A Phase II Clinical Trial of Single Agent Pembrolizumab (MK-3475) in Subjects With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) Who Have Failed Platinum and Cetuximab
Phase: PHASE2
Conditions: Head and Neck Squamous Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Clinical Trial of Single Agent Pembrolizumab 
(MK-3475) in Subjects with Recurrent or Metastatic Head and 
Neck Squamous Cell Carcinoma (HNSCC) Who Have
Failed Platinum and Cetuximab
02-Jan-2018
NCT02255097

Product:  MK-3475 
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Confidential
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 II Clinical Trial of Single Agent Pembrolizumab (MK-3475) in Subjects with 
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) Who Have 
Failed Platinum and Cetuximab
IND NUMBER:  122,325
EudraCT NUMBER:  2014-002447-18
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
2.1
Trial Diagram........................................................................................................ 16
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es) .............................................................. 17
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 17
3.2
Exploratory Objectives......................................................................................... 18
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
4.1
Pharmaceutical and Therapeutic Background .................................................... 19
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 20
4.1.2
Ongoing Clinical Trials....................................................................................... 20
4.1.3
Rationale................................................................................................................ 22
4.2
Rationale for the Trial and Selected Subject Population .................................... 22
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 22
4.2.2
Rationale for Endpoints ...................................................................................... 24
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 24
4.2.3.2
Safety Endpoints .......................................................................................... 25
4.2.3.3
Planned Exploratory Biomarker Research................................................... 25
4.2.3.4
Future Biomedical Research........................................................................ 26
Benefit/Risk ........................................................................................................... 27
4.3
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 27
5.1.1
Subject Inclusion Criteria.................................................................................... 27
5.1.2
Subject Exclusion Criteria .................................................................................. 29
5.1.3
Trial Treatment(s) ................................................................................................ 31
5.2
Dose Selection/Modification .............................................................................. 32
5.2.1
 
 
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5.2.1.1
Dose Selection (Preparation) ....................................................................... 32
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 32
Timing of Dose Administration.......................................................................... 36
5.2.2
5.2.2.1
Pembrolizumab (MK-3475)......................................................................... 36
Trial Blinding/Masking....................................................................................... 38
5.2.3
Randomization or Treatment Allocation............................................................ 38
5.3
Stratification.......................................................................................................... 38
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 38
5.5
Acceptable Concomitant Medications ................................................................ 38
5.5.1
Prohibited Concomitant Medications.................................................................. 39
5.5.2
Rescue Medications & Supportive Care............................................................. 39
5.6
Diet/Activity/Other Considerations..................................................................... 43
5.7
Diet...................................................................................................................... 43
5.7.1
Contraception...................................................................................................... 43
5.7.2
Use in Pregnancy ................................................................................................ 43
5.7.3
Use in Nursing Women....................................................................................... 44
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 44
5.8
Discontinuation of Study Therapy after CR ....................................................... 45
5.8.1
Subject Replacement Strategy............................................................................. 45
5.9
Beginning and End of the Trial ........................................................................... 45
5.10
Clinical Criteria for Early Trial Termination ................................................... 46
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 47
Initial Treatment Phase and Second Course Phase (Retreatment).................. 47
6.1
Initial Treatment Phase ....................................................................................... 47
6.1.1
Second Course Phase (Retreatment) for Pembrolizumab (MK-3475) ............... 51
6.1.2
7.0
TRIAL PROCEDURES ........................................................................................... 54
Trial Procedures ................................................................................................... 54
7.1
Administrative Procedures.................................................................................. 54
7.1.1
7.1.1.1
Informed Consent......................................................................................... 54
7.1.1.1.1
General Informed Consent.................................................................... 54
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 55
 
 
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7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 55
7.1.1.3
Subject Identification Card .......................................................................... 55
7.1.1.4
Medical History ........................................................................................... 55
7.1.1.4.1
Disease Details...................................................................................... 55
7.1.1.5
Prior and Concomitant Medications Review ............................................... 55
7.1.1.5.1
Prior Medications.................................................................................. 55
Prior Treatment Details for Head and Neck Cancer ...................... 56
7.1.1.5.1.1
7.1.1.5.2
Concomitant Medications..................................................................... 56
Subsequent Anti-Cancer Therapy Status........................................ 56
7.1.1.5.2.1
7.1.1.6
Assignment of Screening Number............................................................... 56
7.1.1.7
Assignment of Randomization Number....................................................... 56
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 56
Clinical Procedures/Assessments........................................................................ 57
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 57
7.1.2.2
Physical Exam.............................................................................................. 57
7.1.2.2.1
Full Physical Exam ............................................................................... 57
7.1.2.2.2
Directed Physical Exam........................................................................ 57
7.1.2.3
Vital Signs.................................................................................................... 58
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 58
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 58
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 58
7.1.2.6.1
Initial Tumor Imaging........................................................................... 58
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 59
7.1.2.6.3
Assessment of Disease.......................................................................... 59
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling......................... 61
Laboratory Procedures/Assessments .................................................................. 61
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 62
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 63
7.1.3.2.1
Blood Collection for Serum MK-3475 ................................................. 63
7.1.3.2.2
Blood Collection for Anti-Pembrolizumab Antibodies........................ 63
7.1.3.3
Future Biomedical Research........................................................................ 63
Other Procedures................................................................................................. 63
7.1.4
 
 
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7.1.4.1
Withdrawal/Discontinuation........................................................................ 63
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 64
7.1.4.2
Blinding/Unblinding .................................................................................... 64
7.1.4.3
Calibration of Critical Equipment................................................................ 64
Visit Requirements.............................................................................................. 64
7.1.5
7.1.5.1
Screening...................................................................................................... 65
7.1.5.2
Treatment Period.......................................................................................... 65
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 65
7.1.5.3
Post-Treatment Visits................................................................................... 66
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 66
7.1.5.3.2
Follow-up Visits ................................................................................... 67
7.1.5.3.3
Survival Follow-up ............................................................................... 67
7.1.5.4
Survival Status ............................................................................................. 67
Assessing and Recording Adverse Events .......................................................... 68
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 68
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 69
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 69
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 69
7.2.3.2
Events of Clinical Interest............................................................................ 70
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 71
Evaluating Adverse Events ................................................................................. 72
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 75
8.1
Efficacy Analyses ............................................................................................... 75
8.1.1
Safety Analyses................................................................................................... 77
8.1.2
Power and Sample Size....................................................................................... 77
8.1.3
Interim Analysis.................................................................................................. 77
8.1.4
Statistical Analysis Plan ....................................................................................... 77
8.2
Responsibility for Analyses/In-House Blinding ................................................. 77
8.2.1
Hypotheses/Estimation ....................................................................................... 78
8.2.2
 
 
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Analysis Endpoints ............................................................................................. 78
8.2.3
8.2.3.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints.............................. 78
8.2.3.2
Safety Endpoints .......................................................................................... 78
Analysis Populations........................................................................................... 79
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 79
8.2.4.2
Safety Analysis Populations ........................................................................ 79
Statistical Methods.............................................................................................. 79
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses ................................................... 79
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 81
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 81
8.2.5.3.1
Demographic and Baseline Characteristics .......................................... 81
8.2.5.3.2
Pharmacokinetic Analyses.................................................................... 82
Multiplicity ......................................................................................................... 82
8.2.6
Sample Size and Power Calculations.................................................................. 83
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 84
8.2.8
Interim Analyses ................................................................................................. 84
8.2.9
Compliance (Medication Adherence) ................................................................. 84
8.2.10
Extent of Exposure.............................................................................................. 84
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 84
Investigational Product ........................................................................................ 84
9.1
Packaging and Labeling Information ................................................................. 85
9.2
Clinical Supplies Disclosure................................................................................. 85
9.3
Storage and Handling Requirements.................................................................. 85
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 85
9.5
Standard Policies................................................................................................... 86
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 86
Confidentiality....................................................................................................... 86
10.1
Confidentiality of Data ....................................................................................... 86
10.1.1
Confidentiality of Subject Records ..................................................................... 86
10.1.2
Confidentiality of Investigator Information........................................................ 86
10.1.3
 
