are randomized. If, upon the recommendation 
of DMC, the enrollment in pembrolizumab in combination with chemotherapy arm is paused 
and re-opened, subjects randomized during the pause will be excluded from the efficacy 
analysis population of pembrolizumab in combination with chemotherapy vs. standard 
treatment comparisons.  Details on the approach to handling missing data are provided in 
Section 8.2.5 Statistical Methods.
8.2.4.2
Safety Analysis Populations
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 one 
dose of study treatment. Subjects will be included 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 
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 one laboratory or vital sign measurement obtained subsequent to at least one 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.
8.2.4.3
PRO Analysis Population
The PRO analyses are based on the PRO full analysis set population, defined as subjects who 
have at least one PRO assessment available and have received at least one dose of the study 
medication.
Statistical Methods
This section describes the statistical methods that primarily address the primary and secondary
objectives.  Methods related to exploratory objectives will be described in the sSAP. 
Statistical testing and inference for safety analyses are described in 8.2.5.2. Efficacy results 
that will be considered to be statistically significant after consideration of the strategy for 
controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values may 
be computed for other efficacy analyses as a measure of strength of association between the 
endpoint and the treatment effect rather than formal tests of hypotheses. 
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8.2.5.1
Statistical Methods for Efficacy Analyses
8.2.5.1.1 Progression-Free Survival (PFS)
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment arms. The hazard ratio 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 same 
stratification factors used for randomization (see Section 5.4) will be used as the stratification 
factors in both the stratified log-rank test and the stratified Cox model for the analyses in all 
subjects and in subjects with PD-L1 CPS 1. For analyses in the PD-L1 CPS 20 subgroup, HPV 
status and ECOG status will be used as the stratification factors. In the event that there are low 
event counts (<5) in one or more strata, for the analysis purpose, strata will be combined to 
ensure sufficient number of events in each stratum.  The order of stratification factors to 
combine strata over is as follows:
1. Eliminate ECOG performance score from analysis stratification, leaving stratification 
by PD-L1 tumor expression defined by TPS and HPV status;
2. Eliminate both ECOG performance score and HPV status from analysis stratification, 
leaving stratification by PD-L1 tumor expression defined by TPS;
3. Eliminate all stratification factors.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is objectively 
documented per RECIST 1.1 by central imaging vendor, regardless of discontinuation of study 
drug. Death is always considered as a confirmed PD event. Sensitivity analyses will be 
performed for comparison of PFS based on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by central imaging 
vendor, we will perform 2 sensitivity analyses with a different set of censoring rules. The first 
sensitivity analysis is the same as the primary analysis except that data for any subject who 
misses more than one disease assessment (with or without a subsequent death or progression) 
are censored at the last disease assessment prior to missing visits. The second sensitivity 
analysis is the same as the primary analysis except that it considers discontinuation of treatment 
or initiation of an anticancer treatment subsequent to discontinuation of study-specified 
treatments, whichever occurs later, to be a PD event for subjects without documented PD or 
death. 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 18.
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Table 18
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new 
anticancer 
treatment 
is 
not 
initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Censored at last disease 
assessment if still on study 
therapy; 
progressed 
at 
treatment 
discontinuation 
otherwise
No PD and no death; 
new 
anticancer 
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last disease 
assessment before new 
anticancer treatment
Progressed at date of new 
anticancer treatment
No PD and no death; ≥ 
2 consecutive missed 
disease assessments
Censored at last disease 
assessment
Censored at last disease 
assessment prior to ≥2 
consecutive missed visits
Censored at last disease 
assessment
PD 
or 
death 
documented after ≤ 1 
missed 
disease 
assessment
Progressed at date of 
documented 
PD 
or 
death
Progressed at date of 
documented PD or death
Progressed 
at 
date 
of 
documented PD or death
PD 
or 
death 
documented at any time 
after ≥ 2 missed disease 
assessments
Progressed at date of 
documented 
PD 
or 
death
Censored at last disease 
assessment prior to the ≥ 
2 
missed 
disease 
assessment
Progressed 
at 
date 
of 
documented PD or death
8.2.5.1.2 Overall Survival (OS)
The nonparametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified Cox 
proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% CI
from the stratified Cox model with a single treatment covariate will be reported. The same 
stratification factors used for randomization (see Section 5.4) will be used as the stratification 
factors in both the stratified log-rank test and the stratified Cox model for the analyses in all 
subjects and in subjects with PD-L1 CPS 1.  For analyses in the PD-L1 CPS 20 subgroup, HPV 
status and ECOG status will be used as the stratification factors. In the event that there are low 
event counts (<5) in one or more strata, for the analysis purpose, strata will be combined to 
ensure sufficient number of events in each stratum.  The order of stratification factors to 
combine strata over is the same as specified for PFS analysis.
Since subjects in the standard therapy arm are expected to discontinue treatment earlier 
compared to subjects in the pembrolizumab arms, and they may switch to another anti-PD-1 
treatment following confirmation of progressive disease, adjustment for the effect of crossover 
on OS may be performed based on recognized methods, e.g. the Rank Preserving Structural 
Failure Time model proposed by Robins and Tsiatis (1989) [55], two stage model, etc., based 
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on an examination of the appropriateness of the data to the assumptions required by the 
methods.
8.2.5.1.3 Proportion Progression Free at 6 Months and 12 Months
Kaplan-Meier estimates of the survival function for PFS at 6 months and 12 months will be 
provided by treatment group.  Confidence intervals for the difference between the treatment 
groups (pembrolizumab vs. standard treatment or a combination of pembrolizumab with 
chemotherapy vs. standard treatment) will be constructed using standard methods.
8.2.5.1.4 Objective Response Rate (ORR)
The stratified Miettinen and Nurminen’s method will be used for comparison of the objective
response rates between the treatment groups. The difference in ORR and its 95% CI from the 
stratified Miettinen and Nurminen method with strata weighting by sample size will be 
provided. The same stratification factors used for randomization (see Section 5.4) will be used 
as the stratification factors in the analysis of all subjects and subjects with PD-L1 CPS 1. For 
analyses in the PD-L1 CPS 20 subgroup, HPV status and ECOG status will be used as the 
stratification factors.  In the event that there are low responses (<5) in one or more strata, for 
the analysis purpose, strata will be combined to ensure sufficient number of responses in each 
stratum.  The order of stratification factors to combine strata over is the same as specified for 
PFS analysis.  Sensitivity analyses will be performed for comparison of ORR based on 
investigator's assessment.
8.2.5.1.5 Duration of Response (DOR)
For subjects who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs 
first.  Censoring rules for DOR are summarized in Table 19. DOR will be assessed using 
RECIST 1.1 separately by BICR and by investigator’s assessment.
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided.  Subjects who are alive, have not progressed, have not initiated 
new anticancer treatment, have not been determined to be lost to follow-up, and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing responders 
at the time of analysis.  If a subject meets multiple criteria for censoring, the censoring criterion 
that occurs earliest will be applied.
Table 19
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(nonevent)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(nonevent)
Death or progression after ≥2 
consecutive missed disease 
assessments
Last adequate disease assessment 
prior to the ≥ 2 missed adequate 
disease assessments
Censor
(nonevent)
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Situation
Date of Progression or Censoring
Outcome
Death or progression after ≤ 1 missed 
adequate disease assessments
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
8.2.5.1.6 Summary of Efficacy Analysis Methods
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 20.
Table 20
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data 
Approach
Primary Analyses:
PFS (RECIST 1.1) by 
BICR
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method 
ITT

All subjects

Subjects with PD-L1 
CPS 20 and CPS 1
Censored according 
to rules in Table 18
OS
Testing: Stratified Log-
rank test (for superiority 
hypotheses only)
Estimation: Stratified Cox 
model with Efron's tie 
handling method
ITT

All subjects

Subjects with PD-L1 
CPS 20 and CPS 1
Censored at last 
known alive date
Secondary Analyses:
PFS at 6 months/12 
months (RECIST 1.1) by 
BICR
Kaplan-Meier estimation 
with CI
ITT

