Conditions: Head and Neck Squamous Cell Cancer
Keywords: Squamous cell carcinoma Head and neck carcinoma Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1) Programmed Cell Death Receptor Ligand 2 (PDL2, PD-L2)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 495
Healthy volunteers: no

Brief summary:
This is a study of pembrolizumab (MK-3475, KEYTRUDA®) versus standard treatment (methotrexate, docetaxel or cetuximab) for the treatment of recurrent or metastatic head and neck squamous cell cancer (HNSCC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment. The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.

Detailed description:

Arms:
arm 1: Participants will receive pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle for up to approximately 24 months. Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab for up to approximately 1 additional year at the investigator's discretion. arm 2: Participants will receive standard treatment of either methotrexate 40 mg/m\^2 IV (may be escalated to 60 mg/m\^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle; or docetaxel 75 mg/m\^2 IV on Day 1 of each 3- week cycle; or cetuximab 400 mg/m\^2 IV loading dose on Day 1 and 250 mg/m\^2 IV on Days 8 and 15 of Cycle 1, followed by cetuximab 250 mg/m\^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

Interventions: intervention 1: Pembrolizumab intervention 2: Methotrexate intervention 3: Docetaxel intervention 4: Cetuximab
Intervention descriptions: intervention 1: 200 mg intravenous (IV) on Day 1 of each 3-week cycle. intervention 2: 40 mg/m\^2 IV (may be escalated to 60 mg/m\^2 maximum dose) on Days 1, 8, and 15 of each 3-week cycle intervention 3: 75 mg/m\^2 IV on Day 1 of each 3- week cycle intervention 4: 400 mg/m\^2 IV loading dose on Day 1 and 250 mg/m\^2 IV on Days 8 and 15 of Cycle 1, followed by 250 mg/m\^2 on Days 1, 8, and 15 of each subsequent 3-week cycle.