 
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Confidentiality of IRB/IEC Information............................................................. 87
10.1.4
Compliance with Financial Disclosure Requirements....................................... 87
10.2
Compliance with Law, Audit and Debarment ................................................... 87
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 89
10.4
Quality Management System............................................................................... 90
10.5
Data Management................................................................................................. 90
10.6
Publications ........................................................................................................... 90
10.7
11.0
LIST OF REFERENCES......................................................................................... 92
12.0
APPENDICES........................................................................................................... 95
Merck Code of Conduct for Clinical Trials........................................................ 95
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 97
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 103
Abbreviations ...................................................................................................... 114
12.4
ECOG Performance Status................................................................................ 117
12.5
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 118
12.6
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
12.7
Evaluating Response in Solid Tumors .............................................................. 119
13.0
SIGNATURES......................................................................................................... 120
Sponsor's Representative ................................................................................... 120
13.1
Investigator.......................................................................................................... 120
13.2
 
 
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LIST OF TABLES
    
Table 1 Adequate Organ Function Laboratory Values ......................................................... 29
Table 2 Trial Treatment ........................................................................................................ 32
Table 3 Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab...................................................................... 33
Table 4 Imaging and Treatment after 1st Radiologic Evidence of PD................................. 37
Table 5 Infusion Reaction Treatment Guidelines ................................................................. 42
Table 6 Imaging and Treatment after 1st radiologic evidence of PD................................... 60
Table 7 Laboratory Tests ...................................................................................................... 62
Table 8 Evaluating Adverse Events...................................................................................... 73
Table 9 Primary Analysis Strategy for Efficacy Endpoints.................................................. 76
Table 10 Analysis Strategy for Key Efficacy Variables......................................................... 80
Table 11 Product Descriptions................................................................................................ 85
 
 
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LIST OF FIGURES
          
Figure 1
Trial Design ........................................................................................................ 16
Figure 2
Multiplicity Strategy........................................................................................... 82
Figure 3
Power Curve vs Sample Size of PD-L1 Strong Positive Subjects...................... 83
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
Change from Amendment 055-04 to 055-05
2.2 
Trial Diagram
The trial diagram adding pembrolizumab
extension trial after survival follow-up 
was replaced with the correct trial 
diagram.
Correction.
Changes from Amendment 055-03 to 055-05
6.1
Initial Treatment Phase and 
Second 
Course 
Phase 
(Retreatment)
Survival status activities are shown taking 
place throughout the trial.
The frequency of telephone contacts 
during the survival follow-up phase was 
changed 
from 
every 
12 
weeks 
to 
approximately every 12 weeks.
This change enables flexibility of survival 
status activities, to ensure that current, 
complete survival data are available at the 
time of database locks.
To enable flexibility of survival status 
activities
7.1.5.3.3 
Survival Follow-Up
The frequency of telephone contacts 
during the survival follow-up phase was 
changed 
from 
every 
12 
weeks 
to 
approximately 12 weeks.
To enable flexibility of survival status 
activities.
7.1.5.4 
Survival Status
This section was added to state that the 
Sponsor may request updated survival 
data during the course of the study.
To ensure that current and complete 
survival data are available at the time of 
database locks
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2
Dose Modification 
(Escalation/Titration/Other)
The dose modification guidelines were 
replaced; 
the 
replacement 
guidelines 
identify specific immune-related adverse 
events associated with pembrolizumab.
To 
provide 
current 
comprehensive 
guidelines for management of immune 
related adverse events.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
Change from Amendment 055-04 to 055-05
12.4
Abbreviations
The definition of ORR was changed from 
overall response rate to objective response 
rate.
Correction.
Changes from Amendment 055-03 to 055-05
1.0 
Trial Summary
Once subjects have achieved the trial 
objective or the trial has ended, subjects 
are discontinued from this trial and will be 
enrolled in an extension trial to continue 
protocol-defined 
assessments 
and 
treatment.
This trial has been identified to roll over 
into an extension trial.
2.2 
Trial Diagram
The pembrolizumab extension trial after 
survival follow-up is added.
5.10
Beginning and End of the 
Trial
Upon trial completion, subjects are 
discontinued 
and 
enrolled 
in 
a 
pembrolizumab extension trial. 
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.1
Initial Treatment Phase and 
Second Course Phase 
(Retreatment)
Collection of 30-day and 3-month follow-
up samples for pharmacokinetics and anti-
drug antibodies was removed.
Based on data collected from other 
pembrolizumab trials, it is no longer 
necessary to collect these samples.
6.1
Initial Treatment Phase and 
Second Course Phase 
(Retreatment)
Text was added to allow flexibility around 
the imaging schedule for subjects in 
follow-up.
To maintain subject retention and the 
collection of survival status for every 
subject enrolled.
7.1.2.6.3
Assessment of Disease
7.1.5.3.2
Follow-up Visits
7.1.3.2
Pharmacokinetic/
Pharmacodynamic 
Evaluations
Blood 
samples 
collected 
for 
pharmacokinetics and anti-drug antibodies 
may be only stored, and further analysis 
may be performed if required.   Sections 
7.1.3.2.1 and 7.1.3.2.2 were previously in 
the protocol.
These changes were made to clarify that 
samples collected may be stored and to 
allow flexibility for the continuation of 
their collection.
8.2.5.3.2
Pharmacokinetic Analysis
This analysis, if performed, will be 
reported separately.
This is added to make clear that if PK 
analysis is performed, it will be reported 
in a stand-alone report.
4.1.2
Pre-clinical and Clinical 
Trials
Reference 29 is renumbered 28.
Reference 29 precedes reference 28 in 
previous protocol versions.
4.1.3
Ongoing Clinical Trials
Reference 28 is renumbered 29.
Sequence of references
Reference 42 is removed.
This publication refers to quality of life 
assessment and not to radiologic response.
4.2.2.1
Efficacy Endpoints
Reference 32 is renumbered 31.
Sequence of references
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.2.7
Sample Size and Power 
Calculations
Reference 29 is renumbered 28.
Sequence of references
11.0
List of References
References 29, 28, and 32 are renumbered 
28, 29, and 31.
Sequence of references
Reference 30 is corrected.
Incorrect reference in previous protocol 
versions
References 31, 33 to 41, and 43 to 49 in 
previous protocol versions are removed.
These references are not cited in the 
text.
12.4
Abbreviations
eCRF (electronic Case Report Form) is 
added.
ORST 
(Oncologic 
Response-Solid 
Tumor) is defined.
This abbreviation had not been in 
Section 12.4.
This abbreviation had not been defined 
in the text.
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Ph II Clinical Trial of Pembrolizumab (MK-3475) in Subjects with 
Refractory HNSCC
Trial Phase
II
Clinical Indication
Head and Neck Squamous Cell Carcinoma (HNSCC)
Trial Type
Interventional
Type of control
No Treatment Control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
(Select Groups)
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)
Number of trial subjects
Approximately 150 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 36 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 from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact. After a screening phase of 28 days, eligible subjects will receive 
treatment on Day 1 of each 3-week dosing cycle. Treatment with
pembrolizumab (MK-3475) will continue until documented confirmed 
disease progression, unacceptable adverse event(s), intercurrent illness 
that prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the 
patient, noncompliance with trial treatment or procedure requirements, 
subject receives 24 months of study medication, or administrative 
reasons. After the end of treatment, each patient will be followed for 30 
days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment or 30 days after the end 
of treatment if the patient initiates new anticancer therapy, whichever is 
earlier). Subjects who discontinue for reasons other than radiographic 
disease progression will have post-treatment follow-up for disease status 
until end of study, 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 Investigator is notified by the Sponsor to 
discontinue follow-up.  Once subjects have achieved the trial objective or 
the trial has ended, subjects are discontinued from this trial and will be 
enrolled in an extension trial to continue protocol-defined assessments 
and treatment.
A list of abbreviations used in this document can be found in Section 12.5.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a multicenter, nonrandomized, single-cohort trial of pembrolizumab (MK-3475) in 
subjects with recurrent and/or metastatic head and neck squamous cell carcinoma who have 
progressed on platinum and cetuximab therapy.  Approximately 150 subjects are planned to 
be enrolled in this trial to examine the safety and efficacy of pembrolizumab (MK-3475) in 
this patient population. 
Subjects will receive 200 mg of pembrolizumab (MK-3475)
administered every 3 weeks (Q3W).  Subjects will be evaluated every 6-9 weeks with 
radiographic imaging to assess response to treatment.  RECIST 1.1 response rate as assessed 
by the central vendor will be used as the primary efficacy endpoint.  RECIST 1.1 will be 
adapted as described in Section 4.2.3.1 to accommodate for the tumor response patterns seen 
with pembrolizumab (MK-3475) treatment (e.g., tumor flare), and this adapted RECIST will 
be used as determined by site assessment for treatment decisions.  Adverse events will be 
monitored throughout the trial and graded in severity according to the guidelines outlined in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
Treatment with pembrolizumab (MK-3475) will continue until documented disease 
progression, unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, completion of 24 months of treatment with pembrolizumab (MK-
3475), or administrative reasons. Subjects who attain an investigator-determined confirmed 
complete response (CR) may consider stopping trial treatment after receiving at least 24 
weeks of treatment.  Subjects who discontinue after at least 24 months of therapy for reasons 
other than disease progression or intolerability or who discontinue after attaining a CR may 
be eligible for up to one year of retreatment after they have experienced radiographic disease 
progression.  The decision to retreat will be at the discretion of the investigator only if no 
cancer treatment was administered since the last dose of pembrolizumab (MK-3475), the 
subject still meets the safety parameters listed in the Inclusion/Exclusion criteria and the trial 
remains open (refer to Section 7.1.5.2.1 for further details).  After the end of treatment, each 
subject will be followed for 30 days for adverse event monitoring (serious adverse events and 
events of clinical interest will be collected for 90 days after the end of treatment or 30 days 
after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier).  
Subjects who discontinue treatment 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 contact for overall survival until death, withdrawal of consent or the 
Investigator is notified by the Sponsor to discontinue follow-up, whichever comes first.
The primary objectives of the trial are to determine the safety and tolerability of the 200 mg 
Q3W dose of pembrolizumab (MK-3475), and to determine the anti-tumor activity of 
pembrolizumab (MK-3475) in all subjects and in subjects with PD-L1 strong positive 
recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) receiving 
200 mg Q3W dose.  Secondary objectives include progression-free survival (PFS), overall 
survival (OS) and response duration (DOR).  In addition, the anti-tumor activity of 
 