All subjects

Subjects with PD-L1 
CPS 20 and CPS 1
Censored according 
to primary censoring 
rule in Table 18
ORR (RECIST 1.1) by 
BICR
Stratified Miettinen and 
Nurminen method
ITT

All subjects

Subjects with PD-L1 
CPS 20 and CPS 1
Subjects with 
missing data are 
considered 
nonresponders
Exploratory Analyses:
DOR (RECIST 1.1) by 
BICR
Summary statistics using 
Kaplan-Meier method
All responders in ITT 
Nonresponders are 
excluded in analysis
Sensitivity analyses will be performed for PFS, ORR and DOR based on investigator's assessment.
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8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 21).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse experiences of 
special interest that are identified a priori constitute “Tier 1” safety endpoints that will be 
subject to inferential testing for statistical significance with p-values and 95% confidence 
intervals provided for between-group comparisons.  Other safety parameters will be considered 
Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 95% confidence 
intervals provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters.
Adverse experiences (specific terms as well as system organ class terms) and predefined limits 
of change in laboratory, vital signs, and ECG parameters that are not pre-specified as Tier-1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3," based on the number of events 
observed.  Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit 
the event; all other adverse experiences and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment groups 
of equal size each have less than 4 events and thus would add little to the interpretation of 
potentially meaningful differences.  Because many 95% confidence intervals 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 adverse experiences and predefined limits of 
change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters that are not pre-specified as Tier-1 endpoints will be considered Tier 3 safety 
parameters.  Summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment group in table format. 
For this protocol, there are no Tier 1 events.  Adverse experiences (specific terms as well as 
system organ class terms), consisting of the percentage of subjects with any AE, any drug-
related AE, any Grade 3-5 AE, any serious AE, any AE which is both drug-related and Grade 
3-5, any AE which is both serious and drug-related, dose modification due to AE, and who 
discontinued due to an AE, and death that are not pre-specified as Tier-1 endpoints will be 
classified as belonging to "Tier 2" or "Tier 3," based on the number of events observed.  
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit the event; 
all other adverse experiences will belong to Tier 3.
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Table 21
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-
Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Grade 3-5 AE
X
X
Any Serious AE 
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of subjects in 
one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs (incidence <4 of subjects in 
all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
8.2.5.3
Statistical Methods for PRO Analyses
The Kaplan-Meier method will be used to estimate the TTD survival curve for each of the 
global health status/quality of life, pain and swallowing outcomes in each treatment group. A 
stratified Cox proportional hazard (PH) model with Efron's method of tie handling will be used 
to assess the magnitude of the treatment difference. Stratification factors used for 
randomization will be used in the stratified Cox PH model. The hazard ratio, 95% confidence 
interval, and nominal p-value will be reported.
To assess the treatment effects on the PRO score changes from baseline in the global health 
status/quality-of-life outcome, a constrained longitudinal data analysis (cLDA) model will be 
applied, with the PRO score as the response variable, and treatment by time interaction, and 
stratification factors as covariates. Treatment effect on PRO score change from baseline will 
be primarily evaluated at Week 15. The differences in the least square mean change from 
baseline will be reported at the primary analysis time point.
8.2.5.4
Summaries of Baseline Characteristics and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs in all subjects as well as in subjects with PD-L1 positive 
expression. No statistical hypothesis tests will be performed on these characteristics. The 
number and percentage of subjects randomized, and the primary reason for discontinuation 
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will be displayed. Demographic variables (such as age) and baseline characteristics will be 
summarized by treatment either by descriptive statistics or categorical tables. The reasons for 
exclusion from the ITT population (if any) will be summarized.
Multiplicity
The overall type I error rate is strongly controlled at 2.5% (one-sided) with:

0.19% allocated to each PFS hypothesis of pembrolizumab monotherapy vs. standard 
treatment (H1) and pembrolizumab in combination with chemotherapy vs. standard 
treatment (H4) in subjects with PD-L1 CPS 20;

0.02% allocated to PFS hypothesis of pembrolizumab in combination with 
chemotherapy vs. standard treatment in all subjects (H6);

0.7% allocated to each OS hypothesis of pembrolizumab monotherapy vs. standard 
treatment (H7) and pembrolizumab in combination with chemotherapy vs. standard 
treatment (H11) in subjects with PD-L1 CPS 20;