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase III Randomized Trial of MK-3475 
(Pembrolizumab) versus Standard Treatment in 
Subjects with Recurrent or Metastatic Head and 
Neck Cancer
NCT02252042
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase III Randomized Trial of MK-3475 (Pembrolizumab) versus Standard Treatment in 
Subjects with Recurrent or Metastatic Head and Neck Cancer
IND NUMBER:  122,325
EudraCT NUMBER:  2014-001749-26
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es).............................................................. 17
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
Pre-clinical Studies ............................................................................................. 20
Ongoing Clinical Trials....................................................................................... 21
Information on Other Trial-Related Therapy...................................................... 22
Rationale................................................................................................................ 23
Rationale for the Trial and Selected Subject Population .................................... 23
Rationale for Dose Selection/Regimen/Modification......................................... 24
Rationale for Endpoints ...................................................................................... 25
4.2.3.1
Efficacy Endpoints....................................................................................... 25
4.2.3.1.1
Primary.................................................................................................. 25
4.2.3.2
Modified RECIST........................................................................................ 26
4.2.3.3
Patient Reported Outcomes.......................................................................... 27
4.2.3.3.1
eEORTC QLQ-C30 and eEORTC QLQ-H&N35 ................................ 27
4.2.3.3.2
eEuroQuol EQ-5D ................................................................................ 28
4.2.3.3.3
Health Economic Assessment............................................................... 28
4.2.3.4
Planned Exploratory Biomarker Research................................................... 29
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4.2.3.5
Future Biomedical Research........................................................................ 30
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
Diagnosis/Condition for Entry into the Trial...................................................... 31
Subject Inclusion Criteria.................................................................................... 31
Subject Exclusion Criteria .................................................................................. 34
Trial Treatment(s) ................................................................................................ 36
Dose Selection/Modification .............................................................................. 37
5.2.1.1
Dose Selection (Preparation) ....................................................................... 37
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 37
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 37
5.2.1.2.2
Dose 
Modification 
for 
Standard 
Treatment 
Methotrexate, 
Docetaxel, or Cetuximab ...................................................................... 44
Specific Dose Modifications for Docetaxel ................................... 48
Specific Dose Modifications for Methotrexate .............................. 50
Specific Dose Modifications for Cetuximab.................................. 50
Timing of Dose Administration.......................................................................... 51
5.2.2.1
Pembrolizumab ............................................................................................ 52
5.2.2.2
Methotrexate ................................................................................................ 52
5.2.2.3
Docetaxel ..................................................................................................... 52
5.2.2.4
Cetuximab.................................................................................................... 52
Trial Blinding/Masking....................................................................................... 53
Randomization or Treatment Allocation............................................................ 53
Stratification.......................................................................................................... 53
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 53
Acceptable Concomitant Medications ................................................................ 54
Prohibited Concomitant Medications.................................................................. 54
Rescue Medications & Supportive Care............................................................. 56
Supportive Care Guidelines for Pembrolizumab ................................................ 56
Supportive Care Guidelines for Methotrexate .................................................... 60
Supportive Care Guidelines for Docetaxel ......................................................... 60
Supportive Care Guidelines for Cetuximab........................................................ 60
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Diet/Activity/Other Considerations..................................................................... 61
Diet...................................................................................................................... 61
Contraception...................................................................................................... 61
Use in Pregnancy ................................................................................................ 63
Use in Nursing Women....................................................................................... 63
Subject Withdrawal/Discontinuation Criteria................................................... 63
Treatment after Initial Radiologic Progression................................................... 64
Discontinuation of Study Therapy after CR ....................................................... 66
Subject Replacement Strategy............................................................................. 66
Beginning and End of the Trial ........................................................................... 66
Clinical Criteria for Early Trial Termination ................................................... 66
6.0
TRIAL FLOW CHART ........................................................................................... 67
Initial Treatment Phase........................................................................................ 67
Pembrolizumab Arm........................................................................................... 67
Standard Treatment Arm – Subjects Receiving Methotrexate, Docetaxel, or 
Cetuximab........................................................................................................... 71
Second Course Phase (Retreatment) for Pembrolizumab Arm Only.............. 78
7.0
TRIAL PROCEDURES ........................................................................................... 80
Trial Procedures ................................................................................................... 80
Administrative Procedures.................................................................................. 80
7.1.1.1
Informed Consent......................................................................................... 80
7.1.1.1.1
General Informed Consent.................................................................... 80
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 81
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 81
7.1.1.3
Subject Identification Card .......................................................................... 81
7.1.1.4
Medical History ........................................................................................... 81
7.1.1.4.1
Disease Details...................................................................................... 81
7.1.1.5
Prior and Concomitant Medications Review............................................... 81
7.1.1.5.1
Prior Medications.................................................................................. 81
Prior Treatment Details for Head and Neck Cancer ...................... 81
7.1.1.5.2
Concomitant Medications..................................................................... 82
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Subsequent Anti-Cancer Therapy Status........................................ 82
7.1.1.6
Assignment of Screening Number............................................................... 82
7.1.1.7
Assignment of Randomization Number....................................................... 82
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 82
Clinical Procedures/Assessments........................................................................ 83
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 83
7.1.2.2
Physical Exam.............................................................................................. 83
7.1.2.2.1
Full Physical Exam ............................................................................... 83
7.1.2.2.2
Directed Physical Exam........................................................................ 83
7.1.2.3
Vital Signs.................................................................................................... 84
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 84
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 84
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 84
7.1.2.6.1
Initial Tumor Imaging........................................................................... 85
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 85
7.1.2.6.3
Assessment of Disease.......................................................................... 85
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling......................... 86
7.1.2.8
Patient Reported Outcomes (PROs)............................................................. 87
Laboratory Procedures/Assessments .................................................................. 87
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 87
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 89
7.1.3.2.1
Blood Collection for Serum MK-3475 ................................................. 89
7.1.3.2.2
Blood Collection for Anti-Pembrolizumab Antibodies........................ 89
7.1.3.3
Future Biomedical Research........................................................................ 89
Other Procedures................................................................................................. 89
7.1.4.1
Withdrawal/Discontinuation........................................................................ 89
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 90
7.1.4.2
Blinding/Unblinding .................................................................................... 90
7.1.4.3
Calibration of Critical Equipment................................................................ 90
Visit Requirements.............................................................................................. 90
7.1.5.1
Screening...................................................................................................... 91
7.1.5.2
Treatment Period.......................................................................................... 91
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7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 91
7.1.5.3
Post-Treatment Visits................................................................................... 92
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 92
7.1.5.3.2
Follow-up Visits ................................................................................... 93
7.1.5.3.3
Survival Follow-up ............................................................................... 93
7.1.5.4
Survival Status ............................................................................................. 93
Assessing and Recording Adverse Events .......................................................... 93
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 94
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 95
Immediate Reporting of Adverse Events to the Sponsor.................................... 95
7.2.3.1
Serious Adverse Events ............................................................................... 95
7.2.3.2
Events of Clinical Interest............................................................................ 96
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 98
Evaluating Adverse Events................................................................................. 98
Sponsor Responsibility for Reporting Adverse Events .................................... 101
TRIAL GOVERNANCE AND OVERSIGHT................................................. 101
Scientific Advisory Committee......................................................................... 101
Executive Oversight Committee....................................................................... 101
Data Monitoring Committee............................................................................. 101
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 101
Statistical Analysis Plan Summary ................................................................... 102
Efficacy Analyses ............................................................................................. 102
Safety Analyses................................................................................................. 102
Power and Sample Size..................................................................................... 103
Interim Analysis................................................................................................ 103
Statistical Analysis Plan ..................................................................................... 103
Responsibility for Analyses/In-House Blinding ............................................... 103
Hypotheses/Estimation ..................................................................................... 104
Analysis Endpoints ........................................................................................... 104
8.2.3.1
Efficacy Endpoints..................................................................................... 104
8.2.3.2
Safety Endpoints........................................................................................ 106
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Analysis Population .......................................................................................... 106
8.2.4.1.1
Efficacy Analysis Population.............................................................. 106
8.2.4.1.2
Safety Analysis Populations ............................................................... 106
Statistical Methods............................................................................................ 107
8.2.5.1
Statistical Methods for Efficacy Analyses................................................. 107
8.2.5.1.1
Overall Survival (OS) ......................................................................... 107
8.2.5.1.2
Progression-Free Survival (PFS) ........................................................ 108
8.2.5.1.3
Objective Response Rate (ORR) ........................................................ 110
8.2.5.1.4
Duration of Response.......................................................................... 110
8.2.5.1.5
Exploratory analyses........................................................................... 110
8.2.5.2
Statistical Methods for Safety Analyses .................................................... 113
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 114
Multiplicity ....................................................................................................... 115
Sample Size and Power Calculation ................................................................. 117
Subgroup Analyses and Effect of Baseline Factors.......................................... 117
Interim Analysis................................................................................................ 118
Compliance (Medication Adherence)............................................................... 120
Extent of Exposure............................................................................................ 120
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 120
Investigational Product ...................................................................................... 120
Packaging and Labeling Information ............................................................... 121
Clinical Supplies Disclosure............................................................................... 121
Storage and Handling Requirements................................................................ 121
Returns and Reconciliation................................................................................ 121
Standard Policies................................................................................................. 122
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 122
Confidentiality..................................................................................................... 122
Confidentiality of Data ..................................................................................... 122
Confidentiality of Subject Records................................................................... 122
Confidentiality of Investigator Information...................................................... 122
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Confidentiality of IRB/IEC Information........................................................... 123
Compliance with Financial Disclosure Requirements..................................... 123
Compliance with Law, Audit and Debarment ................................................. 124
Compliance with Trial Registration and Results Posting Requirements...... 125
Quality Management System............................................................................. 126
Data Management............................................................................................... 126
Publications ......................................................................................................... 126
11.0
LIST OF REFERENCES....................................................................................... 127
12.0
APPENDICES......................................................................................................... 132
Merck Code of Conduct for Clinical Trials...................................................... 132
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 134
Understanding the
Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 140
Abbreviations ...................................................................................................... 151
ECOG Performance Status................................................................................ 155
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 156
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 157
List of Strong CYP3A4 Inhibitors..................................................................... 158
13.0
SIGNATURES......................................................................................................... 159
Sponsor's Representative ................................................................................... 159
Investigator.......................................................................................................... 159
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 33
Table 2
Trial Treatments...................................................................................................... 36
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations...................................................................... 38
Table 4
Hematological Toxicity Management Guidelines for Pembrolizumab .................. 43
Table 5
Dose Modification Guidelines for Drug-Related Adverse Events on the 
Standard Treatment Arm........................................................................................ 45
Table 6
Docetaxel Dose Modification for Drug-Related Adverse Events .......................... 49
Table 7
Cetuximab Dose Modification for Rash and Keratitis............................................ 51
Table 8
Infusion Reaction Treatment Guidelines ................................................................ 59
Table 9
Imaging and Treatment After Site-Assessed 1st Radiologic Evidence of PD........ 65
Table 10 Laboratory Tests ..................................................................................................... 88
Table 11 Evaluating Adverse Events..................................................................................... 99
Table 12 Censoring rules for Primary and Sensitivity Analyses of PFS ............................. 110
Table 13 Efficacy Analysis Methods for Primary and Key Secondary Efficacy 
Endpoints.............................................................................................................. 112
Table 14 Analysis Strategy for Safety Parameters .............................................................. 114
Table 15 Summary of Sample size and Decision Guidance at the Interim and Final OS 
Analyses by Design.............................................................................................. 119
Table 16 Summary of Actual Boundaries at Interim and Expected Boundaries at Final 
Analyses with Extended Follow-up ..................................................................... 120
Table 17 Product Descriptions............................................................................................. 121
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LIST OF FIGURES
Figure 1 Trial Diagram.......................................................................................................... 16
Figure 2 Primary and Key Secondary Hypotheses................................................................ 18
Figure 3 Imaging Process...................................................................................................... 26
Figure 4 Type I Error Reallocation Strategy Following Closed Testing Principle............. 116
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-040-14
03-Nov-2021
Added language to allow participants to rollover to a pembrolizumab extension 
study
3475-040-13
21-Apr-2021
To update the dose modification and toxicity management guidelines for irAEs.
3475-040-12
12-Jan-2018
Added guidelines for management of myocarditis.
3475-040-11
02-Nov-2016
Updated statistics section survival follow-up for conducting the primary efficacy 
analysis.
3475-040-10
10-Mar-2016
Decreased sample size due to higher prevalence of a biomarker group during 
enrollment.
3475-040-09
04-Mar-2016
Decreased sample size due to higher prevalence of a biomarker group during 
enrollment and updated statistics.
3475-040-08
16-Jul-2015
Updated methotrexate dose modifications to current SmPC.
3475-040-07
03-Apr-2015
Increased sample size to allow for PD-L1formal testing.
3475-040-06
16-Mar-2015
Increased sample size to allow formal PD-L1 testing and updated statistics.
3475-040-05
23-Mar-2015
Increased sample size to allow formal PD-L1 testing and updated statistics.
3475-040-04
02-Jan-2015
Revised imaging frequency in response to Germany HA.
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Document
Date of Issue
Overall Rationale
3475-040-03
26-Jan-2015
Revised contraception language and dose modification language in response to 
France HA.
3475-040-02
14-Dec-2014
Revised dose modification language in response to MHRA.
3475-040-01
27-Feb-2015
Increased sample size to allow formal PD-L1 testing and updated statistics.
3475-040-00
01-Aug-2014
NA
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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
Trial Summary
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 identified to 
rollover into an extension trial
2.2
Trial Diagram
Pembrolizumab extension trial 
after survival follow-up is 
added to the diagram
5.10
Beginning and End of the Trial
Added that upon trial 
completion, subjects are 
discontinued and may be 
enrolled in a pembrolizumab 
extension trial
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
5.1.2
5.10
6.1.1
6.1.2
7.1.1.1.2
7.1.1.3
Trial Summary
Participant Inclusion Criteria
Beginning and End of Trial
Pembrolizumab Arm
Standard 
Treatment 
Arm-Subjects 
Receiving 
Methotrexate, Docetaxel, 
or 
Cetuximab
Consent and Collection of 
Specimens for Future 
Biomedical Research
Subject Identification Card
Revised informed consent 
language to allow for 
documented informed consent
To allow for operational 
changes needed to 
accommodate the COVID-19 
pandemic and its impact on the 
informed consent process
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
6.1.1 
Pembrolizumab Arm
Corrected format of 
superscripts within the trial 
flow chart table
For clarity
Overall
Overall
Minor editorial/spelling and 
formatting changes
For clarity
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1.0 TRIAL SUMMARY
Abbreviated Title
Ph 3 Trial of MK-3475 (Pembrolizumab) vs. Standard Treatment in 
Recurrent/Metastatic Head and Neck Cancer
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
MK-3475 (also known as pembrolizumab) 200 mg every 3 weeks
Standard Treatment:
Methotrexate 40 mg/m2 once weekly (may be increased to a maximum of 60 
mg/m2 weekly in the absence of toxicity) or
Docetaxel 75 mg/m2 once every 3 weeks or
Cetuximab 400 mg/m2 loading dose and then 250 mg/m2 weekly
Number of trial subjects
Approximately 466 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 24 months
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Each subject will participate in the trial until death, discontinuation from the 
trial, or lost-to-follow-up from the time the subject provides documented 
informed consent through the final contact.  After a screening phase of 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 adverse 
event(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, noncompliance with trial 
treatment or procedures requirements, receives 24 months of study 
medication (pembrolizumab arm only), or administrative reasons.  Subjects 
on the pembrolizumab arm who attain a complete response 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 complete response and stop trial 
treatment may be eligible for up to one year of retreatment upon
experiencing disease progression.  The decision to retreat will be at the 
discretion of the investigator only if they meet the criteria for retreatment and 
the trial is ongoing.  After the end of treatment, each subject will be followed 
for 30 days for adverse event monitoring (serious adverse events [SAEs] will 
be collected for 90 days after the end of treatment).  Subjects who 
discontinue for reasons other than disease progression will have post-
treatment follow-up for disease status until disease progression, initiating a 
non-study 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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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 in 
subjects with advanced head and neck cancer to be conducted in conformance with Good 
Clinical Practices.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
This trial will use an adaptive design based on pre-specified criteria, using an independent, 
external Data Monitoring Committee (DMC) to monitor safety and efficacy.  
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1 Trial Diagram.
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
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
All Subjects
Objective:  To compare the overall survival (OS) in subjects with R/M HNSCC 
treated with pembrolizumab compared to standard treatment.
Hypothesis (H1):  Pembrolizumab prolongs OS in subjects with R/M HNSCC
compared to standard treatment.
Secondary Objective(s) & Hypothesis(es)
Key Secondary Objectives & Hypotheses
PD-L1 Positive Population: Subjects with PD-L1 positive expression defined by ≥1% 
Combined Positive Score (CPS), henceforth abbreviated as PD-L1 1% CPS
Objective:  To compare Overall Survival (OS) in subjects with R/M HNSCC treated 
with pembrolizumab compared to standard treatment. 
Hypothesis (H2):  Pembrolizumab prolongs OS in subjects with R/M 
HNSCC compared to standard treatment.
Objective:  To compare ORR per RECIST 1.1 as assessed by blinded independent 
radiology review in subjects with R/M HNSCC treated with pembrolizumab 
compared to standard treatment. 
Hypothesis (H4): Pembrolizumab increases ORR per RECIST 1.1 by blinded 
independent radiology review in subjects with R/M HNSCC compared to 
standard treatment.
Objective:  To compare PFS per RECIST 1.1 as assessed by blinded independent 
radiology review in subjects with R/M HNSCC treated with pembrolizumab 
compared to standard treatment. 
Hypothesis (H6): Pembrolizumab prolongs PFS per RECIST 1.1 by blinded 
independent radiology review in subjects with R/M HNSCC compared to 
standard treatment. 
All Subjects (regardless of PD-L1 expression)
Objective:  To compare ORR per RECIST 1.1 as assessed by blinded independent 
radiology review in subjects with R/M HNSCC treated with pembrolizumab 
compared to standard treatment. 
Hypothesis (H3): Pembrolizumab increases ORR per RECIST 1.1 by blinded 
independent radiology review in subjects with R/M HNSCC compared to 
standard treatment.
Objective:  To compare PFS per RECIST 1.1 as assessed by blinded independent 
radiology review in subjects with R/M HNSCC treated with pembrolizumab 
compared to standard treatment. 
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Hypothesis (H5): Pembrolizumab prolongs PFS per RECIST 1.1 by blinded 
independent radiology review in subjects with R/M HNSCC compared to 
standard treatment.
Figure 2 Primary and Key Secondary Hypotheses
Other Secondary Objectives & Hypotheses
The following objectives will be evaluated separately among (1) Subjects with PD-L1 1% 
CPS and (2) All Subjects Regardless of PD-L1 Expression.
Objective:  To evaluate the safety and tolerability profile of pembrolizumab.
Objective: To evaluate Time to Progression (TTP) per RECIST 1.1 and Duration of 
Response (DOR) per RECIST 1.1 by blinded independent radiology review in 
subjects with R/M HNSCC treated with pembrolizumab compared to standard 
treatment. 
Objective: To evaluate PFS per modified RECIST by blinded independent radiology 
review in subjects with R/M HNSCC treated with pembrolizumab compared to 
standard treatment.
Exploratory Objectives
1) Objective:  To compare OS, PFS per RECIST 1.1 as assessed by blinded 
independent radiology review, and ORR per RECIST 1.1 as assessed by blinded 
independent radiology review in subjects with strongly positive PD-L1 expression 
defined by ≥50% TPS in R/M HNSCC treated with pembrolizumab compared to 
standard treatment.
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2) Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline in subjects with R/M HNSCC using the EORTC QLQ C-30 and EORTC 
QLQ-H&N35.
3) Objective:  To characterize utilities in previously-treated subjects with R/M HNSCC
cancer using the EuroQol EQ-5D.
4) Objective:  To investigate the relationship between pembrolizumab treatment and 
biomarkers predicting response (e.g., PD-L1, genetic variation, serum sPD-L1) 
utilizing newly obtained or archival tumor tissue and blood, including serum and 
plasma.
5) Objective:  To evaluate the progression free survival by investigator review in the 
next line of therapy (PFS2) in subjects treated with pembrolizumab compared to 
standard treatment.
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 programmed cell death ligand 1 (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 Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (MK-3475, 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 
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superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon 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 non-hematopoietic tissues as well as in 
various tumors [1; 14; 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 non-hematopoietic 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 [14].  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.
Pre-clinical Studies
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 mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in 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].  Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a mono-therapy 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, non-small cell lung 
cancer, a number of advanced solid tumor indications 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 Ib study of 
pembrolizumab in patients with human papillomavirus (HPV)-negative and HPV-positive 
head and neck cancer.  This trial enrolled an initial 60 patient cohort with recurrent and/or 
metastatic squamous cell carcinoma of the head and neck for treatment with single agent 
pembrolizumab.  Preliminary results of this cohort were reported at Annual Meeting of the 
American Society of Clinical Oncology (ASCO) in 2014 [28], showing an overall response 
rate (confirmed and unconfirmed) of 19.6% (10 partial responses [PRs], 1 complete response 
[CR] out of 56 patients evaluable for response).  An additional 16/56 patients (28.6%) 
experienced stable disease (SD), with 51% of patients experiencing some numerical decrease 
in tumor burden from baseline.  Seventeen total patients with CR, PR, or SD remain on 
therapy at the time of the reporting for > 6 months.  There were no new or unexpected 
toxicity signals in this patient cohort, with infrequent grade 3-4 drug-related (DR) adverse 
events (AEs).
In general, pembrolizumab was well tolerated with 58.3% reporting a DR AE and 16.7% 
reporting a Grade 3-5 DR AE.  DR AEs with an incidence ≥ 5% were fatigue (10, 16.7%), 
pruritis (6, 10%), rash (5, 8.3%), nausea (4, 6.7%), decreased appetite (3, 5.0%), and myalgia 
(3, 5.0%).  Of these DR AEs, Grade 3-5 was seen in rash (2, 3.3%).  The reported pre-
specified AEs were adrenal insufficiency (1, 1.7%); diarrhea (1, 1.7%); pruritis (1, 1.7%); 
rash (2, 3.3%); rash, macular (1, 1.7%); pneumonitis (0); alanine aminotransferase (ALT) 
increase (2, 3.3%); and aspartate aminotransferase (AST) increase (2, 3.3%). There were no 
pembrolizumab reported grade 5 DR AEs [28].  Preliminary PD-L1 biomarker data from 
KEYNOTE 012 suggests that the response rate may be enhanced for patients with PD-L1 
IHC expression.  Using a Youden-Index derived PD-L1 IHC cutpoint of 50% tumor 
proportion score (TPS), the response rate (RR) in patients with high PD-L1 expression was 
45.5%, compared to 11.4% in low PD-L1 expression patients.
More recently, when analyzed for durability of response, evolving information show that PD-
L1 expression with a 1% cut-off (≥1%) for IHC testing, using a combined positive score 
(CPS) that accounts for PD-L1 expression in both tumor and infiltrating immune cells may 
be a better predictor of response to pembrolizumab. When analyzed by PD-L1 1% CPS 
positive in the KEYNOTE 012, median PFS and OS were longer for those with demonstrable 
evidence of PD-L1 expression in either tumor or infiltrating immune cells. Importantly, using 
a cut-off of 1% CPS to define PD-L1 positive tumors, 81.1% of the KEYNOTE 012 
metastatic/recurrent HNSCC tumors were PD-L1 positive, with observed objective response 
rates of 21.5% for patients with PD-L1 positive tumors and 4% for patients with PD-L1 
negative tumors. Therefore, based on the evolving information obtained from further analysis 
of the KEYNOTE 012 study, we will plan to evaluate PD-L1 expression using a 1% CPS 
cut-off in addition to the 50% TPS previously specified. We will continue the stratification of 
randomization according to the 50% TPS cut-off as already ongoing, and will plan to 
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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 clinical trial as we remain blinded 
to the ongoing KEYNOTE 040 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
The proposed choice of single agent methotrexate, single agent docetaxel, or single agent 
cetuximab as the standard of care control arm is based on currently approved products in 
head and neck cancer, common usage in the second line setting, input from key opinion 
leaders, and prior precedence in 2nd line (2L) registration trials. 
Methotrexate has a registered indication for usage as a single agent in the treatment of 
epidermoid cancers of the head and neck. It has been the most common comparator standard 
historically for recurrent/metastatic head and neck cancer. For example, randomized studies 
evaluating gefitinib [29], edatrexate [30], and platin-based doublet chemotherapy [31] in 
recurrent/metastatic head and neck cancer have all utilized methotrexate as the comparator 
arm. Contemporary studies including the recently completed phase III trial of afatinib in 
recurrent/metastatic head and neck cancer continue to use methotrexate as the 
comparator. However, its usage in the head and neck cancer community outside of a clinical 
trial is more limited, so other standard of care options are provided for this trial.
Docetaxel has a registered indication in squamous cell carcinoma of the head/neck for locally 
advanced disease in combination with cisplatin and 5-fluorouracil. However, it is commonly 
given in the recurrent/metastatic setting as a single agent with response rates (RR) ranging 
from 6-42%, depending on the line of therapy and patient population.
For example, 
significant clinical activity of weekly docetaxel in a phase II study of 38 subjects was seen 
with a response rate of 42% in the 1L (1st line) recurrent/metastatic setting [32]. In addition, 
a randomized phase II study of weekly docetaxel vs. methotrexate showed a higher response 
rate for docetaxel (27%) in the 1L recurrent/metastatic setting, although survival rates were 
comparable [33]. Phase III studies using weekly docetaxel as the control arm in the 1L/2L 
setting have also been performed, confirming the activity of docetaxel in the predominantly 
2L setting, although RRs were more modest at 6.2% [34]. Thus single agent docetaxel on a 
weekly schedule has been shown to have activity in recurrent/metastatic disease, and is 
utilized particularly in head and neck cancer subjects who have not been previously exposed 
to taxanes.  
Cetuximab has a registered indication for the treatment of recurrent or metastatic squamous 
cell carcinoma of the head and neck progressing after platinum-based therapy. In an open-
label phase II study of 103 recurrent/metastatic head and neck cancer subjects treated with 
single agent cetuximab after failing to respond to platinum-based therapy, the response rate 
was 13% [35]. The activity of single agent cetuximab in recurrent/metastatic disease has also 
been seen in other studies, with response rates of 8-11% [36].
Therefore, these 3 agents will be used as standard treatment options in the comparator arm of 
this study.  This allows the investigator to select from 3 options for subjects randomized to 
the standard therapy arm. When choosing a standard therapy, the investigator should refer to
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the 
Summary 
of 
Product 
Characteristics 
(with 
special 
consideration 
for 
any
contraindications, special warnings and precautions of use), and/or according to local 
guidelines.
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 [37]. And although 
the head and neck region contains a wide diversity of structures and cell types, the vast 
majorities of head and neck cancers arise from the mucosa of the upper aerodigestive tract 
and are predominantly squamous cell in origin.  
Subjects with locally recurrent and metastatic head and neck cancer present a therapeutic 
challenge.
And although both conventional cytotoxic drugs and molecularly targeted 
compounds have activity in metastatic and recurrent head and neck cancer, the prognosis of 
subjects with recurrent or metastatic head and neck squamous cell cancer is generally poor 
despite these therapies. The median survival in most series is 6-9 months with limited 
treatment options and substantial morbidity. Single agent therapy and combination regimens 
using either conventional cytotoxic chemotherapy and/or molecularly targeted agents, 
combined with best supportive care is palliative for subjects with recurrent head and neck 
cancer. The most widely used agents include platinum compounds (cisplatin, carboplatin), 
taxanes (docetaxel, paclitaxel), methotrexate, 5-fluorouracil, and cetuximab.  
After failure of first-line chemotherapy in the recurrent/metastatic setting, objective 
responses to second-line cytotoxic chemotherapy are uncommon, particularly when 
contemporary response criteria are applied. For example, a phase III trial comparing weekly 
intravenous methotrexate with gefitinib, an epidermal growth factor receptor tyrosine kinase 
inhibitor in a heavily pretreated population resulted in an overall response rate to 
methotrexate of 4 percent in 152 subjects, with a median overall survival of 6.7 months 
[29]. Other single agents have produced higher response rates but this has generally been 
associated with increased toxicity, and without an impact on survival. 
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 [38].  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. Site or central assessment of HPV using 
immunohistochemistry (IHC) staining for the p16 protein will be used for this population 
prior to randomization.
Details regarding specific benefits and risks for subjects participating in this clinical trial can
be found in the accompanying IB and Informed Consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
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Rationale for Dose Selection/Regimen/Modification
An open-label Phase I trial (KEYNOTE 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475).  The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
pembrolizumab (MK-3475) showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has 
been identified.
In KEYNOTE 001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab (MK-3475) at a dose of 2 mg/kg versus 10 mg/kg Q3W have been 
completed, and one randomized cohort evaluating of 10 mg/kg Q3W versus 10 mg/kg Q2W 
has also been completed.  The clinical efficacy and safety data demonstrate a lack of 
clinically important differences in efficacy response or safety profile at these doses.  For 
example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab 
therapy were randomized to receive pembrolizumab (MK-3475) at 2 mg/kg versus 10 mg/kg 
Q3W.  The ORR was 26% (21/81) in the 2 mg/kg group and 26% (20/76) in the 10 mg/kg 
group (FAS).  The proportion of subjects with drug-related AE, grade 3-5 drug-related AE, 
serious drug-related AE, death or discontinuation due to an AE was comparable between 
groups or lower in the 10 mg/kg group.  In Cohort B3, advanced melanoma subjects 
(irrespective of prior ipilimumab therapy) were randomized to receive pembrolizumab (MK-
3475) at 10 mg/kg Q2W versus 10 mg/kg Q3W.  The ORR was 30.9% (38/123) in the 
10mg/kg Q2W group and 24.8% (30/121) in the 10 mg/kg Q3W group (APaT).  The 
proportion of subjects with drug-related AE, grade 3-5 drug-related AE, serious drug-related 
AE, death or discontinuation due to an AE was comparable between groups.
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q3W dosing schedule.  Because Q3W dosing is more convenient for patients, 
Q3W dosing will be further studied.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
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with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary
Overall survival (OS) is the gold standard endpoint to demonstrate superiority of 
antineoplastic therapy.  Progression free survival (PFS) may be considered an acceptable 
scientific endpoint for a randomized phase III trial to demonstrate superiority of a new 
antineoplastic therapy as a number of ongoing randomized trials in recurrent/metastatic head 
and neck cancer have used PFS as a primary endpoint.  RECIST 1.1 will be used to 
determine the dates of progression as this methodology is accepted by regulatory authorities
(see Section 12.7).  Because the treatment assignment is unblinded, images will be read by 
independent central radiologists blinded to treatment assignment to minimize bias in the 
response assessments.  In addition, radiologic progression will be based on the central 
assessment of progression, rather than site assessment.  Expedited verification of radiologic 
progression as determined by central review (following site assessment of progression) will 
be communicated to the site.  
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Figure 3 shows the process for tumor assessment by site and central imaging vendor.
Figure 3 Imaging Process
Note: See Site Imaging Manual regarding timing for submission of verification of 
progression scans and for all other study imaging.
4.2.3.2
Modified RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of MK-3475. Immunotherapeutic agents such as MK-3475 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 MK-3475.   
Therefore, RECIST 1.1 will be used with the following adaptations:
If independent central assessment (following initial site-assessed PD) verifies PD, tumor 
assessment should 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 demonstrates ≥ 20% increase in tumor burden compared to 
nadir and an absolute increase in 5mm, PD is confirmed and subjects will be discontinued 
from study therapy (exception noted in section 7.1.2.6.3).  For additional scenarios regarding 
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new lesions and non-target disease, see Procedures Manual. NOTE: If a subject has 
confirmed radiographic progression (i.e. 2 scans at least 28 days apart demonstrating 
progressive disease) is clinically stable or clinically improved, and there is no further 
increase in the tumor dimensions at the confirmatory scan, an exception may be considered 
to continue treatment upon consultation with the Sponsor.
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions (please refer to the Imaging 
section of the Procedures Manual).
In subjects who have a verification of radiological PD by central imaging vendor (following 
site-assessed PD), 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 MK-3475 or standard treatment 
(control arm) 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 performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
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 
progressive disease. 
It must be emphasized that subjects remain on treatment if clinically stable until RECIST 1.1 
defined progression is verified by blinded independent central radiology for both the 
experimental and control arms of the study, and that the schedule of assessments be adhered 
to. If study therapy is discontinued for toxicity but the subject is otherwise stable, the subject 
should continue radiologic assessments as indicated in the flow chart until RECIST 1.1 
defined progression has been established or the subject starts a new anti-cancer therapy.  
4.2.3.3
Patient Reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-H&N35, EQ-5D and Health Economic Assessment 
are not pure efficacy or safety endpoints because they are affected by both disease 
progression and treatment tolerability. 
4.2.3.3.1 eEORTC QLQ-C30 and eEORTC QLQ-H&N35
The EORTC-QLQC30 is the most widely used cancer specific HRQoL instrument, which 
contains 30 items and measures five functional dimensions (physical, role, emotional, 
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cognitive and social), three symptom items (fatigue, nausea/vomiting, and pain), six single 
items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), 
and a global health and quality of life scale [39].
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 [40, 41] 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 [42].  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 metastatic 
squamous cell carcinoma of the head and neck (SCCHN), which led to the FDA approval of 
cetuximab monotherapy in subjects with recurrent or metastatic SCCHN refractory to 
cisplatin [43, 44].  They were also used in the phase III trial of subjects with locoregionally 
advanced head and neck cancer receiving radiotherapy alone with radiotherapy plus 
cetuximab [45].
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 post-treatment 
discontinuation.
4.2.3.3.2 eEuroQuol EQ-5D
The eEuroQol-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 QALYs.  The five health state dimensions in this instrument 
include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression (5).  Each dimension is rated on a three 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 
eEORTC QLQ C-30 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 post-treatment 
discontinuation.
4.2.3.3.3 Health Economic Assessment
The Health Economic Assessment (HEA) form will be completed via an interview with the 
subject by qualified site personnel. The objective of the HEA is for the site personnel to 
collect information from subjects on all the non-study related health care contacts made 
throughout the trial. The HEA is to be completed at various time points as specified in the 
Trial Flow Chart, beginning with Cycle 2 until 30 days post-treatment discontinuation.
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4.2.3.4
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 be limited to:
Immunohistochemistry (IHC)
PD-L1 expression in tumor tissue will be characterized by commercial grade IHC assay to 
explore the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab. Heterogeneous PD-L2 expression has been demonstrated on tumor cells as 
well as stromal cells and associated endothelium that may have independent predictive value 
from PD-L1 expression in head and neck cancer. Pilot analysis of PD-L2 expression by a lab-
developed IHC assay tested in the KEYNOTE 012 B and B2 HNSCC cohorts suggest that 
PD-L2 expression may independently predict clinical benefit of pembrolizumab in tumors 
absent for PD-L1 expression [46]. Therefore, other biomarkers contributing to the PD-1/PD-
L1 axis, including testing for PD-L2 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 further evaluate gene expression 
signatures found to be statistically significantly associated with clinical response to 
pembrolizumab in KEYNOTE 012 B [47] and have also been confirmed independently in the 
B2 HNSCC cohorts to show highly statistically significant associations. These signatures 
contain genes believed to capture a key inflammatory phenotype of an ongoing adaptive 
immune response including IFNγ signaling, cytolytic activity, antigen presentation and T-cell 
trafficking, as well as inhibitory mechanisms that are evident in T-cell homeostasis. The 
hypothesis to be tested in this trial is that pembrolizumab induces responses in tumors that 
reflect an inflamed/immune phenotype
as 
captured by 
such 
gene expression 
signatures. Global profiling will also be pursued. Expression of individual genes of interest 
related to the immune system may also be evaluated. 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 
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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 non-response.  
In addition, 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 adverse events, the data might inform optimal 
use of therapies in the patient population.
4.2.3.5
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 Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
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/PD 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 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
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5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with recurrent or metastatic (R/M) head and neck squamous cell 
carcinoma (HNSCC) of at least 18 years of age will be enrolled in this trial. Note: When 
selecting a standard treatment regimen prior to randomization, investigators should consider 
contraindications, special warnings, and precautions of use that are specific for the treatment. 
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide documented informed consent for the trial.  The 
subject may also provide consent for Future Biomedical Research.  However, the 
subject may participate in the main trial without participating in Future Biomedical 
Research.
2. Be 18 years of age on the day of providing documented informed consent.
3. Have histologically or cytologically-confirmed recurrent (recurrent disease that is not 
amenable to curative treatment with local and/or systemic therapies) or metastatic
(disseminated) head and neck squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx, and larynx that is considered incurable by local therapies.  
Subjects may not have any other primary tumor site (e.g. nasopharynx).
4. Prior platinum failure as defined by, either:
a.
Disease progression after treatment with a platinum-containing regimen for 
recurrent (disease not amenable to curative treatment)/metastatic disease 
Note:  Disease progression may occur at any time during or after a platinum-
containing regimen (e.g. carboplatin or cisplatin) which was administered in 
either 1L or 2L in the recurrent/metastatic setting.
OR
b. Recurrence/progression within 6 months of prior multimodal therapy using 
platinum (e.g. locally advanced setting)
5. Have results from local testing of HPV positivity for oropharyngeal cancer defined as 
p16 IHC testing using the CINtec® assay and a 70% cutoff point.  Please see Section 
7.1.2.7 for details.  If HPV status has previously been tested using this procedure, no 
retesting is required.
Note:  HPV stratification in this trial will be performed using local or central 
testing of HPV status in patients with oropharynx cancer.  Oral cavity, 
hypopharynx, and larynx cancer are not required to undergo HPV testing by 
p16 IHC as by convention they are assumed to be HPV negative.
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6. Have provided tissue for PD-L1 biomarker analysis – and received the PD-L1 results 
– (PD-L1 analysis will be blinded to both site and sponsor) from a newly obtained 
core or excisional biopsy. (Tissue beyond the 42-day window and up to 6 months
may be considered with Sponsor consultation as long as no intervening systemic 
regimen has been taken.) Repeat samples may be required if adequate tissue is not 
provided.
Note:  Patients for whom newly obtained samples cannot be obtained (e.g. 
inaccessible or patient safety concern) may submit an archived specimen only 
upon agreement from the Sponsor.
Note:  If emerging data indicate a high concordance in PD-L1 expression scores 
between newly obtained and archival samples, archived samples may be 
acceptable.
7. Have radiographically 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.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale, as assessed 
within 10 days of treatment initiation.
9. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.
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Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal
Creatinine OR
Measured or calculated creatinine clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5x upper limit of normal (ULN) 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)
≤1.5xULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use 
of anticoagulants
Activated Partial Thromboplastin Time 
(aPTT)
≤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.
10. Female subjects of childbearing potential should have a negative serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication.  A urine test 
can be considered if a serum test is not appropriate.
11. 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 120 days after the last dose of pembrolizumab (Reference Section 
5.7.2) or through 120-180 days after the last dose of docetaxel, methotrexate or 
cetuximab, according to local standard of care.  Subjects of childbearing potential are 
those who have not been surgically sterilized or have not been free from menses for > 
1 year.
Note: For UK subjects: 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 120 days after the last dose of study 
medication (and specifically through 180 days after the last dose of docetaxel or 
methotrexate) (Reference Section 5.7.2). Subjects of childbearing potential are those 
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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, established and/or
preferred contraception for the subject.
12. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of pembrolizumab
or through 120-180 days after the last dose of docetaxel, methotrexate or cetuximab, 
according to local standard of care.
Note: For France subjects: Male subjects should agree to use an adequate method of 
contraception starting with the first dose of study therapy through 120 days after the 
last dose of study therapy (and specifically through 180 days after the last dose of 
docetaxel). 
Note: For UK subjects: Male subjects should agree to use an adequate method of 
contraception starting with the first dose of study therapy through 120 days after the 
last dose of study therapy (and specifically through 180 days after the last dose of 
docetaxel or methotrexate).
Note: Abstinence is acceptable if this is the usual lifestyle, established and/or
preferred 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. Had progressive disease within three months of completion of curatively intended 
treatment for locoregionally advanced or recurrent HNSCC.  
Note: This exclusion criterion is only applicable for subjects who have not had 
treatment in the metastatic/recurrent setting.
3. Is currently participating in and receiving study therapy or has participated in a study 
of an investigational agent and received study therapy or used an investigational 
device within 4 weeks prior to randomization.
Note: Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent or device.
4. Was previously treated with 3 or more systemic regimens given for recurrent and/or 
metastatic disease.
5. Patients previously treated in the recurrent/metastatic setting or resistant in the locally 
advanced setting to one of the 3 standard of care agents in this trial (i.e. docetaxel, 
methotrexate, or cetuximab) may not receive the same agent if randomized to the 
standard treatment arm (see Section 5.2 for details).  
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 
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treatment.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.  
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier.
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.
Note:  Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia 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.  
9. 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 and/or curatively resected in situ cervical 
and/or breast cancers.
10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
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.
11. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.
12. Has active, non-infectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. 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.  
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
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17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or has 
previously participated in Merck MK-3475 clinical trials.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
20. Has received a live vaccine within 30 days of planned start of study therapy.  
Trial Treatment(s)
The treatments to be used in this trial are outlined below in .
Table 2
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each cycle 
(3 week cycles)
Experimental 
Methotrexate*
40 mg/m2
(may be 
increased to a 
maximum of 
60 mg/m2
weekly in the 
absence of 
toxicity – see 
Section 
5.2.2.2)
QW
IV infusion
Days 1, 8, and 15 of 
each cycle
(3 week cycles)
Active-
comparator
Docetaxel
75 mg/m2
Q3W
IV infusion
Day 1 of each cycle 
(3 week cycles)
Active-
comparator
Cetuximab
400 
mg/m2 
loading 
dose 
followed 
by 
250mg/m2 
QW
IV infusion
Days 1, 8 and 15 of 
each cycle
(3 week cycles)
Active-
comparator
*Methotrexate exits slowly from third space compartment (e.g. pleural effusions or ascites).  This results in a prolonged 
terminal plasma half-life and the potential for unexpected toxicities.  In patients with significant third space accumulations, 
it is advisable to evacuate the fluid before treatment.
Note:  Patients resistant to one of the 3 standard of care agents in this trial (i.e. docetaxel, 
methotrexate, or cetuximab) may not receive the same agent if randomized to the standard 
treatment arm.  
Prior resistance or failure to the standard of care agent is defined by:

Recurrence or progression of disease within 6 months of prior multimodal therapy 
using SOC agent (e.g. locally advanced setting)
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
Previously received a SOC containing regimen for recurrent/metastatic disease
Trial treatment should be given on the day of randomization, but up to 3 days after 
randomization is permitted.
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 (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.  
5.2.1.2
Dose Modification (Escalation/Titration/Other)
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 3.
Hematological Toxicity Management Guidelines for Pembrolizumab are provided in Table 4.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive 
treatment should begin if the irAEs are not controlled by corticosteroids.
2. Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve 
or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4. If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE 
decreased to ≤Grade 1 after corticosteroid taper.
irAEs
Toxicity Grade 
(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
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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
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
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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
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
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
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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
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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Table 4
Hematological Toxicity Management Guidelines for Pembrolizumab
Toxicity
Grade
Hold Treatment
Discontinue Subject
Hematological
Any Gr 2 and  
Gr 3 
neutropenia, 
thrombocyto-
penia and
anemia
Neutrophils recover to > 1000 
cells/mm3 
Platelets recover to > 75,000 
cells/mm3
Anemia resolves to Grade 1 or 
baseline
N/A
3 
All other AEs 
other than Gr 3 
neutropenia, 
thrombocyto-
penia and 
anemia
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose 
or inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
4
Neutrophils recover to > 1000 
cells/mm3 
Platelets recover to > 75,000 
cells/mm3
Anemia resolves to Grade 1 or 
baseline
Toxicity resolves to Grade 0-1
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Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the clinical database (the case report form).
In case toxicity does not resolve to Grade 0-1 within 12 weeks after the last infusion, trial 
treatment should be discontinued after consultation with the Sponsor.  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.  Dose interruptions of 
pembrolizumab for intolerable Grade 2 drug-related adverse events may be considered after 
consultation with the Sponsor. Patients who experience a 3rd occurrence of the same toxicity 
requiring dose modification must be discontinued from study medication.   For information 
on the management of adverse events, see Section 5.6.1.
5.2.1.2.2 Dose Modification for Standard Treatment Methotrexate, Docetaxel, or 
Cetuximab
In general, treatment with methotrexate, docetaxel, or cetuximab will be withheld for drug-
related Grade 4 hematologic toxicities and for non-hematologic toxicity Grade 3 and 
subsequent doses modified as per Table 5 below.  Dose modifications will be applied for all 
subsequent doses.  Specific dose modification guidance for docetaxel and cetuximab is found 
below in Sections 5.2.1.2.2.1 and 5.2.1.2.2.2.  Dose modifications for intolerable Grade 2 
drug-related adverse events may be considered after consultation with the Sponsor.  
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Table 5
Dose Modification Guidelines for Drug-Related Adverse Events on the 
Standard Treatment Arm 
Toxicity
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Neutropenia±
Grade 2, 
3
All
Hold 
treatment 
until neutrophils 
recover 
to 
> 
1000 cells/mm3
OR 
to 
>1500 
cells/mm3 
for 
UK and France+
N/A
N/A
Grade 4 
1st 
occurrence
Hold 
treatment 
until neutrophils 
recover 
to 
> 
1000 cells/mm3
OR 
to 
>1500 
cells/mm3 
for 
UK and France+
Restart 
treatment at:
Methotrexate:  
Decrease 
dose by 10 
mg/m2*
Docetaxel: 
60 mg/m2
Cetuximab: 
200 mg/m2
Toxicity 
does 
not 
resolve 
within 
12 
weeks of last 
infusion
Permanent 
discontinuation 
should 
be 
considered for 
any severe or 
life-threatening 
event
2nd 
occurrence
Hold 
treatment 
until neutrophils 
recover 
to 
> 
1000 cells/mm3
OR 
to 
>1500 
cells/mm3 
for 
UK and France+
Restart 
treatment at:
Methotrexate: 
Decrease 
dose by an 
additional 10 
mg/m2*
Docetaxel: 45 
mg/m2
Cetuximab: 
150 mg/m2
3rd 
occurrence
Yes
N/A
Yes
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Toxicity
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Thrombocytopenia
Grade 2, 
3
All
Hold treatment 
until platelets 
recover to > 
75,000 
cells/mm3
N/A
N/A
Grade 4
1st 
occurrence
Hold treatment 
until platelets 
recover to > 
75,000 
cells/mm3
Restart 
treatment at:
Methotrexate:  
Decrease 
dose by 10 
mg/m2*
Docetaxel: 
60 mg/m2
Cetuximab: 
200 mg/m2
Toxicity 
does 
not 
resolve 
within 
12 
weeks of last 
infusion
Permanent 
discontinuation 
should 
be 
considered for 
any severe or 
life-threatening 
event
2nd 
occurrence
Hold treatment 
until platelets 
recover to > 
75,000 
cells/mm3
Restart 
treatment at:
Methotrexate: 
Decrease 
dose by an 
additional 10 
mg/m2*
Docetaxel: 45 
mg/m2
Cetuximab: 
150 mg/m2
3rd 
occurrence
Yes
N/A
Yes
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Toxicity
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Anemia
Grade 2, 
3
All
Until anemia 
resolves to 
Grade 1 or 
baseline
N/A
N/A
Grade 4
1st 
occurrence
Until anemia 
resolves to 
Grade 1 or 
baseline
Restart 
treatment at:
Methotrexate:  
Decrease 
dose by 10 
mg/m2*
Docetaxel: 
60 mg/m2
Cetuximab: 
200 mg/m2
Toxicity 
does 
not 
resolve 
within 
12 
weeks of last 
infusion
Permanent 
discontinuation 
should 
be 
considered for 
any severe or 
life-threatening 
event
2nd 
occurrence
Until anemia 
resolves to 
Grade 1 or 
baseline
Restart 
treatment at:
Methotrexate: 
Decrease 
dose by an 
additional 10 
mg/m2*
Docetaxel: 45 
mg/m2
Cetuximab: 
150 mg/m2
3rd 
occurrence
Yes
N/A
Yes
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Toxicity
Grade
Occurrence
Hold Treatment
Dose 
Modification
Treatment 
Discontinuation
Non-
hematological 
toxicity and other 
hematological 
toxicity 
not 
described above
Exceptions 
for 
subjects receiving 
docetaxel 
and 
cetuximab 
noted 
in 
Section 
5.2.1.2.2.1 
and 
5.2.1.2.2.2 below.
Grade 1, 
2
All
No
None
N/A
Grade 3, 
4
1st 
occurrence
Yes, 
until 
toxicity resolves 
to Grade 0-1 or 
baseline
Restart 
treatment 
at**:
Methotrexate:  
Decrease 
dose by 10 
mg/m2*
Docetaxel: 60 
mg/m2
Cetuximab: 
200 mg/m2
Toxicity 
does 
not 
resolve 
within 
12 
weeks of last 
infusion
Permanent 
discontinuation 
should 
be 
considered for 
any severe or 
life-threatening 
event
2nd 
occurrence
Yes, 
until 
toxicity resolves 
to Grade 0-1 or 
baseline
Restart 
treatment at:
Methotrexate: 
Decrease 
dose by an 
additional 10 
mg/m2*
Docetaxel: 45 
mg/m2
Cetuximab: 
150 mg/m2
3rd 
occurrence
Yes
N/A
Yes
±     Docetaxel is contraindicated in subjects with neutrophil level <1500 mm3.
+      As per the Health Authority requests for these specific countries.
* For subjects receiving methotrexate at higher doses than 40 mg/m2, additional dose modifications 
may occur after consultation with the Sponsor
** Dose reduction is at physician discretion for grade 3 lab abnormalities without clinical significance
In cases where the toxicity does not resolve to Grade 0-1 within 12 weeks after the last 
infusion, trial treatment should be discontinued after consultation with the Sponsor.  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.  For 
information on the management of adverse events, see Section 5.6.1.
Specific Dose Modifications for Docetaxel
Docetaxel should not be given to subjects with bilirubin > ULN, or to subjects with AST 
and/or ALT > 1.5 x ULN with concomitant alkaline phosphatase (AP) >2.5 x ULN as 
subjects with laboratory values above these limits are at increased risk of serious adverse 
events [refer to local product label].  
Note: For UK subjects: subjects with impaired vision, representing a new change from 
baseline while on treatment (ophthalmic events ≥Grade 2), should have docetaxel treatment 
held and be referred promptly for an ophthalmology consultation.+
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Dose modifications for subjects receiving docetaxel are detailed below in Table 6.
Table 6
Docetaxel Dose Modification for Drug-Related Adverse Events
Toxicity
Grade
Occurrence
Hold 
Treatment
Dose 
Modification
Treatment 
Discontinuation
Liver 
dysfunction
AST/ALT 
>2.5 to ≤5 × 
ULN and AP 
≤2.5 × ULN, 
or AST/ALT 
>1.5 to ≤5 × 
ULN and AP 
>2.5 to ≤5 × 
ULN
Yes
Restart 
treatment at 
60 mg/m2
N/A
AST/ALT 
>5 × ULN 
and/or AP 
>5 × ULN
Yes
N/A
Discontinue 
upon onset
Peripheral 
Neuropathy
Grade 3, 4
Yes
N/A
Discontinue 
upon onset
Ophthalmic 
adverse 
events+
≥Grade 2
UK subjects: 
Yes and refer 
for 
ophthalmology 
consultation
N/A
Consult the 
Sponsor
Oral 
Mucositis
Grade 3, 4
1st 
occurrence
Hold until 
resolved
60 mg/m2
Treatment 
discontinuation 
should be 
considered
Grade 3, 4
2nd 
occurrence
Hold until 
resolved
45 mg/m2
Treatment 
discontinuation 
should be 
considered
3rd 
occurrence
Yes
N/A
Yes
+ As per specific UK Health Authority request.
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Specific Dose Modifications for Methotrexate
Renal Impairment
For Sweden subjects: subjects with renal impairment enrolled in the study and receiving 
methotrexate may need close monitoring and/or dose reduction.±
±As per specific Swedish Health Authority request. 
Colitis or Peptic Ulcer
For UK subjects: subjects with ≥grade 2 colitis or peptic ulcer symptoms should discontinue 
methotrexate treatment.+
+ As per specific UK Health Authority request.
Specific Dose Modifications for Cetuximab
Infusion Reactions
Subjects who experience Grade 1, 2 or non-serious Grade 3 infusion reactions should have 
the infusion rate permanently reduced by 50% and continue to receive antihistamine 
premedication prior to administration.  Cetuximab should be discontinued immediately for 
serious infusion reactions that require medical intervention and/or hospitalization.  Subjects 
who experience serious infusion reactions will be discontinued from the study.
Dermatologic Toxicity
The dosing of cetuximab will be delayed 1 to 2 weeks in the case of severe (Grade 3 or 4) 
acneiform rash.  Cetuximab should be discontinued for a grade 4 acneiform rash which has 
not improved after a 2 week delay in treatment.  However treatment may be delayed up to 
12 weeks for grade 3 acneiform rash for recovery.  If dermatologic toxicity improves after 
the delay then the dose of cetuximab will be reduced as indicated in Table 7.  If dermatologic 
toxicity does not improve after the delay cetuximab will be discontinued.  
Keratitis
UK subjects who experience ≥Grade 2 keratitis, representing a new change from baseline 
while on treatment, should have cetuximab treatment held and be referred promptly for an
ophthalmology consultation, as indicated in Table 7.
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Table 7
Cetuximab Dose Modification for Rash and Keratitis
Severe Acneiform 
Rash (Grade 3)
Dose Interruption
Outcome
Dose Modification
1st occurrence
Delay treatment:
Grade 3 up to 12 
weeks
Grade 4 up to 2 weeks
Improved
None, continue at 250 
mg/m2
2nd occurrence
Delay treatment:
Grade 3 up to 12 
weeks
Grade 4 up to 2 weeks
Improved
Permanently reduce dose 
to 200 mg/m2
3rd occurrence
Delay treatment:
Grade 3 up to 12 
weeks
Grade 4 up to 2 weeks
Improved
Permanently reduce dose 
to 150 mg/m2
4th occurrence
Discontinue
N/A
N/A
Keratitis (≥ Grade 2)+
UK 
subjects: 
Hold 
treatment and refer for 
ophthalmology 
consult
N/A
Consult the Sponsor
+ As per specific UK Health Authority request.
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 3 days after 
randomization is permitted).
Trial treatment of methotrexate, docetaxel, 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 3 days after randomization is permitted).
Note: Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons (i.e. elective surgery, unrelated medical events, patient vacation, holidays) not related 
to study therapy. Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption. The reason for interruption should be documented in the patient's 
study record.
All trial treatments will be administered on an outpatient basis.
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5.2.2.1
Pembrolizumab
Trial treatment of pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy
Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
5.2.2.2
Methotrexate
Trial treatment of methotrexate 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).  Methotrexate will be administered as an IV infusion.
All subjects will start treatment at 40 mg/m2.  After the first 3 week cycle if there was no 
hematologic toxicity, no stomatitis, and renal function was normal, the dose may be 
increased by 10 mg/m2 every 3 week cycle to a maximum of 60 mg/m2 (e.g., in the absence 
of toxicity, 50 mg/m2 could be given at Cycle 2 and 60 mg/m2 could be given at Cycle 3 and 
subsequent cycles).
5.2.2.3
Docetaxel
Trial treatment of docetaxel should be administered on Day 1 of each 3 week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  
Docetaxel 75 mg/m2 will be administered as an IV infusion administered over 1 hour or 
following local standard of care.
5.2.2.4
Cetuximab
Trial treatment of 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 infused 
over 120 minutes (maximum infusion rate 10 mg/min) followed by 250 mg/m2 infused over 
60 minutes (maximum infusion rate 10 mg/min) for all subsequent doses starting with the 
Cycle 1 Day 8 administration or following local standard of care.
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Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment.
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 management personnel, unblinded 
Sponsor statistician, and unblinded Sponsor statistical programmer who will be responsible 
for data review to ensure validity of results and informing the timing of the interim analyses 
but who will have no other responsibilities associated with the study.
Access to the allocation schedule and the subject-level PD-L1 results for summaries or 
analyses for presentation to the DMC will be restricted to an unblinded external statistician, 
and, as needed, an external scientific programmer performing the analysis, 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 interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 2 treatment arms.  Subjects will be assigned 
randomly in a 1:1 ratio to pembrolizumab or standard therapy in an unblinded fashion using 
centrally randomized blocks stratified according to ECOG status, HPV status and PD-L1 
status.  Randomization will not be stratified by site.  The choice of standard therapy for a 
subject must be identified and documented prior to randomization.  Patients randomized to 
standard therapy who discontinue will not be crossed-over to pembrolizumab.
Stratification
Randomization will be stratified according to the following factors:
1. Eastern Cooperative Oncology Group (ECOG) Performance Scale (0 vs. 1)
2. HPV status for oropharynx cancer as determined by p16 immunohistochemistry (IHC) 
tested at a local or central laboratory; HPV status for subjects without oropharynx cancer 
is considered HPV negative.
3. PD-L1 Status defined by ≥ 50% TPS (Strong Positive vs. Not)
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
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specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
All concomitant medications received from the date of the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2.
A short course of steroids may be used as concomitant medication for either treatment of an 
adverse event or medical condition with Sponsor approval.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol (with the exception of denosumab)