 
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pembrolizumab (MK-3475) in subjects
with human papillomavirus (HPV) positive 
head/neck cancer will be evaluated as a secondary objective.  The relationship between 
candidate efficacy/resistance biomarkers (including PD-L1 expression in the tumor and its 
microenvironment) and anti-tumor activity of pembrolizumab (MK-3475)
will be 
investigated as an exploratory objective.    
Although subjects will be enrolled regardless of PD-L1 status, subjects will be required to 
provide tissue of a tumor lesion to be evaluated at a central laboratory for expression status of 
PD-L1 by immunohistochemistry (IHC).  
This trial will 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.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
Figure 1
Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To determine the safety and tolerability of 200 mg Q3W dose of 
pembrolizumab (MK-3475) in subjects with recurrent and/or metastatic head and 
neck squamous cell carcinoma who have progressed on platinum and cetuximab 
therapy. 
2) Objective: 
To evaluate anti-tumor activity of pembrolizumab (MK-3475) by 
objective response rate (ORR) using RECIST 1.1 assessed by independent radiology 
review in subjects with recurrent and/or metastatic head and neck squamous cell 
carcinoma who have progressed on platinum and cetuximab therapy.  
Hypothesis: Intravenous administration of single agent pembrolizumab (MK-3475)
to subjects with recurrent and/or metastatic head and neck squamous cell carcinoma
who have progressed on platinum and cetuximab therapy will result in a clinically 
meaningful ORR of greater than 5% based on RECIST 1.1 by independent radiology 
review.
3) Objective: To evaluate anti-tumor activity of pembrolizumab (MK-3475) by ORR 
using RECIST 1.1 assessed by independent radiology review in subjects with PD-L1
strong positive recurrent and/or metastatic head and neck squamous cell carcinoma
who have progressed on platinum and cetuximab therapy.  
Hypothesis:  Intravenous administration of single agent pembrolizumab (MK-3475)
to subjects with PD-L1 strong positive recurrent and/or metastatic head and neck 
squamous cell carcinoma who have progressed on platinum and cetuximab therapy
will result in a clinically meaningful ORR of greater than 5% based on RECIST 1.1
by independent radiology review.
The study can be declared successful in the respective population or subpopulation if either
the hypothesis test for objective (2) or the hypothesis test for objective (3) is significant.
Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective: To evaluate anti-tumor activity of pembrolizumab (MK-3475) by ORR 
using RECIST 1.1 assessed by independent radiology review in subjects with PD-L1
positive recurrent and/or metastatic head and neck squamous cell carcinoma who 
have progressed on platinum and cetuximab therapy.  
Hypothesis: Intravenous administration of single agent pembrolizumab (MK-3475)
to subjects with PD-L1 positive recurrent and/or metastatic head and neck squamous 
cell carcinoma who have progressed on platinum and cetuximab therapy will result in 
a clinically meaningful ORR of greater than 5% based on RECIST 1.1.
 
 
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2) Objective: To estimate the response duration based on RECIST 1.1 by independent 
radiology review in all subjects receiving pembrolizumab (MK-3475) with recurrent 
and/or metastatic head and neck squamous cell carcinoma who have progressed on 
platinum and cetuximab therapy.
3) Objective: To estimate the response duration based on RECIST 1.1 by independent 
radiology review separately in PD-L1 strong positive subjects and in PD-L1 positive 
subjects receiving pembrolizumab (MK-3475) with recurrent and/or metastatic head 
and neck squamous cell carcinoma who have progressed on platinum and cetuximab 
therapy.
4) Objective:  To estimate anti-tumor activity separately in all subjects, in PD-L1 strong 
positive subjects, and in PD-L1 and all PD-L1 positive subjects receiving 
pembrolizumab (MK-3475) by objective response rate (ORR) using modified 
RECIST 1.1 by independent radiology review in subjects with recurrent and/or 
metastatic head and neck squamous cell carcinoma who have progressed on platinum 
and cetuximab therapy.  
5) Objective:  To estimate the anti-tumor activity of pembrolizumab (MK-3475) by 
ORR using RECIST 1.1 by independent radiology review in all subjects with HPV 
positive recurrent and/or metastatic head and neck squamous cell carcinoma who 
have progressed on platinum and cetuximab therapy.
6) Objective:  To estimate the progression-free survival (PFS) using RECIST 1.1 by 
independent radiology review separately in all subjects, in PD-L1 strong positive 
subjects, and in all PD-L1 positive subjects receiving pembrolizumab (MK-3475)
with recurrent and/or metastatic head and neck squamous cell carcinoma who have 
progressed on platinum and cetuximab therapy.
7) Objective: To estimate the overall survival (OS) separately in all subjects, in PD-L1 
strong positive subjects, and in all PD-L1 positive subjects receiving pembrolizumab 
(MK-3475) with recurrent and/or metastatic head and neck squamous cell carcinoma 
who have progressed on platinum and cetuximab therapy.
Exploratory Objectives
3.3
1) Objective:  To estimate the progression-free survival (PFS) using modified RECIST 
1.1 by independent radiology review in subjects receiving pembrolizumab (MK-
3475) with recurrent and/or metastatic head and neck squamous cell carcinoma who 
have progressed on platinum and cetuximab therapy.
2) Objective:  To estimate ORR using RECIST 1.1 assessed by independent radiology 
review in subjects with PD-L1 combined positive score ≥ 1% recurrent and/or 
metastatic head and neck squamous cell carcinoma who have progressed on platinum 
and cetuximab therapy.
 