0.7% allocated to OS noninferiority hypothesis of pembrolizumab in combination with 
chemotherapy vs. standard treatment in all subjects (H13).
For the PFS hypotheses of pembrolizumab monotherapy vs. standard treatment, a fixed 
sequential testing will be applied in the order of PFS superiority in subjects with PD-L1 CPS 
20 (H1), in subjects with PD-L1 CPS 1 (H2), and in all subjects (H3).
For the PFS hypotheses of pembrolizumab in combination with chemotherapy vs. standard 
treatment, a fixed sequential testing will be applied in the order of PFS superiority in subjects 
with PD-L1 CPS 20 (H4) and in subjects with PD-L1 CPS 1 (H5). If H5 is rejected, then the 
corresponding alpha will be fully shifted to PFS superiority hypothesis for all subjects (H6).
If any of the PFS null hypotheses in all subjects (H3 and H6) is rejected, the corresponding 
alpha level will be shifted and distributed to the OS hypotheses for the corresponding 
experimental treatment using the graphical approach of Maurer and Bretz (2013) [57].
For the OS hypotheses of pembrolizumab monotherapy vs. standard treatment, a fixed 
sequential testing will be applied in the order of OS superiority in subjects with PD-L1 CPS 
20 (H7), OS superiority in subjects with PD-L1 CPS 1 (H8), OS noninferiority in all subjects 
(H9) and OS superiority in all subjects (H10). If H10 is rejected, then the corresponding alpha 
will be essentially fully reallocated and distributed equally to H11 and H13 if not already 
significant, with a very small fraction (0.002) reallocated to H1.
For the OS hypotheses of pembrolizumab in combination with chemotherapy vs. standard 
treatment, a fixed sequential testing will be applied in the order of OS superiority in subjects 
with PD-L1 CPS 20 (H11) and OS superiority in subjects with PD-L1 CPS 1 (H12).  If H12 is 
significant, the corresponding alpha will be shifted fully to OS noninferiority in all subjects 
(H13).  If H14 is rejected, then the corresponding alpha will be essentially fully reallocated to 
H7 if not already significant, with a very small fraction (0.001) reallocated to H4.
The alpha reallocation strategy will follow the graphical approach of Maurer and Bretz (2013) 
[57].  Note that if the α-reallocation from OS hypothesis testing occurs at the final analysis 
after hypothesis testing for PFS has been completed, the previously computed p-values for the 
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PFS analyses can be compared to the updated bounds if the PFS hypotheses are not already 
significant.
Figure 3 displays the multiplicity strategy diagram for the study. 
Figure 3
Multiplicity Strategy
Sample Size and Power Calculation
The study plans to randomize approximately 825 subjects with 1:1:1 ratio into the treatment 
groups of pembrolizumab monotherapy, a combination of pembrolizumab with chemotherapy
and standard treatment, stratified by PD-L1 expression (strongly positive vs. not strongly 
positive), HPV status (HPV+ vs. HPV-), and ECOG performance status (0 vs. 1).
The 
prevalence of PD-L1 positive subpopulation is projected to be 50% for PD-L1 CPS 20 and
80% for the PD-L1 CPS 1 subpopulation.
Two interim efficacy analyses are planned in this study.  A Hwang-Shih-DeCani 
alpha-spending function with gamma parameter (-4) is constructed to implement group-
sequential efficacy boundaries for each PFS and each OS hypothesis.  
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PFS:
Two PFS analyses are planned at interim analyses 1 and 2. The PFS hypotheses will be tested 
at interim analysis 1, and a second test of PFS, which will be the final PFS analyses, may occur 
at interim analysis 2 only if superior PFS is not declared at interim analysis 1.  At the time of 
the final PFS analysis:
H1, H4: for subjects with PD-L1 CPS 20, it is expected that approximately 237 PFS events 
will have been observed between one experimental treatment and standard treatment.  
The study has 90% power with each experimental treatment (pembrolizumab 
monotherapy [H1] or pembrolizumab in combination with chemotherapy [H4]) to 
detect a hazard ratio of 0.58 vs. standard treatment at alpha = 0.19% (one-sided).
H2, H5: for subjects with PD-L1 CPS 1, it is expected that approximately 378 PFS events 
will have been observed between one experimental treatment and standard treatment.  
The study has 98.6% power with each experimental treatment (pembrolizumab 
monotherapy [H2] or pembrolizumab in combination with chemotherapy [H5]) to 
detect a hazard ratio of 0.59 vs. standard treatment at alpha = 0.19% (one-sided).  (Note 
that H2 will be tested only if H1 is rejected and H5 will be tested only if H4 is rejected.)
H3: for all subjects: it is expected that approximately 474 PFS events will have been 
observed between pembrolizumab monotherapy and standard treatment.  The study has 
99.6% power with pembrolizumab monotherapy to detect a hazard ratio of 0.6 vs. 
standard treatment at alpha = 0.19% (one-sided).  (Note that H3 will be tested only if 
H1 and H2 are rejected under the multiplicity strategy.)
H6: for all subjects, it is it is expected that approximately 474 PFS events will have been 
observed between pembrolizumab in combination with chemotherapy and standard 
treatment.  The study has 97.7% power with pembrolizumab in combination with 
chemotherapy to detect a hazard ratio of 0.6 vs. standard treatment at alpha = 0.02% 
(one-sided).
The PFS sample size calculation is based on the following assumptions: 1) progression-free 
survival follows an exponential distribution with a median of 6 months in the standard 
treatment arm; 2) hazard ratios are 0.58 for subjects with PD-L1 CPS 20, 0.59 for subjects with 
PD-L1 CPS 1 and 0.6 for all subjects; 3) an enrollment period of 21 months; 4) at least 9
months follow-up at interim analysis 1, and 17 months follow-up at interim analysis 2; and 5)
a yearly dropout rate of 5%.
OS
Three OS analyses are planned at interim analyses 1, 2 and the final analysis.  At the time of 
the final analysis:
H7, H11: for subjects with PD-L1 CPS 20, it is expected that approximately 222 deaths 
will have been observed between one experimental treatment and standard treatment.  
The study has 90.5% power with each experimental treatment (pembrolizumab 
monotherapy [H7] or pembrolizumab in combination with chemotherapy [H11]) to 
detect a hazard ratio of 0.6 vs. standard treatment at alpha = 0.7% (one-sided). 
H8, H12: for subjects with PD-L1 CPS 1, it is expected that approximately 359 deaths will 
have been observed between one experimental treatment and standard treatment.  The 
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study has 94.3% power
with each experimental treatment (pembrolizumab 
monotherapy [H8] or pembrolizumab in combination with chemotherapy [H12]) to 
detect a hazard ratio of 0.65 vs. standard treatment at alpha = 0.7% (one-sided). (Note 
that H8 will be tested only if H7 is rejected and H12 will be tested only if H11 is 
rejected.)
H9, H13: for all subjects, it is expected that approximately 455 deaths will have been 
observed between one experimental treatment and standard treatment.  The study has 
87.85% power with a hazard ratio of 0.85 to establish noninferiority (NI margin = 1.2) 
for each experimental treatment (pembrolizumab monotherapy [H9] or pembrolizumab 
in combination with chemotherapy [H13]) vs. standard treatment at alpha = 0.7% (one-
sided).  (Note that H9 will be tested only if H7 and H8 are rejected under the 
multiplicity strategy.)
H10, H14: for all subjects, it is expected that approximately 455 deaths will have been 
observed between one experimental treatment and standard treatment.  The study has 
90.4% power with each experimental treatment (pembrolizumab monotherapy [H10]
or pembrolizumab in combination with chemotherapy [H14]) to detect a hazard ratio
of 0.7 vs. standard treatment at alpha = 0.7% (one-sided).  (Note that H10 will be tested 
only if H7 through H9 are rejected under the multiplicity strategy and H14 will be 
tested only if noninferiority is established for H13.)
The OS sample size calculation is based on the following assumptions: 1) overall survival
follows an exponential distribution with a median of 10 months in the standard treatment arm;
2) the hazard ratios are 0.6 for subjects with PD-L1 CPS 20, 0.65 for subjects with PD-L1 CPS 
1, 0.7 for all subjects for the superiority hypotheses, and 0.85 for all subjects for the 
noninferiority hypotheses; 3) an enrollment period of 21 months; 4) at least 23 months follow-
up; and 5) a yearly dropout rate of 2%.
The assumptions for median PFS of 6 months and median OS of 10 months in the standard 
treatment arm are based on median PFS and median OS estimates from the EXTREME trial
[40; 54].  The assumptions do not take into account potential prognostic implications in a 
biomarker selected population.  As such, the median of the standard treatment for the PD-L1 
positive subgroup may be more or less than 6 months for PFS, and more or less than 10 months 
for OS. 
The sample size and power calculations were performed in the software EAST 6 and R 
(package “gsDesign”).
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 by treatment group within each category of the following 
classification variables:

Stratification factors
o
PD-L1 subgroup (strongly positive vs. not strongly positive, defined by TPS 
50%)
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o
HPV status (HPV-positive vs. HPV-negative)
o
ECOG status (0 vs. 1)

PD-L1 expression level defined by CPS (≥20 vs. not ≥20; and ≥1 vs. not ≥1)

Age category (<65 vs. ≥65 years)

Sex (female vs. male)

Race (white vs. non-white)

Region (NA vs EU vs ROW)

Smoking status (never vs. former vs. current)

Disease status (recurrent vs. metastatic)
In addition, 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.
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Interim Analyses
8.2.9.1
Safety Interim Analyses
A formal interim safety analysis will take place after 10 subjects in pembrolizumab in 
combination with chemotherapy arm have completed 2 cycles of therapy.  If the majority of 
the enrolled subjects (more than 80%) require a dose modification of platinum and/or 5-FU by 
the end of the 2nd cycle, the dose of the chemotherapies may be reduced for the remainder of 
the study.  If the majority of the participants (more than 80%) require 2 dose modifications of 
platinum and/or 5-FU by the end of the 2nd cycle, the Sponsor may consider discontinuing the 
combination arm. 
Table 22 below summarizes the probabilities of observing the numbers and percentages of 
subjects who require 1 dose modification under different assumptions of true dose modification 
rate θ0, which can be interpreted as the p-values for testing the null hypothesis that the true 
dose modification rate is less than θ0.  These criteria are considered non-binding guidelines, 
i.e., a recommendation would not be based solely on statistical grounds, as many other factors 
(i.e., all aspects of the data from the trial) may be part of the decision process. 
Additionally, safety monitoring interim analyses are planned to be conducted approximately 
every quarter and will commence following the completion of the formal planned safety 
interim analysis.  The number of percentage of subjects with a dose modification, together with 
AE data, will be summarized.  Additional details of the monitoring timing and guidelines will 
be provided in the DMC charter. 
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Table 22
Probability of Observing the Number (%) of Subjects who Require a Dose 
Modification
Observed number 
(%) of subjects
Probabilities (p-values) under different assumptions
θ0 = 0.5
θ0 = 0.6
θ0 = 0.7
θ0 = 0.8
θ0 = 0.9
5 (50.0%)
0.377
0.633
0.850
0.967
0.998
6 (60.0%)
0.172
0.382
0.650
0.879
0.987
7 (70.0%)
0.055
0.167
0.383
0.678
0.930
8 (80.0%)
0.011
0.046
0.149
0.376
0.736
9 (90.0%)
0.001
0.006
0.028
0.107
0.349
The probabilities (p-values) for the monitoring of the first 10 subjects who have completed 2 cycles of therapy were 
calculated from Binomial distribution; and for the quarterly safety monitoring, the probabilities (p-values) can be calculated 
from asymptotical Normal distribution based on the observed proportion of subjects with a dose modification and the 
number of subjects at the time of analysis. 
8.2.9.2
Efficacy Interim Analyses
Two interim analyses are currently planned. Results will be reviewed by an external DMC.
Further details of interim analyses are provided below and will be incorporated into the DMC 
charter.
For each PFS and each OS hypothesis, a Hwang-Shih-DeCani alpha-spending function with 
gamma parameter (-4) is constructed to implement group-sequential efficacy boundaries to 
control the type I error.  The same spending function used for OS superiority hypotheses is 
also implemented to calculate boundaries for the noninferiority hypotheses.  Table 23 provides 
more details on the timing, number of events and decision guidance for each analysis. The 
actual boundaries and the alpha level will be determined from the overall alpha level after 
alpha shifting as a result of a successful analysis and the actual number of events observed at 
the time of the interim analysis using the corresponding alpha-spending function.
In the event that superiority is declared for one or more PFS hypotheses at interim analysis 1, 
the study will continue to follow subjects for OS unless substantial treatment effect is 
demonstrated for all OS hypotheses at the significance level determined from the 
alpha-spending function as specified above.
Interim Analysis 1: interim PFS/OS analyses
The interim analysis will take place when all subjects have been followed up for at least 9 
months. 
Assuming 21 months enrollment period for 825 all subjects, interim analysis 1 is projected to 
occur 30 months after study start.  The primary objective of the analyses is to demonstrate PFS 
superiority of pembrolizumab (monotherapy or in combination with chemotherapy).
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At the time of interim analysis 1, the expected numbers of PFS events observed for the PFS 
hypotheses are specified below.  If the actual number of events for a PFS hypothesis is 
different, the spending function boundaries will be adjusted accordingly for the actual number 
of events for that PFS hypothesis.