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 for 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.

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 
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virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu -
Mist®) are live attenuated vaccines, and are not allowed.
o
Note:  It is acceptable for subjects receiving cetuximab or docetaxel to receive 
live vaccines while participating in the trial.
o
Note: Any licensed COVID-19 vaccine (including for emergency use) in a 
particular country is allowed in the study as long as they are mRNA vaccines, 
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.

Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of 
asthma/COPD are permitted) for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.
o
Note:  For subjects randomized to the standard treatment arm the use of 
glucocorticoids on trial treatment is acceptable and may be required for 
premedication.
o
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g. 
IV contrast dye) is permitted.

Strong inhibitors of the CYP3A4 enzymes (a common list of such agents may be 
found in Section 12.8) for subjects receiving docetaxel.
o
Note:  For subjects randomized to the standard treatment arm that require 
treatment with a strong inhibitor of CYP3A4, docetaxel may not be chosen as 
the standard treatment.   
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.

In subjects receiving methotrexate, the following treatments should be used 
minimally: nephrotoxic therapies, NSAIDs, hepatotoxic therapies (including alcohol) 
and trimethoprim/sulfamethoxazole.

In subjects receiving cetuximab, contact lens use increases the risk of keratitis.
The Exclusion Criteria describes other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
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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 adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. 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 steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). 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. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. (These procedures should be 
documented in the case report form.)

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms of 
Grade 2 events 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 (Grade 3-4 
events require permanent discontinuation).  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.
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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 of Grade 2 events improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks (Grade 3-4 events 
require permanent discontinuation).

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. 

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, non-selective 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. 
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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 of Grade 2 events improve to Grade 1 or less, a steroid taper 
should be started and continued over no less than 4 weeks (Grade 3-4 events 
require permanent discontinuation).

Renal Failure or Nephritis:
o
For Grade 2 events, treat with oral systemic corticosteroids.
o
For Grade 3-4 events, treat with intravenous systemic corticosteroids.
o
When symptoms of Grade 2 events improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks (Grade 3-4 events 
require permanent discontinuation). 

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 8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
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Table 8
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).
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NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following 
initial 
improvement; hospitalization 
indicated for other clinical 
sequelae 
(e.g., 
renal 
impairment, 
pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional 
appropriate 
medical 
therapy may include but is not 
limited to:
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.
Subject is permanently discontinued 
from 
further 
trial 
treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.
Supportive Care Guidelines for Methotrexate
Note: For UK subjects - Subjects with ≥Grade 2 colitis or peptic ulcer symptoms should 
discontinue methotrexate treatment.
Refer to the approved product label for supportive care guidance.
Supportive Care Guidelines for Docetaxel
Pre-medication(s) for docetaxel will be given as per standard of care.  Corticosteroid pre-
treatment or post-treatment of docetaxel is acceptable in concordance with the local label or 
standard of care.
Refer to the approved product label for additional supportive care guidance.
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.
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Guidelines for medical therapy for infusion reactions detailed in Table 8 above are also 
recommended for reactions due to cetuximab.
Refer to the approved product label for additional supportive care guidance.
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
Methotrexate has been reported to cause fetal death and/or congenital anomalies [48].  
Pembrolizumab, docetaxel and cetuximab may also have adverse effects on a fetus in utero.  
Furthermore, it is not known if these agents have transient adverse effects on the composition 
of sperm.  Therefore, non-pregnant, non-breast-feeding 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 two birth control methods can either be two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects receiving pembrolizumab should start using 
birth control from study Visit 1 throughout the study period up to 120 days after the last dose 
of study therapy. Subjects receiving standard treatment should start using birth control from 
study Visit 1 throughout the study period up to 120 days - 180 days after the last dose of 
study therapy (according to local standard of care).
Note: For UK subjects: Subjects should start using birth control from study Visit 
1 throughout the study period up to 120 days after the last dose of study therapy (and 
specifically through 180 days after the last dose of docetaxel or methotrexate).
Note: For France subjects: Male subjects should start using birth control from study 
Visit 1 throughout the study period up to 120 days after the last dose of study therapy 
(and specifically through 180 days after the last dose of docetaxel).
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  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 
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reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
For countries or sites that follow the Clinical Trial Facilitation Group (CTFG) 
guidance, please use the following:
Methotrexate has been reported to cause fetal death and/or congenital anomalies [48].  
Pembrolizumab, docetaxel and cetuximab may also have adverse effects on a fetus in utero.  
Furthermore, it is not known if these agents have transient adverse effects on the composition 
of sperm.  Therefore, non-pregnant, non-breast-feeding women may only be enrolled if they 
are willing to follow the Clinical Trial Facilitation Group (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.
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

Vasectomised partner

Sexual abstinence
Subjects receiving pembrolizumab should start using birth control from study Visit 1 
throughout the study period up to 120 days after the last dose of study therapy. Subjects 
receiving standard treatment should start using birth control from study Visit 1 throughout 
the study period up to 120 days - 180 days after the last dose of study therapy (according to 
local standard of care).
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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 with pembrolizumab or 
standard treatment, the subject will immediately be removed from the study.  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.
Use in Nursing Women
Methotrexate is excreted into breast milk and its use is contraindicated in nursing women
[48].  It is unknown whether pembrolizumab, docetaxel or cetuximab are excreted in human 
milk.  Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  Once a 
subject has discontinued treatment, even though he/she continues to be monitored in the trial, 
he/she may be allowed to begin treatment again if deemed medically appropriate.
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A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) requests to 
discontinue treatment

Radiographic disease progression confirmed by the site at least 28 days after 
verification of progression by central imaging vendor
Note: For unconfirmed radiographic disease progression, please see Section 5.8.1

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to discontinue treatment for the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

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.   