 
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3) Objective: To investigate the relationship between candidate efficacy/resistance 
biomarkers and anti-tumor activity of pembrolizumab (MK-3475) utilizing pre-
treatment tumor biopsies and blood sampling.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475).
Pharmaceutical and Therapeutic Background
4.1.1
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and 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 [18; 19; 20; 13].  Both ligands are type I transmembrane receptors containin g 
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 
 
 
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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 [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients 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.
Pembrolizumab (MK-3475) (previously known as SCH 900475) 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.
Pre-clinical and Clinical Trials
4.1.2
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 Investigator’s Brochure [IB]).
Patients with recurrent and/or metastatic head and neck squamous cell carcinoma who have 
progressed on platinum and cetuximab have limited treatment options.  Treatment options 
commonly utilized in this setting include palliative chemotherapy such as methotrexate or 
taxanes.  After failure of front-line chemotherapy in the recurrent/metastatic setting, 
objective responses to subsequent cytotoxic chemotherapy are uncommon. 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 patients, with a median overall 
survival of 6.7 months [28]. 
Ongoing Clinical Trials
4.1.3
Ongoing clinical trials of pembrolizumab 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.
 
 
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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 from this cohort were reported at the Annual Meeting of 
the American Society of Clinical Oncology (ASCO) in 2014 [29], 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).
Preliminary PD-L1 biomarker data from KEYNOTE 012 suggests that the response rate may 
be enhanced for patients with high PD-L1 IHC expression.  Using a Youden-Index derived 
PD-L1 IHC cutpoint, the response rate (RR) in patients with high PD-L1 expression was 
45.5% (5/11), compared to 11.4% (5/44) 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 plan to evaluate PD-L1 expression using a 1% CPS cut-off 
in addition to the 50% TPS previously specified. We plan to correlate PD-L1 expression with 
clinical outcome according to both IHC criteria.
Additional biomarker data on pembrolizumab (MK-3475) in subjects with non-small cell 
lung cancer (NSCLC) provide evidence that pretreatment tumor PD-L1 expression is a 
predictor of response. In subjects with evaluable tumor PD-L1 expression, a higher rate of 
radiologic responses by RECIST v1.1 (and irRC) occurred in subjects with tumors strongly 
positive for PD-L1, suggesting that PD-L1 may be a predictive biomarker of anti-PD-1 
activity.  This hypothesis that PD-L1 may predict potential response to anti-PD-1 therapy is 
consistent with the previously published results of Topalian et al. [30], who examined PD-L1 
expression in the archival specimens of 42 of the 296 subjects treated with the PD-1 inhibitor 
nivolumab.  Of those 17 subjects whose tumor cells did not stain positive for PD-L1 using a 
5% threshold of tumor cell surface expression, no objective response by RECIST 1.1 was 
observed.  However, among the 25 subjects whose tumor cells were considered positive for 
PD-L1, 9 responded (36%). 
 
 
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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%), 
pruritus (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%); pruritus (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%) [29].
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents.
This is a multicenter, nonrandomized, single-cohort trial of pembrolizumab (MK-3475) in 
subjects with recurrent and/or metastatic head and neck squamous cell carcinoma.  Trials 
evaluating pembrolizumab (MK-3475) in head and neck cancer have demonstrated clinical 
activity in subjects with recurrent and/or metastatic disease.  Refer to Section 4.1.3, Ongoing 
Clinical Trials, for results from the Phase Ib study of pembrolizumab in patients with HPV-
negative and HPV-positive head and neck cancer (KEYNOTE 012).
Participation in this trial will be dependent upon supplying a newly obtained core or 
excisional biopsy of a tumor lesion.  The tissue specimens will be evaluated at a central 
laboratory for expression status of PD-L1 in a retrospective analysis, thus tissue availability, 
but not high biomarker expression is required for study entry.  Therefore subjects will be 
enrolled onto this trial irrespective of PD-L1 expression (including subjects whose tumors do 
not express PD-L1).  If emerging biomarker data from on-going subjects being treated with 
pembrolizumab (MK-3475) in KEYNOTE 012 does not confirm the clinical utility of the 
PD-L1 biomarker in newly obtained tumor tissue to predict response to pembrolizumab 
(MK-3475), the newly obtained tumor sample may become optional, and may be substituted 
by an archival tumor tissue sample.  
Rationale for Dose Selection/Regimen/Modification
4.2.2
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.
 
 
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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 2mg/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 (MK-3475) 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 subjects, 
Q3W dosing will be evaluated in this protocol.
The rationale for further exploration of 2mg/kg and comparable doses of MK-3475 in solid 
tumors is based on: 1) similar efficacy and safety of MK-3475 when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of MK-
3475 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 MK-3475 (as 
assessed by the population PK model) and 4) the assumption that the dynamics of MK-3475 
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 MK-3475 showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 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.
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The primary efficacy objective of this trial is to evaluate the anti-tumor activity of 
pembrolizumab (MK-3475) in subjects with recurrent and/or metastatic head and neck 
squamous cell carcinoma (HNSCC).  Response rates per RECIST 1.1 [31] as assessed by the 
central vendor will be used as the primary response rate efficacy endpoint.
RECIST 1.1 will also be used by the local site for treatment decisions.  However RECIST 1.1 
will be adapted to account for the unique tumor response profile seen with treatment of 
pembrolizumab (MK-3475).
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses which may be 
functionally anergic.  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 criteria may not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab (MK-3475).   Therefore, RECIST 1.1 will 
be used with the following adaptation, termed Modified RECIST 1.1.
If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  If repeat imaging shows < 20% tumor burden 
compared to nadir, stable or improved previous new lesion (if identified as cause for initial 
PD), and stable/improved non-target disease (if identified as cause for initial PD), PD is not 
confirmed. Treatment may be continued as per treatment calendar.  
If repeat imaging confirms progressive disease due to any of the scenarios listed below, 
subjects will be discontinued from trial treatment (exception noted in Section 7.1.2.6.3).  In 
determining whether or not the tumor burden has increased or decreased, Investigators 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial PD is worse (qualitative)

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
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minimum of 4 weeks later.  This decision should be based on the clinical judgment of the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria:

Absence of signs and symptoms indicating disease progression

No decline in ECOG 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
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, but with subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease.  Supportive retrospective independent review of all imaging time points will be 
performed for this trial using Modified RECIST 1.1.  
4.2.3.2
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab (MK-3475) in subjects with HNSCC.  The primary safety analysis will be 
based on subjects who experienced toxicities as defined by CTCAE criteria.  Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab (MK-3475), including serious adverse events (SAEs) and events of clinical 
interest (ECIs).  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.2.3.2.
4.2.3.3
Planned Exploratory Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab (MK-3475)
therapy may also be pursued.  For example, tumor and blood samples from this study may 
undergo proteomic, genomic and transcriptional analyses.  Additional research may evaluate 
factors important for predicting responsiveness or resistance to pembrolizumab (MK-3475)
therapy and other immunologic targets.
 