~211 PFS events between one experimental treatment and standard treatment in 
subjects with PD-L1 CPS 20 (H1 and H4)

~337 PFS events between one experimental treatment and standard treatment in 
subjects with PD-L1 CPS 1 (H2 and H5)

~423 PFS events between one experimental arm and standard treatment in all subjects
(H3 and H6)
For the hypotheses of PFS superiority of one experimental treatment in subjects with PD-L1 
CPS 20 (H1 and H4), alpha level of 0.19% is allocated to the test.  The boundary to demonstrate 
PFS superiority of one experimental treatment over standard treatment corresponds to a one-
sided p-value of 0.0012, which corresponds to an approximate observed hazard ratio of 
~0.6585 or less (approximately a 3.11-month or greater improvement over the median PFS 
from 6 months in the standard treatment arm). 
If H1 is rejected, for the hypothesis of PFS superiority of pembrolizumab monotherapy in 
subjects with PD-L1 CPS 1 (H2), alpha level of 0.19% is shifted from H1. Similarly, if H4 is 
rejected, for the hypothesis of PFS superiority of pembrolizumab combination therapy in 
subjects with PD-L1 CPS 1 (H5), alpha level of 0.19% is shifted from H4. The boundary to 
demonstrate PFS superiority of one experimental treatment over standard treatment in subjects
with PD-L1 CPS 1 corresponds to a one-sided p-value of 0.0012, which corresponds to an 
approximate observed hazard ratio of ~0.7186 or less (approximately a 2.35-month or greater 
improvement over the median PFS from 6 months in the standard treatment arm).
If H1 and H2 are rejected, for the hypothesis of PFS superiority of pembrolizumab 
monotherapy in all subjects (H3), alpha level of 0.19% is shifted from H2.  The boundary to 
demonstrate PFS superiority of pembrolizumab monotherapy over standard treatment in all 
subjects corresponds to a one-sided p-value of 0.0012, which corresponds to an approximate 
observed hazard ratio of ~0.7446 or less (approximately a 2.05-month or greater improvement 
over the median PFS from 6 months in the standard treatment arm). 
For the hypothesis of PFS superiority of pembrolizumab in combination with chemotherapy in 
all subjects (H6), alpha level of 0.02% is allocated to the test.  The boundary to demonstrate 
PFS superiority of the experimental treatment over standard treatment corresponds to a one-
sided p-value of 0.0001, which corresponds to an approximate observed hazard ratio of
~0.7007 or less (approximately a 2.56-month or greater improvement over the median PFS 
from 6 months in the standard treatment arm).
The trial will also examine OS at interim analysis 1. The expected numbers of events for the 
OS hypotheses are:

~171 deaths between one experimental arm and standard treatment in subjects with PD-
L1 CPS 20 (H7 and H11)

~278 deaths between one experimental arm and standard treatment in subjects with PD-
L1 CPS 1 (H8 and H12)
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
~352 deaths between one experimental arm and standard treatment in all subjects (H9, 
H10, H13 and H14)
The hazard ratio at bound, significance level and Z statistics of OS hypotheses provided in 
Table 23 are based on a nominal overall one-sided alpha level of 0.7% each to pembrolizumab 
monotherapy vs. standard treatment, and pembrolizumab in combination with chemotherapy 
vs. standard treatment, though the overall alpha levels for the OS hypotheses may be more than 
0.7% due to alpha shifting as a result of success in other hypotheses.  The actual alpha level 
for an OS hypothesis will be recalculated if the overall alpha level is not the same as the 
specified nominal alpha level given the multiplicity strategy or the expected number of deaths
is not observed. 
Interim Analysis 2: interim OS analyses and final PFS analyses
The interim analysis will take place when all subjects have been followed up for at least 
17 months.
Assuming 21 months enrollment period for 825 all subjects, interim analysis 2 is projected to 
occur 38 months after study start.  The primary objective of the analyses is to demonstrate OS 
superiority of pembrolizumab (monotherapy or in combination with chemotherapy).
The expected numbers of events for the OS hypotheses are:

~205 deaths between one experimental arm and standard treatment in subjects with PD-
L1 CPS 20 (H7, H11);

~332 deaths between one experimental arm and standard treatment in subjects with PD-
L1 CPS 1 (H8, H12); 

~421 deaths between one experimental arm and standard treatment in all subjects (H9, 
H10, H13 and H14).
However, if the expected number of events for an OS hypothesis is not observed, then the 
spending function boundaries will be adjusted accordingly for the smaller number of events 
for that OS hypothesis.
For the hypotheses of OS superiority of one experimental treatment in subjects with PD-L1 
CPS 20 (H7 and H11), an alpha level of 0.7% is allocated to each test.  The boundary to 
demonstrate OS superiority of one experimental treatment over standard treatment in PD-L1 
CPS 20 corresponds to a one-sided p-value of 0.0041, which corresponds to an approximate 
observed HR of ~0.6914 or less (approximately a 4.46-month or greater improvement over the 
median OS from 10 months in the standard treatment arm). 
If H7 is rejected, for the hypothesis of OS superiority of pembrolizumab monotherapy in
subjects with PD-L1 CPS 1 (H8), an alpha level of 0.7% is shifted from H7. Similarly, if H11
is rejected, for the hypothesis of OS superiority of pembrolizumab combination therapy in 
subjects with PD-L1 CPS 1 (H12), alpha level of 0.7% is shifted from H11.  The boundary to 
demonstrate OS superiority of one experimental treatment over standard treatment in PD-L1 
CPS 1 corresponds to a one-sided p-value of 0.0041, which corresponds to an approximate 
observed hazard ratio of ~0.7479 or less (approximately a 3.37-month or greater improvement 
over the median OS from 10 months in the standard treatment arm).
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If H7 through H9 are rejected, for the hypothesis of OS superiority of pembrolizumab 
monotherapy in all subjects (H10), alpha level of 0.7% is shifted from H9.  The boundary to 
demonstrate OS superiority of pembrolizumab monotherapy over standard treatment in all 
subjects corresponds to a one-sided p-value of 0.0041, which corresponds to an approximate 
observed hazard ratio of ~0.7727 or less (approximately a 2.94-month or greater improvement 
over the median OS from 10 months in the standard treatment arm). 
For the hypothesis of OS superiority of pembrolizumab in combination with chemotherapy in 
all subjects (H14), an alpha level of 0.7% is shifted to the test from H13.  The boundary to 
demonstrate OS superiority of pembrolizumab in combination with chemotherapy over 
standard treatment in all subjects is same as the boundary for testing OS superiority of 
pembrolizumab monotherapy over standard treatment in all subjects.
A second test of PFS, which is the final PFS analysis, will be conducted at interim analysis 2
only if superior PFS is not declared for that hypothesis at interim analysis 1.  The expected 
numbers of PFS events at interim analysis 2 are:

~237 PFS events between one experimental treatment and standard treatment in 
subjects with PD-L1 CPS 20 (H1 and H4)

~378 PFS events between one experimental treatment and standard treatment in 
subjects with PD-L1 CPS 1 (H2 and H5)

~474 PFS events between one experimental treatment and standard treatment in all 
subjects (H3 and H6)
If the expected number of PFS events is not observed by the time the analysis is conducted, 
the remaining alpha as defined by the spending function will be accelerated to the analysis at 
that time, and the success boundary for PFS will be recalculated for the actual number of events 
observed at that time considering the correlation between the interim and final PFS analyses
data.  Likewise, if the timing of events occurs faster than anticipated, the test boundary at the 
final PFS analysis will be adjusted to use the remaining Type I error not spent at earlier 
analysis.
Final Analysis: final OS analyses
The final analysis will take place when: 
1) At least 222 deaths are observed between one experimental treatment and standard 
treatment in subjects with PD-L1 CPS 20 (H7 and H11);
2) At least 359 deaths are observed between one experimental treatment and standard 
treatment in subjects with PD-L1 CPS 1 (H8 and H12);
3) At least 455 deaths are observed between one experimental treatment and standard 
treatment in all subjects (H9, H10, H13 and H14);
4) All subjects have been followed up for at least 23 months.
The final analysis is expected to occur ~44 months after study start. For any hypothesis listed 
above, if superiority has not been declared at IA1 or IA2, the specified number of deaths is to 
be observed for the final analysis. If the expected number of deaths for a hypothesis is not 
observed by the time that the trial is open for 44 months, the timing of the final analysis may 
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be delayed for up to 2 months or when the target death event numbers are observed, whichever 
occurs first. This calendar trigger will enable a suitable follow-up after IA2 and prevent the 
trial from continuing to an unreasonable duration. If at the time of the final analysis, the number 
of deaths for one hypothesis is not the same as specified above, the boundary at the final 
analysis will be adjusted to use the remaining Type I error not spent at earlier analyses.
Table 23
Decision Guidance at Each Analysis
Timing of Analysis
Testing
Expected
number of 
events
Value at boundary
Efficacy 
Boundary†
IA1 (interim PFS analyses and interim OS analyses)
30 mos. from study start; 
all 825 subjects enrolled 
and followed up for at 
least 9 months
PFS mono/combo vs. 
SOC in subjects with PD-
L1 CPS 20 (H1/H4)
~211
Z statistic
3.0329
p-value (one-sided)
0.0012
Approx. observed HR 
0.6585
PFS mono/combo vs. 
SOC in subjects with PD-
L1 CPS 1 (H2/H5)
~337
Z statistic
3.0304
p-value (one-sided)
0.0012
Approx. observed HR 
0.7186
PFS mono vs. SOC in all 
subjects (H3)
~423
Z statistic
3.0304
p-value (one-sided)
0.0012
Approx. observed HR 
0.7446
PFS combo vs. SOC in 
all subjects (H6)
~423
Z statistic
3.6551
p-value (one-sided)
0.0001
Approx. observed HR 
0.7007
OS mono/combo vs. SOC 
in subjects with PD-L1 
CPS 20 (H7/H11)
~171
Z statistic
2.7808
p-value (one-sided)
0.0027
Approx. observed HR 
0.6531
OS mono/combo vs. SOC 
in subjects with PD-L1 
CPS 1 (H8/H12)
~278
Z statistic
2.7754
p-value (one-sided)
0.0028
Approx. observed HR 
0.7948
OS noninferiority
mono/combo vs. SOC in 
all subjects (H9/H13)*
~352
Z statistic
2.7754
p-value (one-sided)
0.0028
Approx. observed HR 
0.8926
OS superiority 
mono/combo vs. SOC in 
all subjects (H10/H14)
~352
Z statistic
2.7754
p-value (one-sided)
0.0028
Approx. observed HR 
0.7439
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Timing of Analysis
Testing
Expected
number of 
events
Value at boundary
Efficacy 
Boundary†
IA2 (interim OS analyses and final PFS analyses)
38 mos. from study start; 
all 825 subjects enrolled 
and followed up for at 
least 17 months 
PFS mono/combo vs. 
SOC in subjects with PD-
L1 CPS 20 (H1/H4)
~237
Z statistic
2.9788
p-value (one-sided)
0.0014
Approx. observed HR
0.679
PFS mono/combo vs. 
SOC in subjects with PD-
L1 CPS 1 (H2/H5)
~378
Z statistic
2.9792
p-value (one-sided)
0.0014
Approx. observed HR 
0.7358
PFS mono vs. SOC in all 
subjects (H3)
~474
Z statistic
2.9792
p-value (one-sided)
0.0014
Approx. observed HR 
0.7605
PFS combo vs. SOC in 
all subjects (H6)
~474
Z statistic
3.6331
p-value (one-sided)
0.0001
Approx. observed HR 
0.7162
OS mono/combo vs. SOC 
in subjects with PD-L1 
CPS 20 (H7/H11)
~205
Z statistic
2.6398
p-value (one-sided)
0.0041
Approx. observed HR 
0.6914
OS mono/combo vs. SOC 
in subjects with PD-L1 
CPS 1 (H8/H12)
~332
Z statistic
2.6425
p-value (one-sided)
0.0041
Approx. observed HR 
0.7479
OS noninferiority
mono/combo vs. SOC in 
all subjects (H9/H13)*
~421
Z statistic
2.6425
p-value (one-sided)
0.0041
Approx. observed HR 
0.9272
OS superiority 
mono/combo vs. SOC in 
all subjects (H10/H14)
~421
Z statistic
2.6425
p-value (one-sided)
0.0041
Approx. observed HR 
0.7727
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Timing of Analysis
Testing
Expected
number of 
events
Value at boundary
Efficacy 
Boundary†
Final Analysis (Final OS Analysis)
~ 44 mos. from study start
OS mono/combo vs. SOC 
in subjects with PD-L1 
CPS 20 (H7/H11)
≥222
Z statistic
2.5644
p-value (one-sided)
0.0052
Approx. observed HR
0.7084
OS mono/combo vs. SOC 
in subjects with PD-L1 
CPS 1 (H8/H12)
≥359
Z statistic
2.5641
p-value (one-sided)
0.0052
Approx. observed HR
0.7627
OS noninferiority
mono/combo vs. SOC in 
all subjects (H9/H13)*
≥455
Z statistic
2.5641
p-value (one-sided)
0.0052
Approx. observed HR 
0.9435
OS superiority 
mono/combo vs. SOC in 
all subjects (H10/H14)
≥455
Z statistic
2.5641
p-value (one-sided)
0.0052
Approx. observed HR 
0.7862
† Efficacy decision rules for OS presented in table do not account for any alpha shifting from other 
hypotheses as a result of a successful analysis. P-values based on spending functions determine 
significance of tests; hazard ratios corresponding to significance are approximate.
*NI bounds are calculated with HR=0.85 under the alternative to establish noninferiority (NI margin=1.2).
For the PFS analysis, in the scenario that events have accumulated faster than expected, event-
based analysis will not allow for observing tail behavior that has been important in other trials 
to fully describe the treatment effect over time. For PFS hypotheses, the Lan and DeMets 
(1989) [62] calendar time method will be used for alpha spending to generate the group-
sequential design. The timing and alpha level of the original plan will be maintained for PFS 
hypotheses, regardless of the number of events observed. The sample space ordering required 
for group sequential trials as justified by Maurer and Bretz (2013) [57] will be maintained. 
This ensures strong control of Type I error. The updated bounds for the PFS hypotheses are 
given in Table 24. The bounds are based on initial alpha allocation. A Hwang-Shih-DeCani
[63] (-1.073) spending function has been used to implement alpha spending for PFS hypotheses 
for monotherapy versus SOC in all populations (H1, H2, and H3) and combination therapy
versus control with PD-L1 CPS1 and CPS20 (H4 and H5). A Hwang-Shih-DeCani (-3.079) 
spending function has been used for the PFS hypothesis for combination therapy versus control 
in all subjects (H6). The actual boundaries and the alpha level will be determined from the 
overall alpha level after any alpha shifting as a result of a successful analysis. The alpha level 
at the final analysis for the PFS hypotheses (IA2) will be calculated based on alpha reallocation, 
the alpha used at the interim analysis, and the actual number of events at IA1 and the final PFS 
analysis (IA2). The bounds given in Table 24 will be adjusted accordingly.
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Table 24
Decision Guidance for PFS hypotheses at Each Analysis
Timing of Analysis
Testing
Expected
number of 
events
Value at boundary
Efficacy
Boundary†
IA1 (interim PFS analyses)
30 mos. from study start; all 
825 subjects enrolled and 
followed up for at least 9
months
PFS mono/combo vs. 
SOC in subjects with 
PD-L1 CPS 20 (H1/H4)
~211
Z statistic
3.0357
p-value (one-sided)
0.0012
Approx. observed HR 
0.6581
PFS mono/combo vs. 
SOC in subjects with 
PD-L1 CPS 1 (H2/H5)
~337
Z statistic
3.0357
p-value (one-sided)
0.0012
Approx. observed HR 
0.7184
PFS mono vs. SOC in all 
subjects (H3)
~423
Z statistic
3.0357
p-value (one-sided)
0.0012
Approx. observed HR 
0.7441
PFS combo vs. SOC in 
all subjects (H6)
~423
Z statistic
3.7190
p-value (one-sided)
0.0001
Approx. observed HR 
0.6965
IA2 (final PFS analyses)
38 mos. from study start; all 
825 subjects enrolled and 
followed up for at least 17
months 
PFS mono/combo vs. 
SOC in subjects with 
PD-L1 CPS 20 (H1/H4)
~237
Z statistic
2.9775
p-value (one-sided)
0.0015
Approx. observed HR
0.6792
PFS mono/combo vs. 
SOC in subjects with 
PD-L1 CPS 1 (H2/H5)
~378
Z statistic
2.9755
p-value (one-sided)
0.0015
Approx. observed HR 
0.7363
PFS mono vs. SOC in all 
subjects (H3)
~474
Z statistic
2.9755
p-value (one-sided)
0.0015
Approx. observed HR 
0.7606
PFS combo vs. SOC in 
all subjects (H6)
~474
Z statistic
3.5924
p-value (one-sided)
0.0002
Approx. observed HR 
0.7188
† Efficacy decision rules for PFS presented in table do not account for any alpha shifting from other hypotheses 
as a result of a successful analysis. P-values based on spending functions determine significance of tests; hazard
ratios corresponding to significance are approximate.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