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 adverse event monitoring (serious adverse events 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 progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
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 
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cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions.
If independent central assessment verifies initial site assessed 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 (see Figure 3).  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 progressive disease, subjects 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 non-target lesions (please refer to the Procedures 
Manual).
The decision to continue study treatment after disease progression is verified by the central 
imaging vendor is at the Investigator’s discretion based on the clinical status of the subject as 
described in Table 9 below.  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 performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Table 9
Imaging and Treatment After Site-Assessed 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Central imaging 
vendor 
assessment 
verifies
PD
following site-
assessed 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
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Note:  Central imaging assessment should be performed immediately after site-assessed PD 
to verify PD.  Patients should remain on treatment until central imaging assessment is 
performed.
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 two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one 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, and the trial is open.  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.
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.  The 
overall trial ends when the last subject completes the last trial 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, participants 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 futility, early benefit or safety at the recommendation 
of the Data Monitoring Committee (DMC).
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6.0 TRIAL FLOW CHART
Initial Treatment Phase
Pembrolizumab Arm
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening (Visit 1)
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:
-42 to -1
-28 to -1
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days post 
discon
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
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
Post-study Anticancer Therapy 
Status
X
X
Survival Statusc
< -------------------------------------------------------------------------------------------------------------------- >
X
Clinical Procedures/Assessments
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 and Weightk
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
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Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening (Visit 1)
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:
-42 to -1
-28 to -1
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days post 
discon
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
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, FT4 and TSHz
Xn
X
X
Xj
Xp
Laboratory Procedures/Assessments: 
analysis performed by CENTRAL 
laboratory
Pharmacokineticsq
Xq,r
Xq
Xq
Xq
Xq
Anti-pembrolizumab Antibodiesq
Xq
Xq
Xq
Xq
Xq
Blood for Geneticsy
X
Correlative Blood Sampless
X
X
X
X
Efficacy Measurements
Tumor Imaging
Xt
Xu
Xu
Xb,v
X
Tumor Tissue Collection
Archival or Newly Obtained Tissue 
Collection 
for 
Subjects 
with 
Oropharynx Cancer Tested Locally
or Centrally for HPV Status for 
Stratification (newly obtained may 
be obtained 42 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 42 days prior to 
treatment initiation)
Xw
Patient Reported Outcomes
EuroQol EQ-5D
Xx
Xx
Xx
Xj, x
Xj, x
Xx
Xx
EORTC QLQ-C30
Xx
Xx
Xx
Xj, x
Xj, x
Xx
Xx
EORTC QLQ-H&N 35
Xx
Xx
Xx
Xj, x
Xj, x
Xx
Xx
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Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening (Visit 1)
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:
-42 to -1
-28 to -1
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days post 
discon
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
Health 
Economic 
Assessment 
(HEA)
Xx
Xx
Xj, x
Xj, x
Xx
Xx
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.  
Imaging should be performed at 9 weeks after randomization date 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) until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs first.
c. After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, the subject 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 
participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a 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 3 days of randomization.
e. Documented 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 signed.
f. Signing the informed consent for future biomedical research (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 of first dose of study treatment. Concomitant medications – Enter new medications started during the trial 
through the Safety Follow-up visit.  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 after 
the last dose of trial treatment or 30 days after the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial 
treatment.
j. To be repeated every 2 cycles after Cycle 6. 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.  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.  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. 
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.
089QY3


Product:  MK-3475 (SCH 900475)
70
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening (Visit 1)
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:
-42 to -1
-28 to -1
+3d
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days post 
discon
Every 6 
weeks post 
discon or 
per 
footnote
Every 12 
weeks
q. Both PK and anti-pembrolizumab antibody for pembrolizumab arm only; pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and 
every 4 cycles thereafter, 30 days after discontinuation of study drug, and 3 months after discontinuation of study drug (or until the subject starts new anti-cancer therapy).  All 
pre-dose trough samples should be drawn within 24 hours before infusion of pembrolizumab.  
r. PK for pembrolizumab arm only; additional post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. An additional 
single PK sample should be drawn between 72 and 168 hours after Cycle 1 dosing. 
s. Blood for correlative studies (includes blood, plasma and serum for DNA, RNA, and exploratory biomarkers) should be collected predose Cycle 1, Cycle 2, Cycle 3, and at 
treatment discontinuation. Detailed instructions with specific timepoints per sample are provided in the Procedures Manual.
t. The initial tumor imaging will be performed within 28 days prior to randomization date.  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 date.  
u. The first on-study imaging time point will be performed at 9 weeks (± 7 days) after randomization date 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.  The same imaging technique should be used in a subject throughout the trial.  On-study scans showing initial progression should be submitted immediately to the 
central imaging vendor and progressive disease should be verified by the central imaging and confirmed at least 4 weeks later prior to subject discontinuation from treatment.  
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 isn’t 
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 or centrally 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. (Newly obtained tissue may be obtained up to 42 days prior to treatment initiation. 
Tissue beyond the 42-day window and up to 6 months may be considered with Sponsor consultation as long as no intervening systemic regimen has been taken.) Detailed 
instructions for tissue collection, process and shipment are provided in the Procedures Manual.  If the subject signs the Future Biomedical Research (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 most relevant and strongly recommended that ePROs are administered prior to drug administration, adverse event evaluation and disease status notification.  Health 
economic assessment (HEA) to be completed by trained personnel prior to all other study procedures.  All ePROs are to be performed prior to Cycle 1, Cycle 2, Cycle 3, Cycle 4  
and every 2 cycles thereafter (e.g., Cycle 6, Cycle 8, Cycle 10) up to a year or  End of Treatment, whichever occurs first, and the 30-day safety follow-up visit.  If the subject 
does not complete the ePROs the MISS_MODE form must be completed to capture the reason the assessment was not performed.
y. This sample should be drawn for planned, exploratory 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.
z. After Cycle 1, lab samples for T3, FT4, and TSH can be collected ±3 days before/after the scheduled time point. T3 or FT3 can be assayed based on local standards.
089QY3


Product:  MK-3475 (SCH 900475)
71
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Standard Treatment Arm – Subjects Receiving Methotrexate, Docetaxel, or Cetuximab
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
Administrative 
Procedures
Informed 
Consente
X
Informed 
Consent for 
Future 
Biomedical 
Researchf
X
Inclusion/Exclu
sion Criteria
X
Subject 
Identification 
Card
X
Demographics 
and Medical 
History
X
Prior and 
Concomitant 
Medication 
Reviewa,g
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment 
Administrationa
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
089QY3


Product:  MK-3475 (SCH 900475)
72
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
Clinical 
Procedures/Ass
essments
Review Adverse 
Eventsa,h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead 
Electrocardiogra
m (Local)
X
Full Physical 
Examination
X
X
Directed 
Physical 
Examination
X
X
X
X
X
X
Vital Signs and 
Weighta,k
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/Ass
essments: 
analysis 
performed by 
LOCAL 
laboratory
Pregnancy Test 
– Serum or 
Urine l
X
PT/INR and 
aPTTm
X
089QY3


Product:  MK-3475 (SCH 900475)
73
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
CBC with 
Differentiala,o
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
Chemistry 
Panela,o
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
Urinalysiso
Xn
X
X
Xj
Xp
T3, FT4 and 
TSHx
Xn
X
X
Xj
Xp
Laboratory 
Procedures/Ass
essments: 
analysis 
performed by 
CENTRAL 
laboratory
Blood for 
Geneticsw
X
Correlative 
Blood Samplesq
X
X
X
X
Efficacy 
Measurements
Tumor Imaging
Xr
Xs
Xs
Xb, s, t
X
089QY3


Product:  MK-3475 (SCH 900475)
74
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
Tumor Tissue 
Collection
Archival or 
Newly Obtained 
Tissue 
Collection for 
Subjects with 
Oropharynx 
Cancer Tested 
Locally or 
Centrally for 
HPV Status for 
Stratification 
(newly obtained 
may be obtained 
42 days prior to 
treatment 
initiation)u
X
089QY3


Product:  MK-3475 (SCH 900475)
75
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
Newly Obtained 
Tissue 
Collection for 
Biomarker 
Analysis (tested 
centrally) On all 
Subjects Prior to 
Randomization 
for Stratification 
(may be 
obtained 42 
days prior to 
treatment 
initiation)u
X
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
089QY3


Product:  MK-3475 (SCH 900475)
76
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
Health 
Economic 
Assessment
Xv
Xv
Xj,
v
Xj,
v
Xv
Xv
a.
In general, assessments/procedures are to be performed prior to the treatment dose.  Subjects receiving docetaxel will be dosed on Day 1 of each 3 week cycle and will not have 
visits/procedures on Day 8 or Day 15. Subjects receiving methotrexate or cetuximab will be dosed on Days 1, 8 and 15 of each 3 week cycle.  Imaging should be performed at 
9 weeks after randomization date 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) until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs first.
c.
After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, the subject 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 
participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a 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 3 days of randomization.
e.
Documented 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 signed.
f.
Signing the informed consent for future biomedical research (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 of first dose of trial treatment. Concomitant medications – Enter new medications started during the trial 
through the Safety Follow-up visit.  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 
after the last dose of trial treatment or 30 days after the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to 
trial treatment.
j.
To be repeated every 2 cycles after Cycle 6. 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.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.
089QY3


Product:  MK-3475 (SCH 900475)
77
Protocol/Amendment No.: 040-14 
MK-3475-040-14 Final Protocol
03-Nov-2021
Confidential
Trial Period:
Screening Phase
Treatment Cycles (3-Week Cycles)a
End of 
Treat-
ment
Post-Treatment
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:
-42 to
-1
-28 to 
-1
+3d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3 ± 3 ± 3 ± 3 ± 3 ± 3 ± 3
± 3
± 3
At time 
of 
discon
30 days 
post 
discon
Every 6 
weeks 
post 
discon
Every 
12 
weeks
n.
ECOG and laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  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.
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.
Blood for correlative studies (includes blood, plasma and serum for DNA, RNA, and exploratory biomarkers) should be collected predose Cycle 1, Cycle 2, Cycle 3, and at 
treatment discontinuation. 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 date.  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 date.  
s.
The first on-study imaging time point will be performed at 9 weeks (± 7 days) after randomization date 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 
in cycle starts.  The same imaging technique should be used in a subject throughout the trial.  On-study scans showing initial progression should be submitted immediately to 
the central imaging vendor and progressive disease should be verified by the central imaging and confirmed at least 4 weeks later prior to subject discontinuation from 
treatment.  
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 isn’t 
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 or centrally 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. (Newly obtained tissue may be obtained up to 42 days prior to treatment 
initiation. Tissue beyond the 42-day window, and up to 6 months, may be considered with Sponsor consultation as long as no intervening systemic regimen has been taken.)  
Detailed instructions for tissue collection, process and shipment are provided in the Procedures Manual.  If the subject signs the Future Biomedical Research (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 most relevant and strongly recommended that ePROs are administered prior to drug administration, adverse event evaluation and disease status notification.  Health 
economic assessment (HEA) to be completed by trained personnel prior to all other study procedures.  All ePROs are to be performed prior to Cycle 1, Cycle 2, Cycle 3, Cycle 
4 and every 2 cycles thereafter (e.g., Cycle 6, Cycle 8, Cycle 10) up to a year or  End of Treatment, whichever occurs first, and the 30-day safety follow-up visit.  If the subject 
does not complete the ePROs the MISS_MODE form must be completed to capture the reason the assessment was not performed.
w. This sample should be drawn for planned, exploratory 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.
x.
After Cycle 1, lab samples for T3, FT4, and TSH can be collected ±3 days before/after the scheduled time point. T3 or FT3 can be assayed based on local standards.
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Second Course Phase (Retreatment) for Pembrolizumab Arm Only
Trial Period:
Treatment Cycles (3-Week Cycles)a
End of Treatment
Post-Treatment
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 discon
30 days post 
discon
Every 6 weeks 
post discon or 
per footnote
Every 12 
weeks
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
Xs
Chemistry Panelo
Xn
X
X
X
X
X
X
Xs
T3, FT4 and TSHt
Xn
Xj
Xj
Xs
Laboratory Procedures/Assessments: 
analysis performed by CENTRAL
laboratory
Pharmacokineticsp
X
X
X
Xp
Xp
Anti-pembrolizumab Antibodiesp
X
X
X
Xp
Xp
Efficacy Measurements
Tumor Imagingq
X
X
X
Xr
Xq
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.  
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 anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs first.
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Trial Period:
Treatment Cycles (3-Week Cycles)a
End of Treatment
Post-Treatment
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 discon
30 days post 
discon
Every 6 weeks 
post discon or 
per footnote
Every 12 
weeks
c. After the start of new anti-cancer treatment or documented disease progression by the central imaging vendor, the subject 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 
participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a 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 during the trial through the Safety Follow-up visit.  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 after 
the last dose of trial treatment or 30 days after the start of new anti-cancer treatment, 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.  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 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.
m.Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
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. Both PK and anti-pembrolizumab antibody for pembrolizumab arm only; Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and 
every 4 cycles thereafter, 30 days after discontinuation of study drug, and 3 months after discontinuation of study drug (or until the subject starts new anti-cancer therapy).  All 
pre-dose trough samples should be drawn within 24 hours before infusion of pembrolizumab.  
q. 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 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.
r. 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 isn’t mandatory.
s. 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.
t. After Cycle 1, lab samples for T3, FT4, and TSH can be collected ±3 days before/after the scheduled time point. T3 or FT3 can be assayed based on local standards.
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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.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain documented informed consent 
before performing any procedure related to the Future Biomedical Research sub-trial.  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 documented 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.  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.
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7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up
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.
Investigators must choose a standard treatment (methotrexate, docetaxel, or cetuximab) prior 
to randomization and document the selection in the interactive voice/integrated web response
system. When choosing a standard therapy, the investigator should refer to the Summary of 
Product Characteristics (with special consideration for any contraindications, special 
warnings and precautions of use), and/or follow local 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.
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Administration of trial medication will be witnessed by the investigator and/or trial 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 will be 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.  Adverse events 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 terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an 
event of clinical interest (ECI) of a potentially immunologic etiology (termed immune-
related adverse events, or irAEs); see Section 5.6.1.1 and the separate ECI guidance 
document in the administrative binder 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 physician exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam 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.
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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 computed tomography (CT)
(preferred) or magnetic resonance imaging (MRI), but the same imaging technique should be 
used consistently for an anatomic region in a subject throughout the trial.  CT scan is the 
more commonly used modality and is preferred for the majority of patients.  An MRI can be 
utilized if clinically appropriate.  Imaging should include head, neck, chest and abdomen at 
all timepoints specified in the Trial 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.  .
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1 
will be used to determine subject eligibility.  The central imaging vendor will receive all 
images from the sites and verify progressive disease following site assessed progressive 
disease.  The Sponsor will also receive radiologic images for a retrospective analysis of 
subject eligibility and treatment response to be performed by the central vendor, using 
RECIST 1.1. Although RECIST 1.1 references to maximum of 5 target lesions in total and 
2 per organ, Merck allows maximum of 10 target lesions in total and 5 per organ, if clinically 
relevant to enable a broader sampling of tumor burden. 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.
In addition, radiologic progression will be based on the independent central verification of 
progression, rather than site assessment.  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.)
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7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to randomization.  The site 
study team must review pre-trial images to confirm the subject has measurable disease per 
RECIST 1.1.  The baseline imaging scan must be submitted to the central imaging vendor for 
retrospective confirmation of eligibility.
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.  
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 
randomization date.  Subsequent imaging should be performed every 6 weeks (42 days ± 7 
days), or more frequently if clinically indicated. Subjects who remain on treatment for a year 
will have imaging performed every 9 weeks.  Imaging should not be delayed for delays in 
cycle starts.  
Per RECIST 1.1, response 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 (e.g. 6 weeks later), whichever is clinically indicated.  
Imaging should continue to be performed until initial site-assessed disease progression is 
verified by the central imaging vendor, the start of new anti-cancer treatment, withdrawal of 
consent, death, or the end of the study, whichever occurs first.  Disease progression may be 
confirmed by the site at least 4 weeks after the first scan indicating progressive disease in 
clinically stable subjects.  Subjects who have unconfirmed disease progression may continue 
on treatment 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).  Initial scans
showing site-assessed PD should be submitted to the central imaging vendor immediately 
and the site will be notified when the imaging vendor verifies disease progression using 
RECIST 1.1.  Sites should also assess tumor response and progression per modified RECIST 
for subjects on both treatment arms and this data will be collected in the clinical database.
Modified RECIST is RECIST 1.1 adapted as follows to account for the unique tumor 
response seen in this class of therapeutics.  
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If imaging shows PD, tumor assessment should be repeated 4 weeks later at the site in 
order to confirm PD with the option of continuing treatment for clinically stable subjects 
(see Table 9).  Clinically stable is defined by the following criteria:

Absence of signs and symptoms indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions (please refer to the Procedures 
Manual).  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.  If radiologic progression is not confirmed, 
then the subject should resume/continue trial treatment and have their next scan according to 
the every 6 weeks (42 ± 7 days) schedule.  
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the Sponsor.
Imaging during the follow-up period is to be repeated every 9 weeks (63 ± 7 days) after 
1 year for subjects who discontinue trial treatment for reasons other than disease progression 
until the subject experiences disease progression by site assessment followed by central 
imaging verification or starts a new anti-neoplastic therapy.  
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).  
Note:  Tumor p16 expression must be evaluated by local assessment by means of 
IHC analysis with CINtec® p16 Histology assay (Ventana Medical Systems Inc., 
and Roche Diagnostics International Ltd.) using ‘Benchmark Ultra’ autostainer 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:  Subjects without available local p16 testing results may submit tumor tissue
for central p16 testing.
All subjects will submit either a newly obtained core or excisional biopsy (fine needle 
aspirate not adequate) to a central lab for characterization of PD-L1 status.
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Blood for correlative biomarker studies (RNA and DNA) should be collected predose at
Cycle 1, at Cycle 2, at Cycle 3 and at treatment discontinuation; blood for correlative 
samples (plasma and serum) should be collected 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)
The EuroQol EQ-5D, EORTC QLQ C-30, and EORTC QLQ-H&N35 questionnaires will be 
administered by trained site personnel and completed electronically by subjects prior to all 
other study procedures in the following order: EuroQol EQ-5D first, then EORTC QLQ C-
30, and lastly the EORTC QLQ-H&N35 at the time points specified in the Trial Flow Chart.  
It is most relevant and strongly recommended that ePROs are administered prior to drug 
administration, adverse event evaluation and disease status notification.
The health economic assessment (HEA) form will be completed via an interview with the 
subject by qualified site personnel after the subject completes all other questionnaires.  The 
form captures all non-study related health care contacts made throughout the trial.
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.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10.
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Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
aPTT
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Total 
triiodothyronine 
(T3) or Free T3
Red Blood Cell 
Count
Bicarbonateb
Microscopic exam, if 
abnormal results are 
noted
Free thyroxine (T4)
Absolute 
Neutrophil Count
Calcium
Urine pregnancy testa
Thyroid 
stimulating 
hormone (TSH)
Absolute 
Lymphocyte 
Count
Chloride
Creatinine
Blood 
for 
correlative 
studies
Glucose
PK (for subjects on the 
pembrolizumab arm only)
Phosphorus
Anti-pembrolizumab
Antibodies (for subjects 
on the pembrolizumab 
arm only)
Potassium
Sodium
Total Bilirubin  
Direct 
Bilirubin, 
if 
total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood Urea Nitrogen
Lactate 
dehydrogenase 
(LDH)
Carbon 
dioxide (CO2 
or 
bicarbonate)b
Uric acid
Ureac
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 these tests are not done as part of standard of care in your region, then these tests do not need to 
be performed.
c Blood Urea Nitrogen is preferred; if not available urea may be tested.
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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment.  After Cycle 1, pre-dose 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 Flowchart (Sections 6.1.1 and 6.2). Blood samples for PK and 
ADA collected may be stored. Analysis will be performed only 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 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 only be drawn for subjects in the 
pembrolizumab arm.
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 only be drawn for subjects in the pembrolizumab arm.
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
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.  Subjects on the pembrolizumab arm who a) attain a CR or b) 
complete 24 months of treatment with pembrolizumab may discontinue treatment with the 
option of restarting treatment if they meet the criteria specified in Section 7.1.5.2.1.  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).
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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@merck.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 with the study 
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments
See protocol-specified guidance in the Administrative Binder and Procedures 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.
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7.1.5.1
Screening
Approximately 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.

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.

Archival tumor 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 42 
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 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 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 two treatments with pembrolizumab beyond the date 
when the initial CR was declared
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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 confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab

Did not receive any anti-cancer 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 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing 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 120 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 are outlined in Section 6.0 – Trial Flow Chart.
7.1.5.3
Post-Treatment 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 anti-cancer 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 anti-cancer therapy, whichever occurs first.  SAEs 
that occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  
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Subjects who are eligible for retreatment with pembrolizumab (as described in Section 
7.1.5.2.1) may have up to two safety follow-up visits, one after the Treatment Period and one 
after the Second Course Phase.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than 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 anti-cancer therapy, disease progression, 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 anti-cancer treatment will be collected if new treatment is initiated.
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 and verified by central 
review or starts a new anti-cancer therapy, the subject moves into 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 
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 Data 
Monitoring Committee (eDMC) review, interim, and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor-defined time period will be contacted for their survival status (excluding 
participants that have previously recorded a death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
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have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before 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 adverse events must be 
reported by the investigator. Such events will be recorded at each examination on the 
Adverse Event case report forms/worksheets.  The reporting timeframe for adverse events 
meeting any serious criteria is described in section 7.2.3.1. The investigator will make every 
attempt to follow all subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
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 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.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
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If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) 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 of 
completing the trial or 30 days following cessation of treatment, 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 serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
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Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 11 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until randomization, any 
serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study (reference Section 7.2.3.3 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 serious adverse event, or follow up to a serious adverse 
event, including death due to any cause other than progression of the cancer under study 
(reference Section 7.2.3.3 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 serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is 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.
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For the time period beginning at randomization through 14 days following cessation of 
treatment, 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 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).
1. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-
Related Adverse Event Guidance Document”).  This document can be found in the 
administrative binder and provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.  
ECIs (both non-serious and serious adverse events) identified in this guidance document 
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.
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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.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or 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 self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product? Is the time of onset of the AE compatible with a 
drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED 
BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's product 
is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.2.9 - 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, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
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protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, along with an 
explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.  No 
separate Statistical Analysis Plan (SAP) will be issued for this study, with the exception of a 
PRO analysis plan.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analyses
The primary and key secondary endpoints, primary analysis population, and statistical 
methods that will be employed for the efficacy analyses are presented in Table 13.  The 
intention-to-treat (ITT) population will serve as the primary analysis population in this study. 
The primary efficacy endpoint is:

Overall survival (OS) (i.e., time from randomization to death due to any cause) in all 
subjects (H1).
Key secondary efficacy endpoints include:

OS in subjects with PD-L1 1% CPS (H2)

ORR per RECIST 1.1 in all subjects (H3)

ORR per RECIST 1.1 in subjects with PD-L1 1% CPS (H4)

Progression-free-survival (PFS) per RECIST 1.1 in all subjects (H5)