 
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Assays may include but are not be limited to:
Immunohistochemistry
In addition to PD-L1 expression, other exploratory biomarkers (e.g. PD-1 expression, 
markers of T-cell phenotype) may also be evaluated.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed to assess expression of approximately 700 genes and 
attempt to define a gene set critical for clinical response to pembrolizumab (MK-3475).  The 
hypothesis to be tested is that pembrolizumab (MK-3475) induces responses in tumors that 
reflect an inflamed/ immune phenotype based on gene expression signatures capturing PD-
L1 & interferon-gamma transcriptional programs.  Global profiling will also be pursued.  
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., IL-10).
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 can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood.  There is a potential that the hypermutated state 
and/or increased T-cell clonality may correlate with response to pembrolizumab (MK-3475)
therapy, and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell 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.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens routinely and 
specifically collected for future biomedical research during this clinical trial.   This research 
may include genetic analyses (DNA), gene expression profiling (RNA), proteomics, 
metabolomics (serum, plasma) and/or the measurement of other analytes.
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 
 
 
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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.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
pembrolizumab (MK-3475) during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with head and neck squamous cell carcinoma of at least 18 years of 
age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial. The 
subject may also provide consent/assent 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 day of signing informed consent.
3. Have histologically or cytologically-confirmed recurrent or metastatic head and neck 
squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx 
that is considered incurable by local therapies.
a.
Note: Subjects with oropharynx cancer must have an assessment of HPV 
status from tumor tissue.
 
 
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4. Be resistant to platinum (either cisplatin or carboplatin) and cetuximab-based therapy.  
Resistance is defined as tumor progression or recurrence within 6 months of the last 
dose of platinum and cetuximab therapy in the adjuvant (e.g. with radiation after 
surgery), primary (e.g. with radiation), recurrent, or metastatic setting.  Subject must 
be resistant to both platinum and cetuximab.
a.
Note:  Any number of previous systemic regimens given for recurrent and/or 
metastatic disease is allowed.
b. Note: Platinum and cetuximab do not need to be given concurrently (i.e. can 
be given with sequential regimens) however the patient must have recurred
within 6 months of the last dose for each of these therapies.
5. Have provided tissue for PD-L1 biomarker analysis from a newly obtained core or 
excisional biopsy. Repeat samples may be required if adequate tissue is not provided. 
a.
Note:  Subjects for whom newly obtained samples cannot be obtained (e.g. 
inaccessible or subject safety concern) may submit an archived specimen only 
upon agreement from the Sponsor.
b. Note:  If emerging data does not demonstrate the clinical utility of PD-L1 in 
newly obtained samples, archived samples may be acceptable.
6. Have measurable disease based on RECIST 1.1 as determined by central review.
Tumor lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
8. 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 
calculateda
creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
≤1.5 X ULN 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)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
9. Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  
10. Female subjects of childbearing potential 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 childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
11. 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.
Subject Exclusion Criteria
5.1.3
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.
 
 
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2. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks prior to the first dose of trial 
treatment.
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.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.  
4. 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.
5. 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.  
6. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer.
7. 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.
8. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
9. Has active, non-infectious pneumonitis.
 
 
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10. Has an active infection requiring systemic therapy.
11. 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.  
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
13. 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.
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if 
the patient has previously participated in Merck MK-3475 clinical trials.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
17. Has received a live vaccine within 30 days of planned start of study therapy.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
18. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject.
Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in Table 2.
 
 
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Table 2
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment
Period
Use
Pembrolizumab 
(MK-3475)
200 mg
Q3W
IV infusion
Day 1 of each 3 week 
cycle
Experimental
Trial treatment should begin on or as close as possible to the date of treatment 
allocation/assignment.
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
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of dose of pembrolizumab (MK-3475) to be used in this trial is 
provided in Section 4.0 – Background & Rationale.  Details on preparation and 
administration of pembrolizumab (MK-3475) are provided in the Pharmacy Manual. 
5.2.1.2
Dose Modification (Escalation/Titration/Other)
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 
5.6 and the Events of Clinical Interest Guidance Document for supportive care guidelines, 
including use of corticosteroids.
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
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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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial 
treatment should be discontinued after consultation with the Sponsor.  Subjects who 
experience a recurrence of the same severe or life-threatening event at the same grade or 
greater with rechallenge of pembrolizumab (MK-3475) should be discontinued from trial 
treatment.  With Investigator and Sponsor agreement, subjects with a laboratory adverse 
event still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic 
and controlled.  For information on the management of adverse events, see Section 5.6.1.  
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, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
Timing of Dose Administration
5.2.2
Pembrolizumab (MK-3475) should be administered on Day 1 of each three week cycle after 
all procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
5.2.2.1
Pembrolizumab (MK-3475)
Pembrolizumab (MK-3475) 200 mg 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 reason for any delay in infusion outside of the protocol specified window should be 
documented in the patient’s chart and recorded in the case report form (CRFs). Central 
venous catheters (CVCs) or vascular access devices (VADs) may be used to administer 
treatment.
The Pharmacy
Manual contains specific instructions for the preparation of the 
pembrolizumab (MK-3475) infusion fluid and administration of infusion solution.
Treatment after initial evidence of radiologic disease progression
Immunotherapeutic agents such as pembrolizumab (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 as a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions.  
If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  If repeat imaging shows a reduction in the tumor 
 
 
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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 (exception noted in Section 7.1.2.6.3).  In determining 
whether or not the tumor burden has increased or decreased, Investigators should consider all 
target lesions as well as non-target lesions.
When feasible, subjects should not be discontinued until progression is confirmed; however, 
the decision to continue study treatment after the 1st evidence of disease progression is at the 
Investigator’s discretion based on the clinical status of the subject as described in Table 4
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 4
Imaging and Treatment after 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat imaging at 
> 4 weeks to 
confirm PD
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging at 
> 4 weeks to 
confirm PD if 
possible
Discontinue 
treatment
Repeat scan 
confirms PD
No additional 
imaging required
Discontinue 
treatment 
(exception noted 
in Section 
7.1.2.6.3)
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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Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Although this is an open-label trial, the study team at the Sponsor consisting of the clinical, 
statistics and data management personnel will remain blinded to PD-L1 patient-level 
biomarker results until the time that a study report is written. While the study team is blinded 
to PD-L1 patient-level biomarker results, access to the PD-L1 patient-level biomarker results 
will be limited to an unblinded Sponsor statistician and Sponsor statistical programmer who 
will be responsible for data review but who have no other responsibilities associated with the 
trial.
Randomization or Treatment Allocation
5.3
Allocation will occur centrally using an interactive voice response system / integrated web 
response system (IVRS/IWRS). There is one treatment arm. Subjects will be assigned 
pembrolizumab (MK-3475).
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1
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 within 30 days before the screening visit 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.
 
 
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Prohibited Concomitant Medications
5.5.2
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

Chemotherapy

Investigational agents other than pembrolizumab (MK-3475)

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor.  

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, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine.

Glucocorticoids 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.
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g. IV contrast 
dye) is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
medication.  Subjects may receive other medications that the investigator deems to be 
medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
5.6
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. 
 
 
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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.

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
 
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
Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
 
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
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
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.
 
 
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Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. Percutaneous endoscopic gastrostomy (PEG) tubes are 
acceptable for prophylactic feeding.
Contraception
5.7.2
Pembrolizumab (MK-3475) may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab (MK-3475) has transient adverse effects on the composition of 
sperm.  Non-pregnant, non-breast-feeding women may 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 should start using birth control from study Visit 1 
throughout the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab 
(MK-3475), 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.
 
 
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Use in Nursing Women
5.7.4
It is unknown whether pembrolizumab (MK-3475) is 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
5.8
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.
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) withdraws 
consent for treatment

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2.
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 
7.1.2.6.3.

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test
 
 
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
Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of treatment with pembrolizumab (MK-3475)
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab (MK-3475) 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 and events of 
clinical interest will be collected for 90 days after the end of treatment or 30 days after the 
end of treatment if the subject initiates new anticancer therapy, whichever is earlier, as 
described in Section 7.2.3.1).  Subjects who discontinue study drug for reasons other than 
progressive disease will have post-treatment follow-up for disease status until end of study 
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.
Discontinuation of Study Therapy after CR
5.8.1
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 (MK-3475) and had at 
least two treatments with pembrolizumab (MK-3475) 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 (MK-3475) at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab (MK-3475), 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.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study related phone call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator). Upon study completion, subjects are discontinued and enrolled in a 
pembrolizumab extension trial.
 