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Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives
the study medication infusion.  Summary statistics will be provided on Extent of Exposure for 
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.
Table 25
Product Descriptions
Product Name & Potency
Dosage Form
Comments
Pembrolizumab (MK-3475)
100 mg/4 mL
Solution for infusion
Provided centrally by the 
Sponsor
Cetuximab 100 mg/20 mL
Solution for infusion
Provided centrally by the 
Sponsor or locally by the 
trial site, subsidiary or 
designee
Carboplatin 600 mg/60 mL
Solution for infusion
Provided centrally by the 
Sponsor or locally by the 
trial site, subsidiary or 
designee
Cisplatin 50 mg/50 mL
Solution for infusion
Provided centrally by the 
Sponsor or locally by the 
trial site, subsidiary or 
designee
Fluorouracil 1000 mg/20 mL;
Fluorouracil 500 mg/10 mL
Solution for infusion
Provided centrally by the 
Sponsor or locally by the 
trial site, subsidiary or 
designee
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
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Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
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.
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.
Standard Policies
Trial site personnel will have access to a central electronic 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.
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 
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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.
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 member 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 
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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 or through a secure password-protected electronic portal 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 -
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.
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 
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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.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multicenter 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 Coordinating Investigator), 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 Coordinating Investigator 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) Coordinating Investigator].  The Sponsor may consider one or more factors in 
the selection of the individual to serve as the Protocol Coordinating Investigator and or CSR 
Coordinating Investigator (e.g., availability of the Coordinating Investigator during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol 
Coordinating Investigator must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  MSD, as Sponsor 
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of this trial, will review this protocol and submit the information necessary to fulfill these 
requirements.  MSD entries are not limited to FDAMA/FDAAA 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 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
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.
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 
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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 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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3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
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programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
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5. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
6. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61. 
7. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.
8. Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in renal 
cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81. 
9. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. Clin 
Cancer Res 2008;14(16):5220-7.
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor-infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94. 
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4. 
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51. 
14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival 
of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic 
cell infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-
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15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53. 
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16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 2009;10:840-
841. 
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of 
aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106. 
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11. 
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic 
lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-59. 
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7. 
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory 
T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor 
prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6. 
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value of 
tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-24. 
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57. 
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703. 
25. Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ cell 
infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant 
chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 2010;59:909-19. 
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits 
B cell receptor-mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48. 
28. Chow L, Mehra R, Haddad R, Gupta S, Weiss J, Berger R, Burtness B, Tahara M, Keam 
B, Le D, Cheng J, Heath K, Pathiraja K, Seiwert T. A phase Ib study of MK-3475 in 
patients with human papillomavirus (HPV) associated and non-HPV associated head and 
neck (H/N) cancer. ESMO 2015 Abstract #2866, Sep 2015.
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29. Mehra R, Seiwert T, Mahipal A, Weiss J, Berger R, Eder J, Burtness B, Tahara M, Keam 
B, Le D, Muro K, Geva R, Chung H, Lin C, Meister A, Hille D, Cheng D, Chow L, Haddad 
R.  Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous 
cell carcinoma (R/M HNSCC): Pooled analyses after long-term follow-up in KEYNOTE-
012. ASCO 2016 Abstract #6012, Jun 2016.
30. Price K, Cohen E. Current treatment options for metastatic head and neck cancer. Curr 
Treat Options Oncol. 2012 Mar; 13(1):35-46.
31. Bauml J, Seiwert T, Pfister D, Worden F, Liu S, Gilbert J, Saba N, Weiss J, Wirth L, Sukari 
A, Kang H, Gibson M, Massarelli E, Powell S, Meister A, Shu X, Cheng J, Haddad R.  
Preliminary results from KEYNOTE-055: Pembrolizumab after platinum and cetuximab 
failure in head and neck squamous cell carcinoma (HNSCC).  ASCO 2016 Abstract #6011, 
Jun 2016.
32. Chow L, Mehra R, Haddad R, Mahipal A, Weiss J, Berger R, Eder J, Burtness B, Tahara 
M, Keam B, Le D, Muro K, Geva R, Chung H, Lin C, Ayers M, Aurora-Garg D, Lunceford 
J, Cheng J, Seiwert T.  Biomarkers and response to pembrolizumab (pembro) in 
recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).  ASCO 2016 
Abstract #6010, Jun 2016.
33. Liverpool consortium (1990). "A phase III randomised trial of cisplatin, methotrextate, 
cisplatin + methotrexate and cisplatin + 5-FU in end stage squamous carcinoma of the head 
and neck. Liverpool Head and Neck Oncology Group." Br J Cancer 61(2): 311-315.
34. Forastiere, A. A., T. Leong, E. Rowinsky, B. A. Murphy, D. R. Vlock, R. C. DeConti and 
G. L. Adams (2001). "Phase III comparison of high-dose paclitaxel + cisplatin + 
granulocyte colony-stimulating factor versus low-dose paclitaxel + cisplatin in advanced 
head and neck cancer: Eastern Cooperative Oncology Group Study E1393." J Clin Oncol 
19(4): 1088-1095.
35. Forastiere, A. A., B. Metch, D. E. Schuller, J. F. Ensley, L. F. Hutchins, P. Triozzi, J. A. 
Kish, S. McClure, E. VonFeldt, S. K. Williamson and et al. (1992). "Randomized 
comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus 
methotrexate in advanced squamous cell carcinoma of the head and neck: a Southwest 
Oncology Group study." J Clin Oncol 10(8): 1245-1251.
36. Gibson, M. K., Y. Li, B. Murphy, M. H. Hussain, R. C. DeConti, J. Ensley, A. A. Forastiere 
and G. Eastern Cooperative Oncology (2005). "Randomized phase III evaluation of 
cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer 
(E1395): an intergroup trial of the Eastern Cooperative Oncology Group." J Clin Oncol 
23(15): 3562-3567.
37. Jacobs C1, L. G., Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, 
Mortimer JE, Einhorn LH, Schacter L, et al. (1992). "A phase III randomized study 
comparing cisplatin and fluorouracil as single agents and in combination for advanced 
squamous cell carcinoma of the head and neck." J Clin Oncol 10(2): 257-263.
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38. Schornagel, J. H., J. Verweij, P. H. de Mulder, F. Cognetti, J. B. Vermorken, P. Cappelaere, 
J. P. Armand, J. Wildiers, A. de Graeff, M. Clavel and et al. (1995). "Randomized phase 
III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent 
squamous cell carcinoma of the head and neck: a European Organization for Research and 
Treatment of Cancer Head and Neck Cancer Cooperative Group study." J Clin Oncol 13(7): 
1649-1655.
39. Schrijvers, D., J. Johnson, U. Jiminez, M. Gore, P. Kosmidis, H. Szpirglas, K. Robbins, J. 
Oliveira, R. Lewensohn, J. Schuller, A. Riviere, C. Arvay, P. Langecker, H. Jacob, E. 
Cvitkovic and E. Vokes (1998). "Phase III trial of modulation of cisplatin/fluorouracil 
chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck 
cancer. Head and Neck Interferon Cooperative Study Group." J Clin Oncol 16(3): 1054-
1059.
40. Vermorken, J. B., R. Mesía, F. Rivera, E. Remenar, A. Kawecki, S. Rottey, J. Erfan, D. 
Zabolotnyy, H. R. Kienzer, D. Cupissol, F. Peyrade, M. Benasso, I. Vynnychenko, D. De 
Raucourt, C. Bokemeyer, A. Schueler, N. Amellal and R. Hitt (2008). "Platinum-based 
chemotherapy plus cetuximab in head and neck cancer." N Engl J Med 359(11): 1116-
1127.
41. Parker, D., Bray, F., Ferlay, J., Pisani, P. Global Cancer Statistics, 2002. CA Cancer J Clin. 
2005;55(2):74-108
42. Peyrade, F., D. Cupissol, L. Geoffrois, F. Rolland, C. Borel, C. Ciais, S. Faivre and J. 
Guigay (2013). "Systemic treatment and medical management of metastatic squamous cell 
carcinoma of the head and neck: review of the literature and proposal for management 
changes." Oral Oncol 49(6): 482-491.
43. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of 
patients with human papillomavirus-positive head and neck squamous cell carcinoma in a 
prospective clinical trial. J Natl Cancer Inst 2008;100:261-9.
44. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The 
European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life 
instrument for use in international clinical trials in oncology. J Natl Cancer Inst 
1993;85(5):365-76.
45. Mehanna HM and Morton RP. Patient’s views on the utility of quality of life questionnaires 
in head and neck cancer: a randomized trial. Clin. Otolaryngol. 2006;31:310-316.
46. Tschiesner U, Rogers SN, Harreus U, Berghaus A, Cieza A. Content comparison of quality 
of life questionnaires used in head and neck cancer based on the international classification 
of functioning, disability and health: a systemic review. Eur Arch Otorhinolaryngol. 
2008;265:627-637.
47. Bjordal K, Ahlner-Elmquist MA, Tollesson E, Jensen AB, Razavi D, Maher EJ, et al. 
Development of a European Organization for Research and Treatment of Cancer (EORTC) 
questionnaire module to be used in quality of life assessments in head and neck cancer 
patients. Acta Oncologica. 1994;33(8):879-885.
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48. Bjordal K, de Graeff A, Fayers PM, Hammerlid E, van Pottelsberghe C, Curran D, et al. A 
12 country field study of the EORTC QLQ-C30 (version 3.0) and the head and neck cancer 
specific module (EORTC QLQ-H&N35) in head and neck patients. EORTC Quality of 
Life Group. Eur J Cancer. 2000 Sep;36(14):1796-807.
49. Chera BS, Eisbruch A, Murphy BA, Ridge JA, Gavin P, Reeve BB, et al. Recommended 
patient-reported core set of symptoms to measure in head and neck cancer treatment trials. 
J Natl Cancer Inst. 2014 Jul 8;106(7):[4 p.].
50. Mesía R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, et al. Quality of life of patients 
receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or 
metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010 
Oct;21(10):1967-73.
51. Machiels J, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB et al. Afatinib 
versus methotrexate as second-line treatment for patients with R/M HNSCC who 
progressed after platinum-based therapy: primary efficacy results of LUX-head and neck 
1, a phase III trial. ESMO 2014 Congress; 2014 Sep 27; Madrid, ES. 2014.
52. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:139-44.
53. King MT. The interpretation of scores from the EORTC quality of life questionnaire QLQ-
C30. Quality of Life Research 1996;5:555-67.
54. Rivera F, Garcia-Castaño A, Vega N, Vega-Villegas ME, & Guitiérrez-Sanz L. Cetuximab 
in metastatic or recurrent head and neck cancer: the EXTREME trial. Expert Rev 
Anticancer Ther. 2009;9(10):1421-1428.
55. Robins JM, Tsiatis AA. Correcting for noncompliance in randomized trials using rank 
preserving structural failure time models. Communication in Statistics – Theory and 
Methods 1991;20(8):2609-2631.
56. Miettinen O, Nurminen M. Comparative Analysis of two rates. Statistics in Medicine 
1985;4:213-226.
57. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials Using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013;5(4):311-320.
58. Bossi P, Miceli R, Locati LD, Ferrari D, Vecchio S, Moretti G, et al. A randomized, phase 
2 study of cetuximab plus cisplatin with or without paclitaxel for the first line treatment of 
patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. 
Ann Oncol. 2017 Sep 8. [Epub ahead of print].
59. Vermorken JB, Peyrade F, Krauss J, Mesía R, Remenar E, Gauler TC, et al. Cisplatin, 5-
fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic 
squamous cell carcinoma of the head and neck: results of the randomized phase I/II 
ADVANTAGE trial (phase II part). Annals of Oncology. 2014;25(3):682–8.
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60. Cohen EEW, Saba NF, Gitlitz B, Haddad R, Sukari A, Neupane P, et al. Active8: A 
randomized, double-blind, placebo-controlled phase 2 study of chemotherapy plus 
cetuximab in combination with motolimod immunotherapy in patients with recurrent or 
metastatic squamous cell carcinoma of the head and neck. Poster session presented at 
European Society for Medical Oncology, 2016 Oct 7-11; Copenhagen, DK.
61. Cohen EE, Harrington KJ, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al.  Head and 
neck cancer, excluding thyroid - Pembrolizumab (pembro) vs standard of care (SOC) for 
recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 
KEYNOTE-040 trial. [abstract]. ESMO. 2017;28:5. Abstract no. 628.
62. Lan KKG, DeMets DL. Group sequential procedures: calendar versus information time.
Stat Med. 1989;8:1191-8.
63. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med. 1990;9:1439-45.
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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 Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our products. 
As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in compliance 
with the highest ethical and scientific standards. Protection of participants in clinical trials is the overriding concern in
the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in compliance with local 
and/or national regulations (including all applicable data protection laws and regulations), and International Council for 
Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by MSD 
irrespective of the party (parties) employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in nature, or which are retrospective.
Further, this Code does not apply to investigator-initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy and/or 
pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine patient 
preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial and shall respect the data protection rights of all participants, trial site staff and, where applicable, third 
parties. All trial protocols are and will be assessed for the need and capability to enroll underrepresented groups. 
Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including people 
of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD selects 
investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and staff, 
previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are evaluated 
by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to raise 
awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented groups 
and those disproportionately impacted by the disease under study. MSD will support clinical trial investigators to 
enroll underrepresented groups and expand access to those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice (GCP). 
MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the extent 
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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. Subject Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance with 
local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate hazard 
and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will inform 
regulatory authorities of such new measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. Potential 
participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, 
trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is obtained. 
Participants may withdraw from an MSD trial at any time, without any influence on their access to, or receipt of, medical 
care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of MSD), 
ethics committee, and/or regulatory authorities will have access to confidential medical records that might identify the 
participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an ethics 
committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish to 
alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted above, 
all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
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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 Research
The leftover DNA and tumor specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The leftover DNA and 
tumor specimen(s) will be stored to provide a resource for future trials conducted by MSD
focused on the study of biomarkers responsible for how a drug/vaccine enters and is 
removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may 
interact with, or other aspects 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 MSD or designees and research will 
be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
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 Visit 1.  If delayed, present consent at 
next possible Subject Visit. Informed consent must be obtained prior to collection of 
all Future Biomedical Research specimens.  Consent forms signed by the subject will 
be kept at the clinical trial site under secure storage for regulatory reasons.  Information 