PFS per RECIST 1.1 in subjects with PD-L1 1% CPS  (H6)
Baseline ECOG status (0 vs. 1), HPV status (HPV positive or negative for oropharynx 
cancers only; patients with non-oropharynx cancers are considered HPV negative by 
convention), and PD-L1 expression (PD-L1 Strong Positive vs. PD-L1 Not Strong Positive, 
where PD-L1 Strong Positive is defined as a PD-L1 tumor proportion score of ≥50% by 
IHC) will be the stratification variables in stratified analyses of all subject population.  
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 (ASaT) population will be employed for safety analyses.
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Power and Sample Size
The study will randomize approximately 466 subjects stratified by ECOG performance status 
(0 vs. 1), HPV status (HPV+ or  HPV- for subjects with oropharynx cancer, HPV- for 
subjects without oropharynx cancer), and PD-L1 status (PD-L1 Strong Positive vs. PD-L1 
Not Strong Positive) with a 1:1 ratio into the pembrolizumab arm and the standard treatment
arm. The sample size calculation is determined by OS events in all subjects.
The final OS analysis in all subjects (H1) will be carried out after approximately 340 deaths 
have occurred between the pembrolizumab arm and standard treatment arm.   With 340 
events, the study provides 90% power to demonstrate superiority in OS of pembrolizumab
relative to standard therapy at the alpha=2.5% (one-sided) level assuming proportional 
hazards with a true HR of 0.7.  The sample size calculation is based on the following 
assumptions: 1) overall survival follows an exponential distribution with a median of 
6.2 months in the control arm; 2) the hazard ratio for OS between pembrolizumab and control 
is 0.70 (deemed to be clinically meaningful in this population); 3) an enrollment period of 
16 months; and 4) a yearly discontinuation from trial rate of 5%. 
The family wise type I error rate for this study is strictly controlled at 2.5% (one-sided) for 
testing OS in all subjects. There are three planned analyses of OS in all subjects. If the OS 
analysis is successful in all subjects, then the key secondary hypotheses will be tested.  
Additional details are provided in Section 8.2.6 Multiplicity.
Interim Analysis
There will be two interim analyses for OS. Results of the interim analysis will be reviewed 
by the external data monitoring committee (DMC).  
Further details of interim analyses are provided in Section 8.2.9 Interim Analysis and Table 
15 as well as in the DMC Charter.
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 IVRS vendor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. 
Although the trial is open label, analyses or summaries generated by randomized treatment 
assignment, actual treatment received, and/or PD-L1 biomarker status will be limited and 
documented. In addition, the independent radiologist(s) will perform the central imaging 
review without knowledge of treatment group assignment.
The 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
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unblinded Sponsor clinical scientist, unblinded data management personnel, unblinded 
Sponsor statistician and unblinded Sponsor statistical programmer will have access to the 
subject-level PD-L1 results for the purpose of data review and informing the timing of the 
interim analyses and will have no other responsibilities associated with the study and have no 
access to the treatment allocation.  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.  
Access to the allocation schedule and the subject-level PD-L1 results for summaries or 
analyses for presentation to the DMC will be restricted to an unblinded external statistician, 
and, as needed, an external scientific programmer performing the analysis, who will have no 
other responsibilities associated with the study.
Treatment-level results for the interim OS analysis in all subjects and PD-L1 1% CPS
subjects will be provided by the external unblinded statistician to the DMC. The DMC will 
serve as the primary reviewer of the results of the OS analyses and will make 
recommendations for discontinuation of the study or modification to an Executive Oversight 
Committee of the SPONSOR.  
If the DMC recommends modifications to the design of the protocol or discontinuation of the 
study, this Executive Oversight Committee may be unblinded to results at the treatment level 
in order to act on these recommendations.  Limited additional SPONSOR personnel may be 
unblinded to the treatment level results of the OS analyses, if required, in order to act on the 
recommendations of the DMC or facilitate regulatory filing after the OS analyses. The extent 
to which individuals are unblinded with respect to results of interim analyses will be 
documented.  Additional logistical details 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 external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol violators, or data validation efforts after the OS analysis.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3. 
Analysis Endpoints
8.2.3.1
Efficacy Endpoints
Primary
Overall Survival
Overall Survival (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.
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Secondary
Key Secondary Endpoints
Progression-free survival (PFS) - RECIST 1.1 by blinded independent radiology review
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on blinded independent radiology 
review or death due to any cause, whichever occurs first. See Section 8.2.5.1.2 for definition 
of censoring.  
Supportive analyses of PFS will be conducted using site radiology review.
Objective Response Rate (ORR) – RECIST 1.1 by blinded independent radiology 
review
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon 
blinded independent radiology review per RECIST 1.1.  
Supportive analyses of ORR will be conducted using site radiology review.
Other Secondary Endpoints
Time to Progression (TTP) – RECIST 1.1 by blinded independent radiology review
Time to Progression (TTP) is defined as the time from randomization to the first documented 
disease progression. If there is no documented disease progression, TTP is censored at the 
last tumor assessment date.
Supportive analyses of TTP will be conducted using site radiology review.
Duration of Response – RECIST 1.1 by blinded independent radiology review
For subjects who demonstrated confirmed CR or PR, duration of response is defined as the 
time from first documented evidence of CR or PR until disease progression or death. 
Subjects who are alive, have not progressed, have not initiated new anti-cancer treatment, 
and have not been determined to be lost to follow-up are considered ongoing responders at 
the time of analysis.
Supportive analyses of response duration will be conducted using site radiology review.
Progression-free survival (PFS) – modified RECIST by blinded independent radiology 
review
Modified RECIST is similar to RECIST 1.1 with the exception that a confirmation 
assessment of PD (at least 4 weeks after the initial PD assessment) is required for subjects 
who remain on treatment following a documented PD per RECIST 1.1. Subjects who 
discontinue treatment following a documented PD assessment per RECIST 1.1 will be 
counted as having disease progression on the date of the documented PD assessment. See 
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Section 8.2.5.1.1 for definition of censoring and section 4.2.3.1 for a more detailed definition 
of modified RECIST criteria.
Exploratory
Exploratory endpoints of this study include but are not limited to exploratory candidate 
biomarkers predictive of response to treatment, patient-reported outcomes (PROs), and PFS2. 
PROs while on treatment and post-discontinuation will be examined.
PFS2 is defined as the time from randomization to subsequent disease progression after 
initiation of new anti-cancer therapy, or death from any cause, whichever occurs first. The 
subsequent disease progression is assessed by investigator and may not follow response 
criteria for RECIST 1.1. If progression after next-line therapy cannot be measured, a PFS2
event is defined as discontinuation of next-line treatment or death from any cause, whichever 
occurs first. Subjects who are alive and for whom a PFS2 event has not been observed will be 
censored at the last time known to be alive and without a second disease progression.
8.2.3.2
Safety Endpoints
Safety measurements are described in Section 7.
Analysis Population
8.2.4.1.1 Efficacy Analysis Population
The analysis of efficacy endpoints are based on the intention-to-treat (ITT) population, i.e., 
subjects will be included in the treatment group to which they are randomized. Details on the 
approach to handling missing data are provided in Section 8.2.5 Statistical Methods. This
definition of ITT population will be used in the efficacy analyses for all subjects and PD-L1 
1% CPS subjects.
8.2.4.1.2 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 1 
dose of study treatment. Subjects will be included in the treatment group corresponding to 
the trial treatment they actually received for the analysis of safety data.   
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. 
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At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
trial treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 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 (i.e., 
unadjusted) 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.
8.2.5.1
Statistical Methods for Efficacy Analyses
The family wise type I error rate for this study is strictly controlled at 2.5% (one -sided). 
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
multiple analyses is described in Section 8.2.6 and Section 8.2.9.
8.2.5.1.1 Overall Survival (OS)
The 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% 
confidence interval 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 
applied to both the stratified log-rank test and the stratified Cox model for all subject 
population as well as PD-L1 1% CPS subject population. For the primary OS analysis in all 
subjects, an additional sensitivity analysis replacing the PD-L1 Strong Positive vs. Not 
Strong Positive by the PD-L1 1% CPS vs. Not 1% CPS in the stratified analysis will be 
performed.
Subjects in the standard therapy arm are expected to discontinue treatment earlier compared 
to subjects in the pembrolizumab arm and may switch to another anti PD-1 treatment
following verification of progressive disease by central review.  As an exploratory analysis, 
the Rank Preserving Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis 
(1991) [49] will be used to adjust for the effect of crossover to other PD-1 therapies on OS. 
The RPSFT model provides a randomization-based estimate of treatment effect (RBEE) 
corrected for the bias induced by crossover. The 95% confidence intervals of the hazard ratio 
for OS after adjustment of the cross-over effect will be provided. The Kaplan-Meier 
estimates of the OS rate at 9 weeks, 27 weeks (when most cross-overs are likely to occur) 
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and other time points of interest will also be compared between the two treatment groups to 
explore the confounding effect of subsequent treatments. 
8.2.5.1.2 Progression-Free Survival (PFS)
The non-parametric 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% confidence interval 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 
applied to both the stratified log-rank test and the stratified Cox model for all subjects and 
PD-L1 1% CPS subjects.       
Since disease progression is assessed periodically, progressive disease (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 site 
assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by blinded 
independent radiology review, two sensitivity analyses with different sets of censoring rules
will be performed. The first sensitivity analysis is the same as the primary analysis except 
that it censors at the last disease assessment without PD when PD or death is documented 
after more than one missed disease assessment. The second sensitivity analysis is the same as 
the primary analysis except that it considers discontinuation of treatment or initiation of new 
anticancer treatment, whichever occurs later, to be a PD event for subjects without 
documented PD or death. The censoring rules for primary and sensitivity analyses are 
summarized in Table 12. We will also perform the following two additional PFS sensitivity 
analyses: 1) a PFS analysis using time to scheduled tumor assessment visit from 
randomization as opposed to actual tumor assessment time; 2) Finkelstein (1986)’s 
likelihood-based score test for interval-censored data, which modifies the Cox proportional 
hazard model for interval censored data, will be used as a supportive analysis for the PFS 
endpoint. The interval will be constructed so that the left endpoint is the date of the last 
disease assessment without documented PD and the right endpoint is the date of documented 
PD or death, whichever occurs earlier.
The proportional hazards assumption for the primary PFS analyses will be examined using 
both graphical and analytical methods. The proportional hazard assumption will be tested at 
the 0.05 significance level by including treatment*function(time) as a factor in the model; 
nonsignificance (p>0.05) of this factor would suggest proportionality. A kernel-based 
estimate of log-hazard vs. time will be used to identify the appropriate functional form of the 
treatment effect-by-time interaction in a Cox PH model.  Further, a visual examination of the 
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plot of the differences in the log cumulative hazards, log(H2(t)) – log(H1(t)) versus time for 
each level of treatment group will also be examined.  If the proportional hazards model 
assumption holds then each curve should be roughly constant and parallel to the horizontal 
axis.
To 
account 
for 
the 
possible 
non-proportional 
hazards 
effect 
associated 
with 
immunotherapies, a supportive analysis will be conducted using a test for the restricted mean 
survival time (RMST) proposed by Uno, Tian, et al [50] for equality of two survival 
functions based on weighted differences of Kaplan-Meier curves.  Thus, the PFS within each 
treatment group will be estimated using this approach, the 95% confidence intervals for the 
difference will be computed, and a test for differences between treatment groups will be 
performed.  The cutoff for determining the RMST will be the last month for which at least 30 
subjects within each treatment group are still at risk.  
In addition, it is likely that a parametric model will fit data well and can be used as an 
alternative approach to comparing treatment group event rates over time. A Weibull model 
that allows the shape parameter to be a function of the covariates can also be used to examine 
the proportional hazards assumption where event rates change over time [51]; these will be 
fit with the gamlss.cens R package (package and reference are available the R library at 
http://cran.r-project.org).  Other supportive analyses may include a cure model to compare 
treatment groups.
One key assumption for the stratified Cox proportional hazard model is that the hazard ratio 
(HR) is constant across strata.  If strong departures from constant HR are observed in the 
stratified PFS analysis for all subjects, a sensitivity analysis may be performed using the two-
step weighted Cox model approach by Mehrotra et al [52].  In this approach, the treatment 
effect is estimated within each stratum and the stratum-specific estimates are subsequently 
combined using sample size weights.
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Table 12
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
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 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
8.2.5.1.3 Objective Response Rate (ORR)
Stratified Miettinen and Nurminen’s method with strata weighting by sample size will be 
used for comparison of the objective response rates between the treatment groups. A 95% 
confidence interval for the difference in response rates between the pembrolizumab arm and 
the standard therapy arm will be provided. The same stratification factors used for 
randomization (see Section 5.4) will be applied to the analysis. 
ORR by site radiology assessment and ORR in the subgroup of subjects with PD-L1 1% CPS
will be analyzed using the same approach as the primary ORR analysis.
8.2.5.1.4 Duration of Response
If sample size permits, response duration will be summarized descriptively using Kaplan-
Meier medians and quartiles.  Only the subset of subjects who show a complete response or 
partial response will be included in this analysis. Response duration will be assessed using 
RECIST 1.1 separately by independent radiology review and by site radiology review.
8.2.5.1.5 Exploratory analyses
An exploratory analysis of PFS2 will be conducted using the same methods as for the 
secondary analysis of PFS. The non-parametric Kaplan-Meier method will be used to 
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estimate the PFS2 curve in each treatment group. The treatment difference in PFS2 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% 
confidence interval 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 applied to both the stratified log-rank test and the 
stratified Cox model for all subjects and PD-L1 1% CPS subjects.
Exploratory analyses of the treatment effect comparing pembrolizumab to standard treatment 
for OS, PFS, and ORR using RECIST 1.1 as assessed by blinded independent radiology 
review in the subgroup of subjects with strongly positive PD-L1 expression defined by ≥50% 
TPS will be carried out.
EORTC QLQ-C30, EORTC QLQ H&N35, and EQ-5D will be summarized as part of the 
exploratory analysis. Longitudinal and descriptive data analysis will be used to evaluate 
patient-reported outcomes. Several approaches will be considered to address the issue of 
informative missing data: (i) truncating the analysis observation period at the visit closest to 
median duration of treatment in the comparator arm, (ii) hierarchical pattern mixture models 
incorporating reason for missingness (a model that treats disease progression as a time-
varying covariate) and (iii) multiple imputation methods. The difference in PRO score for 
progressed patients compared to patients with no radiographic evidence of tumor progression
will be evaluated within each treatment arm. For HEA, descriptive statistics by treatment 
group will include total counts of each type of healthcare contact, as well as the total number 
of hospital days. The detailed PRO analysis plan will be included in a separate document.
Additional exploratory analyses of the relationship between treatment and predictive 
biomarkers predictive of response will be summarized using descriptive statistics.
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Table 13
Efficacy Analysis Methods for Primary and Key Secondary Efficacy 
Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data Approach
Primary Hypothesis 1 (H1)
OS
Testing: 
Stratified 
Log-rank test
Estimation: Stratified 
Cox 
model 
with 
Efron's tie handling 
method
ITT in all subjects
Censored 
at 
date 
last 
known alive
Key Secondary Hypothesis 2 (H2)
OS
Testing: 
Stratified 
Log-rank test
Estimation: Stratified 
Cox 
model 
with 
Efron's tie handling 
method
ITT
in PD-L1 1% 
CPS subjects
Censored 
at 
date 
last 
known alive
Key Secondary Hypothesis 3 (H3)
ORR 
(RECIST 
1.1) 
by 
independent radiology review
Stratified 
Miettinen 
and 
Nurminen 
method with strata 
weighting by sample 
size
ITT in all subjects
Missing 
response 
considered non-responder
Key Secondary Hypothesis 4 (H4)
ORR 
(RECIST 
1.1) 
by 
independent radiology review
Stratified 
Miettinen 
and 
Nurminen 
method with strata 
weighting by sample 
size
ITT
in PD-L1 1% 
CPS subjects
Missing 
response 
considered non-responder
Key Secondary Hypothesis 5 (H5)
PFS 
(RECIST 
1.1) 
by 
independent radiology review
Testing: 
Stratified 
Log-rank test
Estimation: Stratified 
Cox 
model 
with 
Efron's tie handling 
method
ITT in all subjects

Primary Approach

Sensitivity Analysis 1

Sensitivity Analysis 2
More details available in 
Table 12
Key Secondary Hypothesis 6 (H6)
PFS 
(RECIST 
1.1) 
by 
independent radiology review
Testing: 
Stratified 
Log-rank test
Estimation: Stratified 
Cox 
model 
with 
Efron's tie handling 
method
ITT in PD-L1 1% 
CPS subjects

Primary Approach

Sensitivity Analysis 1

Sensitivity Analysis 2

More details available 
in Table 12
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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 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
Time to Grade 3-5 AE
Time to first Grade 3-5 AE is defined as the time from the first day of study drug to the first 
event of Grade 3-5 AE. For patients without a Grade 3-5 AE, the time to first Grade 3-5 AE 
is censored at 30 days post last study dose. The Kaplan-Meier method will be used to 
estimate the curve of time to first Grade 3-5 AE.  The treatment difference in time to first 
Grade 3-5 AE will be assessed by the log-rank test.  A 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% confidence interval from the 
Cox model with a single treatment covariate will be reported.  
The analysis of safety results will follow a tiered approach (Table 14). 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.
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For this protocol, there are no Tier 1 events.  The broad clinical and laboratory AE categories 
consisting of the percentage of subjects with any AE, a drug related AE, a serious AE, a 
Grade 3-5 AE, an AE which is both Grade 3-5 and drug-related, an AE which is both drug-
related and serious, an AE which results in dose modification, and who discontinued due to 
an AE will be considered Tier 2 endpoints.  P-values (Tier 1 only) and 95% confidence 
intervals (Tier 1 and Tier 2) will be provided for between-treatment differences in the 
percentage of subjects with events; these analyses will be performed using the Miettinen and 
Nurminen method (1985) [53], an unconditional, asymptotic method.
To properly account for the potential difference in follow-up time between the study arms, 
which is expected to be longer in the pembrolizumab arm, AE incidence density adjusted for 
treatment exposure analyses may be performed as appropriate.  Based on emerging external 
data, the supportive analysis strategy for safety parameters may be modified to improve the 
integrity and efficiency of the design. Should this happen, the change will be documented 
elsewhere, if not in a protocol amendment, at the earliest time before any unblinding of the 
data.
Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
p-
Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
None
X
X
X
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
SOC = System Organ Class.
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis tests will be performed on these 
characteristics. The number and percentage of subjects randomized, and the primary reason 
for discontinuation will be displayed. Demographic variables (such as age) and baseline 
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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 family-wise type I error rate for this study is strongly controlled at 2.5% (one-sided) with
full alpha allocated to the OS hypothesis in all subjects (H1). A Hwang-Shih-DeCani alpha-
spending function with the gamma parameter (-4) and beta-spending function with the 
gamma parameter (-16) are constructed to implement group sequential boundaries that 
control the type I error rate as well as allow for non-binding futility analysis. Two interim 
analyses for OS in all subjects are planned in this trial and further details of the interim 
analysis strategy can be found in Section 8.2.9.
If the pembrolizumab arm is demonstrated to have a superior OS to the control arm for all 
subjects (H1) at any analysis, the alpha allocated at that analysis will be rolled into the OS 
hypothesis for PD-L1 1% CPS subjects to test H2. The ORR per RECIST 1.1 endpoints will 
be tested if H2 is rejected and PFS per RECIST 1.1 will be tested if the ORR endpoints are 
rejected in their respective populations. The hierarchical order for testing key secondary 
endpoints and alpha spending scheme according to the method of Maurer and Bretz (2013) 
[54] are illustrated in Figure 4.   
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Figure 4
Type I Error Reallocation Strategy Following Closed Testing Principle
The ORR and PFS per RECIST 1.1 are planned to be tested twice at the first and second 
interim. 2% of alpha will be allocated to the first interim and 0.5% will be allocated to the 
second interim, and will be split evenly between all subjects and 1% CPS subjects: i.e. 1% 
alpha will be allocated to the first interim and 0.25% to the second interim for all subjects 
and the same for PD-L1 1% CPS subjects for ORR and PFS endpoints, following the 
sequential testing procedure illustrated above.  
Based on emerging data external to this study [55, 56], the initial projected number of death 
events at the final analysis is revised in Amendment 11 onward to account for the delayed
separation in the overall survival curves that have been observed with immunotherapies.
Thus, additional follow-up time is incorporated into the trial to ensure that the final analysis 
is conducted at an appropriate time to characterize the potential benefit of immunotherapy.
With the delayed final analysis, the efficacy and futility spending functions remain 
unchanged. The information fractions based on the previously planned number of death 
events at the final analysis were used hence the alpha allocated to IA1 and IA2 were kept 
intact and the remaining alpha will be spent at the final analysis to ensure the type I error rate 
is strongly controlled at 2.5% (one-sided). The efficacy boundaries (nominal p-value and 
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boundary hazard ratio) at the final analysis will be calculated using the actual number of 
death events taking into account the correlation with the previous interim analysis.
Sample Size and Power Calculation
The study is event-driven and plans to randomize approximately 466 subjects with 1:1 ratio 
into the pembrolizumab arm and the standard therapy arm. 
OS Analysis in All Subjects (H1):  The final OS analysis in all subjects will be conducted 
after ~340 deaths have occurred between the pembrolizumab arm and the standard therapy 
arm. The final OS analysis is expected to occur at approximately twelve months after the last 
subject is enrolled in the study. This is to ensure adequate survival follow-up to account for 
the delayed separation in the OS curves that have been observed with immunotherapies.
Under the proportional hazard assumption with 340 events at the final analysis, the study 
provides 90% power to demonstrate superiority in OS of pembrolizumab relative to standard 
therapy at the alpha=2.5% (one-sided) level with a true HR of 0.7.    Success for OS at the 
final analysis approximately corresponds to an observed hazard ratio of < 0.80.  The sample 
size calculation is based on the following assumptions: 1) OS follows an exponential 
distribution with a median of 6.2 months in the standard therapy arm, 2) hazard ratio between 
MK-3475 and standard therapy is 0.7, 3) an enrollment period of 16 months; and 4) a yearly 
discontinuation from trial rate of 5%. To further investigate the impact of the delayed 
separation of OS curve on the actual power, a simulation study was carried out using the 
current study design parameters from the above but with a piece-wise time varying hazard 
ratio: the hazard ratio was specified as 1, 0.73, 0.60, 0.55, 0.52, and 0.49 at the beginning of 
time intervals of month 0, 3.5, 5.5, 7.5, 9.5, and 11.5 since randomization respectively. With 
1,000 simulations the overall study power with 340 events at the final analysis given the 
hazard ratio assumption above is approximately 77%. 
The assumptions for the median OS of 6.2 months in the standard therapy arm are based on 
estimates of median OS from 2L and 3L trials of single agents [29; 30; 31; 32; 33; 34; 35; 
36]. 
The sample size, power calculations, and simulations were performed in the software EAST 
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 within each category of the following classification 
variables:

Stratification Factors:
o
PD-L1 subgroup (PD-L1 Strong Positive vs. Not PD-L1 Strong Positive)
o
HPV status (HPV positive vs. HPV negative)
o
ECOG status (0 vs. 1)
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
Age category (≤65 vs. >65 years)

Line of therapy (first line vs. second line vs. third line)

Sex (female vs. male)

Race (white vs. non-white)

Geographic region of enrolling site (East Asia vs. non-East Asia)

Smoking status (never vs. former vs. current)

Brain metastasis status (baseline brain metastasis vs. no baseline brain metastasis)

Investigators’ choice of standard therapy identified prior to randomization
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Interim Analysis
There are two planned interim analyses.  In this study, the futility bounds are non-binding, 
which means the bounds are considered guidance rather than strict bounds. Results of the 
interim analyses of OS for all subjects will be reviewed by a data monitoring committee 
(DMC).  Further details of interim analyses are provided below and will be incorporated into 
the DMC Charter.
For OS in all subjects, a Hwang-Shih-DeCani alpha-spending function with the gamma 
parameter (-4) and beta-spending function with the gamma parameter (-16) are constructed to 
implement group sequential boundaries that control the type I error rate as well as allow for 
non-binding futility analysis. The actual boundary for each interim OS analysis will be 
determined from the number of OS events observed at the time of the data lock for the 
specified analysis using the alpha-spending function
Interim Analysis 1 for OS in all subjects (H1):
The first interim analysis will take place when approximately 144 OS events have occurred 
between the pembrolizumab arm and the standard therapy arm for all subjects at the alpha 
level determined by the spending function boundaries and actual number of OS events (Table 
15). Success at the interim analysis 1 for the OS analysis corresponds to an approximate 
observed hazard ratio < 0.63 (approximately a 3.6-month improvement or greater in median 
OS) for all subjects. If H1 is rejected, the same alpha boundary determined by H1 will be 
used to test the first key secondary endpoint: OS in PD-L1 1% CPS subjects (H2). If H2 is 
rejected, ORR and PFS endpoints can be tested according to the rules for the sequential 
testing and alpha allocation detailed in Section 8.2.6 Multiplicity.    
Interim Analysis 2 for OS in all subjects (H1):
The second interim analysis will take place when approximately 216 OS events have 
occurred between the pembrolizumab arm and the standard therapy arm for all subjects at the 
alpha level determined by the spending function boundaries and actual number of OS events. 
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Success at the interim analysis 2 for the OS analysis corresponds to an approximate observed 
hazard ratio < 0.72 (approximately a 2.4-month improvement or greater in median OS) for all 
subjects. If H1 is rejected, the same alpha boundary determined by H1 will be used to test the 
first key secondary endpoint: OS in PD-L1 1% CPS subjects (H2). If H2 is rejected, ORR 
and PFS endpoints can be tested according to the rules for the sequential testing and alpha 
allocation detailed in Section 8.2.6 Multiplicity.  
Final Analysis for OS in all subjects (H1):
As mentioned in Section 8.2.6 and 8.2.7 the final analysis will be conducted when 
approximately 340 deaths have occurred between the pembrolizumab arm and the standard 
therapy arm for all subjects to allow for further follow-up in all subjects. This is expected to 
occur approximately twelve months after the last subject was enrolled in the study and to 
ensure adequate survival follow-up to account for delayed separation of the OS curves. At 
the final analysis the remaining alpha not spent at IA1 or IA2 will be used and the final 
analysis boundary values (nominal p-value and boundary hazard ratio) will be calculated 
using the actual number of death events taking into account the correlation with the previous 
interim analysis. Success at the final OS analysis corresponds to an approximate observed 
hazard ratio < 0.80. If H1 is rejected, the same alpha boundary determined by H1 will be 
used to test the first key secondary endpoint: OS in PD-L1 1% CPS subjects (H2). The ORR 
and PFS endpoints will not be tested formally at the final analysis.
Table 15
Summary of Sample size and Decision Guidance at the Interim and Final OS 
Analyses by Design
Analysis
Criteria for Conduct 
of Analysis
Boundary
Z statistics
p value 
(1-sided)
~Observed HR 
at boundary
IA 1:  
OS in all subjects (H1) OS Events: 144
Efficacy
-2.75
0.0030
0.63
Futility†
1.75
0.96
1.34
IA 2:  
OS in all subjects (H1) OS Events: 216
Efficacy
-2.43
0.0075
0.72
Futility†
0.157
0.56
1.02
Final Analysis:
OS in all subjects (H1) OS Events: 288
Efficacy
-2.01
0.022
0.79
Futility
-2.01
0.022
0.79
IA = Interim Analysis.
†: Futility boundary is non-binding.
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Table 16
Summary of Actual Boundaries at Interim and Expected Boundaries at Final 
Analyses with Extended Follow-up
Analysis
OS Events
(Alpha Spent)
Boundary
p value 
(1-sided)
~Observed HR 
at boundary
IA 1:  
OS in all subjects (H1)
160 (0.0038§)
Efficacy
0.0038
0.65
Futility†
0.92
1.2
IA 2:  
OS in all subjects (H1)
245 (0.0097§)
Efficacy
0.0120
0.75
Futility†
0.277
0.93
Final Analysis:
OS in all subjects (H1)
340‡ (0.0114)
Efficacy
0.0186
0.80
Futility
0.0186
0.80
IA = Interim Analysis.
†: Futility boundary is non-binding.
‡: Expected to occur approximately 12 months after the last subject was enrolled to ensure adequate survival follow-up
§: Actual alpha spent at each interim analyses
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages 
of subjects and infusion/injection visits with any deviation in these measures will be reported 
for the ITT population.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 17.
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Table 17
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 25 mg  / mL
Solution for Infusion
Cetuximab 5 mg / mL
Solution for Infusion
Methotrexate 25 mg / mL
Solution for infusion
Docetaxel 20 mg / mL
Solution for infusion
The cetuximab, methotrexate and docetaxel will be provided centrally by the Sponsor or 
locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements. All other products will be provided locally by the trial site, 
subsidiary or designee.
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.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open label. Pembrolizumab and cetuximab will be provided as 
non-kitted single vials or as single vials in a kit box. All other products will be provided as a 
kit with a single vial.
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 
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personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented. 
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 
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, 
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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 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.
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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 Merck, is provided in Section 12.1 -
Merck 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 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 
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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 multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration 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.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck 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.    
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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. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures,
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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.
11.0 LIST OF REFERENCES
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Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
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Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. 
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Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
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Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et 
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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 
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7.
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.
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.  
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Zhang, X., Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, et al., Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity 
2004;20(3):337-47.
10.
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate 
with immunoreceptor tyrosine-based switch motif of programmed death 1 upon 
primary human T cell stimulation, but only receptor ligation prevents T cell 
activation. J Immunol 2004;173:945-54.
11.
Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome 
and downstream signaling to PKCtheta. FEBS Lett 2004;574:37-41.
12.
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
13.
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, 
et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. 
Mol Cell Biol 2005;25:9543-53.
14.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
15.
Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. Expression 
of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int 
Immunol 1996;8(5):765-72.
16.
Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR. Activation induced 
expression of human programmed death-1 gene in T-lymphocytes. Exp Cell Res 
1997;232:25-8.
17.
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.
18.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune 
evasion. Nat Med 2002;8(8):793-800.  
19.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
20.
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade 
of programmed death-1 ligands on dendritic cells enhances T cell activation and 
cytokine production. J Immunol 2003;170:1257-66.  
21.
Fourcade J, Kudela P, Sun Z, Shen H, Lenzner D, Guillaume P, et al. PD-1 is a 
regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J 
Immunol 2009;182:5240-9.
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22.
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro, H, et al. Clinical 
significance and therapeutic potential of the programmed death-1 ligand/programmed 
death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007;13:2151-7.
23.
Cai G, Karni A, Oliveira EM, Weiner HL, Hafler DA, Freeman GJ. PD-1 ligands, 
negative regulators for activation of naive, memory, and recently activated human 
CD4+ T cells. Cell Immunol 2004;230:89-98.
24.
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell 
exhaustion: an update on implications for chronic infections and tumor evasion. 
Cancer Immunol Immunother 2007;56:739-45.
25.
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PDL1 
on tumor cells in the escape from host immune system and tumor immunotherapy by 
PD-L1 blockade. Proc Natl Acad Sci USA 2002;99:12293-7.
26.
Tsushima, F, Tanaka, K, Otsuki, N, Youngnak, P, Iwai, H, Omura K, Azuma, M. 
Predominant expression of B7-H1 and its immunoregulatory roles in oral squamous 
cell carcinoma. Oral Oncol 2006;42:268-74.
27.
Korman A, Chen B, Wang C, Wu L, Cardarelli J, Selby M. Activity of Anti-PD-1 in 
Murine Tumor Models: Role of "Host" PD-L1 and Synergistic Effect of Anti-PD-1 
and Anti-CTLA-4. J Immunol 2007;178:abstr. 48.37.
28.
Seiwert T, Burtness B, Weiss J, Gluck I, Eder JP, Pai SI, et al. A phase Ib study of 
MK-3475 in patients with human papillomavirus (HPV) associated and non-HPV 
associated head and neck (H/N) cancer. ASCO 2014 Abstract #6011, Jun 2014.
29.
Stewart J, Cohen E, Licitra L, Van Herpen C, Khorprasert C, Soulieres D, et al. Phase 
III study of gefitinib compared with intravenous methotrexate for recurrent squamous 
cell carcinoma of the head and neck. Journal of Clinical Oncology 2009;27(11):1864-
1871.
30.
Schornagel JH, Verweij J, de Mulder PHM, Cognetti F, Vermorken JB, Coppeloere 
P, et al. 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 Head and Neck Cancer 
Cooperative Group Study. Journal of Clinical Oncology 1995;13(7):1649-1655
31.
Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. 
Randomized comparison of cisplatin plus fluorouracil and carboplatin plus 
fluorouracil versus methotrexate in advance squamous-cell carcinoma of the head and 
neck: A Southwest Oncology Group Study. Journal of Clinical Oncology 
1992;10(8):1245-1251.
32.
Hitt R, Amador ML, Quintela-Fandino M, Jimeno A, del Val O, Hernando S, et al. 
Weekly docetaxel in patients with recurrent and/or metastatic squamous cell 
carcinoma of the head and neck. Cancer 2006;106(1):106-111.
33.
Guardiola E, Peyrade F, Chaigneau L, Cupissol D, Tchiknavorian X, Bompas E, 
Madroszyk A, Ronchin P, Schneider M, Bleuze JP, Blay JY, Pivot X. Results of a 
randomised phase II study comparing docetaxel with methotrexate in patients with 
recurrent head and neck cancer. Eur J Cancer. 2004;40(14):2071-6.
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34.
Argiris A, Ghebremichael M, Gilbert J, Lee J-W, Sachidanandam K, Kolesar JM, et 
al. Phase III randomized, placebo-controlled trial of docetaxel with or without 
gefitinib in recurrent or metastatic head and neck cancer: An Eastern Cooperative 
Oncology Group Trial. Journal of Clinical Oncology. 2013;31:1405-1414. 
35.
Vermorken J, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-
label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of 
cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell 
carcinoma of the head and neck who failed to respond to platinum-based therapy. 
Journal of Clinical Oncology. 2007;25(16):2171-2177.
36.
Fury MG, Sherman E, Lisa D, Agarwal N, Algazy K, Brockstein B, et al. A 
Randomized phase II study of cetuximab every 2 weeks at either 500 or 750 mg/m2
for patients with recurrent or metastatic head and neck squamous cell cancer. J. Natl 
Compr Canc Netw 2012;10:1391-1398.
37.
Parkin DM, Bray F, and Pisani P. Global Cancer Statistics, 2002. CA Cancer J Clinc. 
2005;55(2):74.
38.
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.
39.
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.
40.
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.
41.
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.
42.
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.
43.
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki, A, Rottey S, et al. 
Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J 
Med. 2008;359:1116-7.
44.
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.
45.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy 
plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 
2006;354:567-78.
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46.
Yearley J, Gibson C, Yu N, Moon C, Murphy E, McClanahan T. PD-L2 expression in 
human tumors: relevance to anti-PD-1 therapy in cancer. Eur J Can 2015 ESMO 
Annual Meeting:51(33 Suppl):18LBA S718.
47.
Seiwert TY, Haddad RI, Gupta S, Mehra R, Tahara M, Berger R, et al. Antitumor 
activity and safety of pembrolizumab in patients (pts) with advanced squamous cell 
carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 
expansion cohort. J Clin Onc 2015 ASCO Annual Meeting;33(18 Suppl):LBA6008.
48.
Methotrexate 
Prescribing 
Information, 
Hospira, 
Oct 
2011.
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/011719s117lbl.pdf)
49.
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using 
rank preserving structural failure time models.  Communication in Statistics – Theory 
and Methods 1991;20(8):2609-2631
50.
Uno H, Tian L, Claggett B, Wei LJ. A versatile test for equality of two survival 
functions based on weighted differences of Kaplan-Meier curves. (to be appeared in 
Statistics in Medicine)
51.
Anderson KM. A nonproportional Hazards Weibull Accelerated Failure Time 
Regression Model.  Biometrics 1991;47:281-288.
52.
Mehrotra DV, Su S-C, Li X. An efficient alternative to the stratified Cox model 
analysis. Statist. Med 2012;31:1849-1856.
53.
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985;4:213-
26.
54.
Maurer W, Bretz F. Multiple Testing in Group Sequential Trials using Graphical 
Approaches. Statistics in Biopharmaceutical Research 2013;5(4):311-320.
55.
Gillison ML, Blumenschein G, Fayette J, et al. Nivolumab (nivo) vs investigator’s 
choice (IC) for recurrent or metastatic (R/M) head and neck squamous cell carcinoma 
(HNSCC): CheckMate-141. 2016 AACR Annual Meeting:abstr CT099.
56.
Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab 
(nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic 
(R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J 
Clin Oncol 2016 ASCO Annual Meeting:34(suppl; abstr 6009).
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
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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 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 DNA  and tumor
specimen(s) will be stored to provide a resource for future trials conducted by Merck 
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 Merck 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 the 
Future Biomedical Research sub-trial.
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 the Future Biomedical Research sub-trial in 
order to participate in the main 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 main 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 this sub-trial's 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 Merck 
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, Merck 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 Merck 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 Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck 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 Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
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 Merck 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 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
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 Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
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returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
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 Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck 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 Merck 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 Merck 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 Merck 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 the Future Biomedical 
Research sub-trial will be maintained by Merck.  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 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
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data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
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 Merck 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 Merck) 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, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck 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 Merck 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. 
Merck 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 Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
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obtained from future biomedical research will be entered into clinical records, nor will it 
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@merck.com.
14. 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
AE
Adverse Event
ADA
Anti-Drug 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
ß-HCG
Beta Human Chorionic Gonadotropin
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
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
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
Electronic Patient Reported Outcomes
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Abbreviation/Term
Definition
ERC
Ethics Review Committee
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
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HEA
Health Economic Assessment
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
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
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
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Abbreviation/Term
Definition
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum Tolerated Dose
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PFS
Progression Free Survival
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PT
Prothrombin Time
PS
Performance Status
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
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
SOC
Standard of Care
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Abbreviation/Term
Definition
SOP
Standard Operating Procedures
TIL
Tumor Infiltrating Lymphocytes
TPS
Tumor Proportion Score
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
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 Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html).
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Response Evaluation Criteria in Solid Tumors (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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List of Strong CYP3A4 Inhibitors
For subjects receiving docetaxel, avoid using concomitant strong CYP3A4 inhibitors (e.g., 
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin and voriconazole) Taxotere (docetaxel) Prescribing 
Information, 12/2013.
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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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