 
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Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory
requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
 
 
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6.0 TRIAL FLOW CHART
Initial Treatment Phase and Second Course Phase (Retreatment)
6.1
Initial Treatment Phase
6.1.1
Trial Period:
Screening Phase
Treatment Cyclesa
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
Approx. 
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 Administrationh
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
Xi
Xi
12-Lead ECG (Local)x
X
Full Physical Examinationx
X
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weightk
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
analysis performed by LOCAL laboratory
Pregnancy Test – Serum or Urinel
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
Xp
Chemistry Panelo
Xn
X
X
X
X
X
X
Xp
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
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
Approx. 
every 12 
weeks
Urinalysiso
Xn
X
X
Xj
Xp
T3, FT4 and TSHo
Xn
X
X
Xj
Xp
HPV Statusw
X
Laboratory Procedures/Assessments: 
analysis performed by CENTRAL 
laboratory
Pharmacokineticsq
Xq
Xq
   Xq
Anti-MK-3475 Antibodiesq
Xq
Xq
   Xq
Correlative Blood Samplesr
X
X
X
X
Blood for Geneticsv
X
Efficacy Measurements
Tumor Imaging
Xs
Xt
Xt
Xb
Tumor Tissue Collection
Newly Obtained Tissue Collection 
Xu
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 1st dose and every 6 weeks thereafter (42 days ± 7 days) regardless of any treatment delays.  After 1 year, imaging will occur every 9 weeks (± 7 
days).  
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status every 6 weeks (± 7 days) in 
the first year and every 9 weeks (± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) notified by the Sponsor, whichever occurs 
first. If imaging assessment beyond the protocol-required imaging time frame is necessary, the reason for the extended imaging schedule should be documented in the subject’s chart and 
recorded in the Oncologic Response-Solid Tumor (ORST) eCRF for each imaging assessment completed within the extended time frame. The maximum imaging time frame allowed is 
no greater than twice the imaging time frame noted for the specific year of follow-up (ie, first year follow-up is every 6 weeks; the maximum imaging schedule allowance is every 12 
weeks. Second year follow-up is every 9 weeks; the maximum imaging schedule allowance is every 18 weeks).  Every effort should be made to target the protocol-required imaging 
schedule as closely as possible; however, in the interest of the subject’s continued participation in the follow-up phase of the study, the extended imaging time frame may be considered 
at the discretion of the investigator.
c. After the start of new anti-cancer treatment or documented local site-assessed disease progression, 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 trial.  Upon Sponsor notification, all subjects who do not/will not have a 
scheduled trial visit or trial contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted.  Cycle 1 treatment must be given within 3-5 days of enrollment.
e. Written consent must be obtained prior to performing any protocol specified procedure.  Please note that the window for acquiring the “newly obtained” tissue specimen is within 42 days 
of the first dose of study drug and written consent should be obtained prior to acquiring the specimen if a biopsy for the study is performed.  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 window specified for screening procedures (e.g., within 28 days 
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
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
Approx. 
every 12 
weeks
prior to the first dose of trial treatment for required lab tests).  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 
appendices of the Central Lab Manual and Section 12.2 of the Protocol.  
g. Prior medications – Record all medications taken within 30 days of the screening visit. Concomitant medications – Enter new medications started during the trial through the Safety 
Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
h. Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons.  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 reason for any delay in infusion outside of the protocol specified window should be documented in the patient’s chart and recorded on the eCRFs. 
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 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 up to 1 year.
k. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.
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. 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. Pre-dose trough PK and anti-pembrolizumab (MK-3475) antibody samples will be collected at Cycles 1, 2, 4, 8, and every 4 cycles thereafter. All pre-dose trough samples should be 
drawn within 24 hours before infusion of pembrolizumab (MK-3475). Additional post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab (MK-3475)
infusion at Cycles 1 and 8.  An additional, single PK sample should be drawn between 72 and 168 hours after Cycle 1 dosing.
r. Blood for correlative studies should be collected prior to Cycle 1, Cycle 2, Cycle 3 and again at treatment discontinuation.
s. The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment and must be sent to the central vendor to confirm measureable disease for study 
eligibility.  Imaging should include the head, neck, chest, and abdomen; imaging of the pelvis is optional (refer to Section 7.1.2.6). Scans performed as part of routine clinical management 
are acceptable for use as the screening scan if they are of diagnostic quality, meet the requirements specified by the protocol, and are performed within 28 days prior to the first dose of 
trial treatment.  
t.
The first on-study imaging time point will be performed at 9 weeks (± 7 days) after first dose of study treatment and then every 6 weeks (± 7 days) thereafter or more frequently if 
clinically indicated. After 1 year, imaging time point will occur every 9 weeks (± 7 days). Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts 
or extension of pembrolizumab (MK-3475) cycle frequencies. Imaging should include the head, neck, chest, and abdomen; imaging of the pelvis is optional (refer to Section 7.1.2.6). The 
same imaging technique should be used in a subject throughout the trial.  On-study scans, including the baseline scans, should be submitted immediately to the central imaging vendor. 
u. Baseline tumor tissue for biomarker analysis from a newly obtained core or excisional biopsy (FNA not adequate) must be provided to the central vendor for PD-L1 biomarker testing.
Confirmation of tissue adequacy should be received from the central vendor prior to the first dose of trial treatment.  A “newly obtained” sample may be obtained up to 42 days prior to 
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
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
Approx. 
every 12 
weeks
treatment initiation. Tissue beyond the 42-day window may be considered with Sponsor approval as long as no intervening systemic therapy has been administered. Tissue that has been 
previously irradiated is acceptable. Detailed instructions for tissue collection, process and shipment are provided in the appendices of the Central Lab 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. This sample should be drawn for planned, exploratory genetic analysis of DNA unless there is either a documented law or regulation prohibiting collection, or unless the IRB/IEC does
not approve of the collection. If the sample is collected, any leftover extracted DNA will be stored for future biomedical research if the subject signs the optional Future Biomedical
Research consent.
w. Subjects with oropharynx cancer must have an assessment of HPV status from tumor tissue. Any prior HPV status included in the patient’s medical history may be used.
x. In the event that a screening assessment is delayed due to a central vendor assessment (i.e. assessment of measureable disease by the central imaging vendor or assessment of tumor 
adequacy), Sponsor approval may be granted to allow testing outside of the visit window.
 
 
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Second Course Phase (Retreatment) for Pembrolizumab (MK-3475)
6.1.2
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
Approx. 
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
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments:  
analysis performed by LOCAL laboratory
Pregnancy Test – Serum or Urinel
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
Xs
Chemistry Panelo
Xn
X
X
X
X
X
X
Xs
T3, FT4 and TSHo
Xn
Xj
Xj
Xs
Laboratory Procedures/Assessments: 
analysis performed by CENTRAL 
laboratory
Pharmacokineticsp
X
X
Xp
Anti-pembrolizumab Antibodiesp
X
X
Xp
Efficacy Measurements
Tumor Imagingq
X
X
X
Xr
Xq
 
 
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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
Approx. 
every 12 
weeks
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 every 6 
weeks by radiologic imaging until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) until notified by the Sponsor, whichever occurs 
first. If imaging assessment beyond the protocol-required imaging time frame is necessary, the reason for the extended imaging schedule should be documented in 
the subject’s chart and recorded in the ORST eCRF for each imaging assessment completed within the extended time frame. The maximum imaging time frame 
allowed is no greater than twice the imaging time frame noted for the specific year of follow up (ie, first year follow-up is every 6 weeks; the maximum imaging 
schedule allowance is every 12 weeks. Second year follow-up is every 9 weeks; the maximum imaging schedule allowance is every 18 weeks).  Every effort should 
be made to target the protocol-required imaging schedule as closely as possible; however, in the interest of the subject’s continued participation in the follow-up 
phase of the study, the extended imaging time frame may be considered at the discretion of the investigator.
c.
After the start of new anti-cancer treatment or disease progression documented 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 trial. Upon 
Sponsor notification, all subjects who do not/will not have a scheduled trial visit or trial contact during the Sponsor-defined time period will be contacted for their 
survival status (excluding subjects who 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.
 