contained on the consent form alone cannot be traced to any specimens, test results, or 
medical information once the specimens have been rendered de-identified.
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Subjects are not required to participate in Future Biomedical Research in order to 
participate in the trial. Subjects who decline to sign the Future Biomedical Research
informed consent will not have the specimen collected nor will they be discontinued 
from the trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for appropriate 
specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for Future Biomedical Research purposes. Any 
specimens for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the MSD approved 
policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an objective 
to the main trial, this analysis is detailed in the main body of this protocol (Section 8.0
– Statistical Analysis Plan).  These specimens will be processed, analyzed, and the 
remainder of the specimen will be destroyed.  The results of these analyses will be 
reported along with the other trial results.  A separate specimen will be obtained from 
properly-consented subjects in this protocol for storage in the biorepository for Future 
Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
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, MSD has developed secure policies and procedures.  All specimens 
will be de-identified as described below. 
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At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first 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 first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a MSD designated storage/lab facility.  
The second code is linked to the first code via a second key. The specimen is now double 
coded.  Specimens with the second code are sometimes referred to as de-identified 
specimens. The use of the second code provides additional confidentiality and privacy 
protection for subjects over the use of a single code.  Access to both keys would be needed 
to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the MSD designated facility to an Entrusted Keyholder at MSD.  The second 
code will be logged into the primary biorepository database at MSD and, in this database, 
this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen will 
be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by the 
MSD Entrusted Keyholder under strict security policies and procedures.  The MSD
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would be 
directly linked to the full clinical data set would be those situations mandated by regulatory 
authorities (e.g., EMEA, FDA), whereby this information would be directly transferred to 
the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the MSD Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the highly 
validated conditions usually associated with regulatory approval of diagnostics.  The scope 
of research performed on these specimens is limited to the investigation of the variability 
in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by MSD, 
or an additional third party (e.g., a university investigator) designated by MSD.  The 
investigator conducting the analysis will be provided with double coded specimens.  Re-
association of analysis results with corresponding clinical data will only be conducted by 
the MSD Entrusted Keyholder.  Any contracted third party analyses will conform to the 
specific scope of analysis outlined for Future Biomedical Research.  Future Biomedical 
Research specimens remaining with the third party after the specific analysis is performed 
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will be returned to the sponsor or destroyed and documentation of destruction will be 
reported to MSD.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   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 MSD using the designated mailbox 
(clinical.specimen.management@msd.com) and a form will be provided by MSD to obtain 
appropriate information to complete specimen withdrawal.  Subsequently, the subject's 
specimens will be removed from the biorepository and be destroyed. A letter will be sent 
from MSD to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction.  Any analyses in progress 
at the time of request for 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 
specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  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 
MSD 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 MSD policies and procedures and this destruction will be 
documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from Future Biomedical 
Research will be maintained by MSD.  This is done to separate the future exploratory test 
results (which include genetic data) from the clinical trial database thereby maintaining a 
separation of subject number and these results.  The separate databases are accessible only 
to the authorized Sponsor 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 in international standards (e.g., ISO17799) 
to protect against unauthorized access.  The MSD Entrusted Keyholder maintains control 
over access to all specimen data.  These data are collected for future biomedical research 
purposes only and will not be used for any other purpose.
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9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported to 
the subject or family, and this information will not be entered into the clinical database 
maintained by MSD on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in exploratory 
research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by MSD) to subjects enrolled and will 
be advised that counseling should be made available for all who choose to participate in 
this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, MSD will publish the results without revealing specific 
subject information, inform all trial sites who participated in the MSD clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for public 
access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on MSD clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens from 
subjects and controls to represent the ethnic and gender population representative of the 
disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
MSD 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.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure MSD database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
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be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@msd.com.
14. 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
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff
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Abbreviations
Abbreviation/Term
Definition
1L
First Line
2L
Second Line
5-FU
5-fluorouracil
AE
Adverse Event
ADA
Antidrug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
ASaT
All-Subjects-as-Treated
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
AxMP
Auxiliary medicinal product
BICR
Blinded independent central review
BSA
Body Surface Area
CBC
Complete Blood Count
CI
Confidence Interval
CNS
Central Nervous System
CPS
Combined Positive Score
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
EOC
Executive Oversight Committee
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
Electronic Patient-Reported Outcomes
ERC
Ethics Review Committee
EU
European Union
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FNA
Fine Needle Aspirate
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Abbreviation/Term
Definition
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
HR
Hazard ratio
HrQoL
Health-related Quality of Life
IA1
Interim analysis 1
IA2
Interim analysis 2
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IHC
Immunohistochemistry
INR
International Normalized Ratio
IO
Immuno-oncology
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention-To-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NA
North America
N/A
Not Applicable
NCI
National Cancer Institute
NPV
Negative Predictive Value
NSAID
Nonsteroidal Anti-inflammatory Drug
NSCLC
Nonsmall Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PBPK
Physiologically based pharmacokinetic 
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Abbreviation/Term
Definition
PD-1/L-1
Programmed death-1/programmed death ligand-1
PD
Progressive Disease
PFS
Progression-Free Survival
PGt
Pharmacogenetic
PH
Proportional Hazard
PI
Principal Investigator
PIN
Personal Identification Number
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic
PO
Oral Administration
PPV
Positive Predictive Value
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
ROW
Rest of World
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SmPC
Summary of Product Characteristics
SOC
Standard of Care
sSAP
Supplemental statistical analysis plan
SOP
Standard Operating Procedures
TPS
Tumor Proportion Score
TRAE
Treatment-related Adverse Event
TSH
Thyroid-Stimulating Hormone
TTD
Time to Deterioration
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell
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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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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html).
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RECIST 1.1 Criteria for Evaluating Response in Solid Tumors
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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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 – 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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