 
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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
Approx. 
every 12 
weeks
p.
Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, every 4 cycles thereafter.  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. Imaging should include the head, neck, chest, and abdomen; imaging of the pelvis is 
optional (refer to Section 7.1.2.6). 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 does not need to be performed.
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.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
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
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 written 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 patient qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically 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 30 days before the screening visit. Prior treatment for head and neck cancer will be 
recorded separately and not listed as a prior medication.
 
 
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Prior Treatment Details for Head and Neck Cancer
7.1.1.5.1.1
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record 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
7.1.1.5.2.1
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 allocated by non-random assignment and will receive a 
randomization number. The randomization number identifies the subject for all procedures 
occurring after allocation to treatment.  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.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab (MK-3475) doses 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 (MK-3475) infused will be compared to the total volume 
prepared to determine compliance to each dose of pembrolizumab (MK-3475) administered.
The instructions for preparing and administering pembrolizumab (MK-3475) will be 
provided in the Pharmacy Manual.
Clinical Procedures/Assessments
7.1.2
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 Appendix 12.7).  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 (MK-3475) all AEs of unknown 
etiology associated with pembrolizumab (MK-3475) 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 physical 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 Appendix 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 
imaging section of 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 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 used 
if clinically appropriate.
Imaging should include the head, neck, chest, and abdomen at all timepoints specified in the 
Study Flow Chart.  Imaging of the pelvis is optional.  A CT from the vertex (of the head) to 
the thoracic inlet is strongly preferred.  If a CT from the vertex is not feasible, then a brain 
CT may be completed instead.  For an individual subject, imaging should be consistent at all 
timepoints, (i.e. follow-up scans should image the same areas as the baseline area, using the 
same imaging modality).
Real-time determination of measurable disease by independent radiology review at screening 
will be used to determine subject eligibility.  All tumor imaging including scheduled imaging 
specified in the Study Flow Chart and unscheduled imaging should be submitted to the 
central imaging vendor. 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.
7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.  The central imaging vendor must review the baseline scan to determine subject 
eligibility.  The baseline imaging scan should be submitted to the central imaging vendor
immediately.
 
 
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Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality, meet the requirements specified in the 
imaging manual, and performed within 28 days prior to the first dose of trial treatment.  
7.1.2.6.2 Tumor Imaging During Trial
The first imaging assessment should be performed at 9 weeks (63 days ± 7 days) from the 
date of 1st dose.  Subsequent imaging should be performed every 6 weeks (42 days ± 7 days),
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 (6 weeks later), whichever is clinically indicated. Imaging should 
then return to the original schedule beginning with the next protocol-specified timepoint.
Subjects who obtain a confirmation scan at 4 weeks do not need to undergo the next 
scheduled imaging assessment if it is due < 4 weeks later; imaging may resume at the 
subsequent scheduled timepoint. (e.g. If a subject obtains a scan at Week 13 to confirm a 
Week 9 response, they will not be required to complete the scheduled Week 15 scan.  The 
next imaging would then occur at Week 21 as usual.)
Imaging should continue to be performed until radiographic disease progression, the start of 
new anti-cancer treatment, withdrawal of consent, death, or notification by the Sponsor, 
whichever occurs first.  Disease progression may be confirmed 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.  Scans should be submitted to the central imaging vendor in a 
timely fashion.  Sites should also assess tumor response and progression per modified 
RECIST 1.1 and this data will be collected in the clinical database.   Site assessment of tumor 
response and progression will be used for all patient decision making in the trial.
Modified RECIST 1.1 is RECIST 1.1 adapted as follows to account for the unique tumor 
response seen in this class of therapeutics (refer to Section 4.2.2.1). 
 
 
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If radiologic imaging shows PD, tumor assessment may be repeated 4 weeks later at the 
site in order to confirm PD with the option of continuing treatment for clinically stable 
subjects as discussed below in Table 6.  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
Table 6
Imaging and Treatment after 1st radiologic evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat imaging at >
4 weeks at site to 
confirm PD
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scan 
by site
Repeat imaging at >
4 weeks to confirm 
PD per physician 
discretion only
Discontinue 
treatment
Repeat scan 
confirms PD
No additional 
imaging required
Discontinue 
treatment
No additional 
imaging required
N/A
Repeat scan shows 
SD, PR or CR
Continue regularly 
scheduled imaging 
assessments
Continue study 
treatment at the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions.  Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation. If radiologic 
progression is confirmed (by subsequent scan) then the subject will be discontinued from 
trial treatment.  
If radiologic progression is not confirmed, then the subject should resume/continue trial 
treatment and have their next scan at the regularly scheduled interval. Subjects who obtain a 
confirmation scan at 4 weeks do not need to undergo the next scheduled imaging assessment 
if it is due < 4 weeks later.
Imaging may be performed at the next scheduled imaging 
timepoint if the subject remains clinically stable.
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.
 
 
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Imaging during the follow-up period is to be repeated every 6 weeks (± 7 days) for the first 
year patients are on study and then every 9 weeks (± 7 days) after 1 year for subjects who 
discontinue trial treatment for reasons other than disease progression. Follow-up scans should 
be continued until the subject experiences confirmed disease progression or starts a new anti-
neoplastic therapy.  
If imaging assessment beyond the protocol-required imaging time frame is necessary for the 
subject’s continued participation in the follow-up phase of the study, an extended imaging 
schedule may be considered at the discretion of the investigator. Please refer to Section 6.1-
Initial Treatment Phase and Second Course Phase (Retreatment).
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling
Subjects with oropharynx cancer must have an assessment of HPV status from tumor tissue
(see Section 6.1.1).  
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 and HPV status, 
performed retrospectively.  Upon receipt of the sample, the central lab will perform an H&E 
to confirm the sample contains sufficient tumor for PD-L1 analysis. Confirmation of tissue 
adequacy should be received from the central vendor prior to the first dose of trial treatment.  
Repeat samples may be required if adequate tissue is not provided.
A “newly obtained” sample may be obtained up to 42 days prior to treatment initiation. 
Tissue beyond the 42-day window may be considered with Sponsor approval as long as no 
intervening systemic therapy has been administered.  Tissue that has been previously 
irradiated is acceptable. Subjects for whom newly obtained samples cannot be obtained (e.g. 
inaccessible or subject safety concern) may submit an archival specimen only upon 
agreement from the Sponsor.  
Submission of tissue in formalin or embedded tumor tissue sample blocks is preferred. If 
submitting unstained slides, the slides should be freshly cut and submitted to the testing 
laboratory within 14 days from site slide sectioning date otherwise a new specimen will be 
requested. Detailed instructions for tissue collection, processing, and shipment are provided 
in the appendices of the Central Lab Manual.
Blood for correlative biomarker studies should be collected pre-dose Cycle 1, Cycle 2, Cycle 
3, and again at treatment discontinuation. 
Detailed instructions for tissue collection, 
processing and shipment are provided in the appendices of the Central Lab Manual.
Laboratory Procedures/Assessments
7.1.3
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 patient can be found in the Procedures 
Manual for the study.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 7.
Table 7
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)/FT3b
Red Blood Cell 
Count
Bicarbonate
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
Blood for FBR
Creatinine
Blood for correlative studies
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
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 considered standard of care in your region.
c Blood Urea Nitrogen is preferred; if not available urea may be tested.
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.
 
 
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7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity of and exposure to pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in Section 6.1-Initial Treatment Phase and Second Course Phase 
(Retreatment).C. Blood samples for PK and ADA that are collected may be only stored at 
this time. Further analysis may be performed if required. If ongoing PK and/or ADA 
sampling is deemed 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 appendices of the Central Lab Manual.  
7.1.3.2.2 Blood Collection for Anti-Pembrolizumab Antibodies
Sample collection, storage and shipment instructions for anti- pembrolizumab (MK-3475) 
antibody samples will be provided in the appendices of the Central Lab Manual.  Anti-
pembrolizumab (MK-3475) antibody samples should only be drawn for all study subjects 
participating in the study.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA

Leftover tumor tissue
Other Procedures
7.1.4
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 who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab (MK-3475) 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 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 the Central Lab Manual.
Visit Requirements
7.1.5
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 subject allocation, 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.

A “newly obtained” tissue sample is not required to be obtained within 28 days prior 
to the first dose of trial treatment. The sample should be obtained within 42 days of 
the first dose. See Section 7.1.2.7 for additional details regarding tumor tissue 
requirements.
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 who stop pembrolizumab (MK-3475) with SD or better may be eligible for up to 
one year of additional MK-3475 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 (MK-3475) after attaining an 
investigator-determined confirmed CR according to RECIST 1.1

Was treated for at least 24 weeks with pembrolizumab (MK-3475)
before discontinuing therapy AND

Received at least two treatments with pembrolizumab (MK-3475)
beyond the date when the initial CR was declared
 
 
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OR
o
Had SD, PR or CR and stopped pembrolizumab (MK-3475) 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 (MK-3475)

Did not receive any anti-cancer treatment since the last dose of pembrolizumab (MK-
3475)

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 (MK-3475).  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.  
 
 
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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.  
Subjects who are eligible for retreatment with pembrolizumab (MK-3475) (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 radiographic 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). Every effort should be made to collect information
regarding disease status until the start of new anti-cancer therapy, radiographic disease 
progression, death, end of study or if the subject begins retreatment with pembrolizumab 
(MK-3475) as detailed in Section 7.1.5.2.1.  Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. If imaging assessment beyond the 
protocol-required imaging time frame is necessary for the subject’s continued participation in
the follow-up phase of the study, an extended imaging schedule may be considered at the 
discretion of the investigator. Please refer to Section 6.1-Initial Treatment Phase and Second 
Course Phase (Retreatment) .
Subjects who are eligible to receive retreatment with pembrolizumab (MK-3475) 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 6.1.2 –  
Second Course Phase (Retreatment) for Pembrolizumab (MK-3475).
7.1.5.3.3 Survival Follow-up
Once a subject experiences confirmed disease progression 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.
7.1.5.4
Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival data 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 interim and/or 
final analysis.  Upon Sponsor notification, all subjects who do not/will not have a scheduled 
study visit or study contact during the Sponsor-defined time period will be contacted for their 
survival status (excluding subjects who have a previously recorded death event in the 
collection tool).
 
 
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Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment allocation
must be reported by the investigator if they cause the subject to be excluded from the trial, or 
are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. From the time of 
treatment allocation 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 
7.2.1
Sponsor
For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of pembrolizumab 
(MK-3475). 
No specific information is available on the treatment of overdose of 
pembrolizumab (MK-3475). In the event of overdose, the subject should be observed closely 
for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.
 
 
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If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
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 treatment 
allocation 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 treatment allocation through 120 days 
following cessation of Sponsor’s product or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
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;
 
 
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●
Is a congenital anomaly/birth defect;
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose;
●
Is an other important medical event 
Refer to Table 8 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment allocation, 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 treatment allocation 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 treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to 
the Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation through 90 days following cessation of 
treatment, any ECI, or follow up to an ECI, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, whether or not related to the 
Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
 
 
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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).
3. 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.  
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
 
 
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The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the 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
7.2.4
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 8
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) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 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 
test drug 
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 there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
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 obtaining PD-L1 positivity status, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9).  
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, 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.
Statistical Analysis Plan Summary
8.1
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).
The primary purpose of this study is to investigate the safety, tolerability, and anti-tumor 
activity of pembrolizumab (MK-3475) 200 mg Q3W administered intravenously to subjects 
with recurrent and/or metastatic head and neck cancer who have failed prior platinum and 
cetuximab therapy.
Efficacy Analyses
8.1.1
The full analysis set (FAS) population (defined as all subjects with a baseline scan with 
measurable disease by independent radiology review who receive at least one dose of study 
treatment) will serve as the primary population for the analyses of efficacy data in this trial.  
Supportive analyses of efficacy will be conducted in the all Patients as Treated (APaT) 
population as well as the FAS.  Objective response rate will be used to evaluate the primary 
efficacy hypotheses and will be estimated separately for all subjects and for subjects who are 
PD-L1 strong positive, where PD-L1 strong positive is defined as PD-L1 tumor proportion 
score greater than or equal to 50% by IHC.  A 97.5% confidence interval along with a one-
sided p-value for testing the null hypothesis based on the binomial distribution will be 
provided for ORR.  The respective study is considered to have reached the efficacy objective 
if the p-value for testing the primary hypothesis in all subjects is less than 1.25% OR if the p-
value for testing the primary hypothesis in PD-L1 strong positive subjects is less than 1.25%. 
A stepdown procedure controls Type I error between the primary PD-L1 strong positive 
hypothesis and the secondary PD-L1 positive hypothesis. An outline of the efficacy analysis 
strategy is presented in Table 9 below.
 
 
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Table 9
Primary Analysis Strategy for Efficacy Endpoints
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary:
ORR (RECIST 1.1) based 
on independent radiology 
review
Exact test of binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
ORR(RECIST 1.1) in 
PD-L1 strong positive 
subjects* based on
independent radiology 
review
Exact test of binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Secondary:
ORR(RECIST 1.1) in 
PD-L1 positive subjects†
based on independent
radiology review
Exact test of binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Response Duration based 
on independent radiology 
review
Summary statistics using 
Kaplan-Meier method
All responders
Non-responders are 
excluded in analysis
Response Duration in 
PD-L1 strong positive 
subjects based on 
independent radiology 
review
Summary statistics using 
Kaplan-Meier method
All responders
among PD-L1 
strong 
positive* 
subjects
Non-responders are 
excluded in analysis
Response Duration in 
PD-L1 positive subjects 
based on independent
radiology review
Summary statistics using 
Kaplan-Meier method
All responders
among PD-L1 
positive†
subjects
Non-responders are 
excluded in analysis
ORR (modified RECIST 
1.1) in all subjects, all 
PD-L1 positive subjects, 
and all PD-L1 strong 
positive subjects
Point estimate and 95% CI 
using exact binomial methods
FAS
Subjects with missing 
data are considered 
non-responders
ORR (RECIST 1.1) in 
HPV positive subjects
Point estimate and 95% CI 
using exact binomial methods
FAS
Subjects with missing 
data are considered 
non-responders
Progression-free survival
in all subjects, all PD-L1 
positive subjects, and all 
PD-L1 strong positive 
subjects
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
Overall survival in all 
subjects ,  all PD-L1 
positive subjects, and all 
PD-L1 strong positive 
subjects
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
* PD-L1 strong positive is defined as PD-L1tumor proportion score ≥50% by IHC.
†PD-L1 positive is defined as PD-L1tumor proportion score exceeding 0% by IHC.
 
 
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Safety Analyses
8.1.2
The All-Patients-as-Treated population will be employed for safety analyses.  
Power and Sample Size
8.1.3
Assuming that approximately 135 of the 150 enrolled subjects with recurrent and/or 
metastatic head and neck cancer will be evaluable for the primary efficacy analysis in the 
FAS population, the study has approximately 85% power to demonstrate that the ORR is 
>5% with a type I error rate of 1.25%
  Success for this 
hypothesis requires at least 14/135 responses.  
Assuming that the prevalence of PD-L1 strong positive subjects with recurrent and/or 
metastatic head and neck cancer is 20%~30%, then among the 150 enrolled subjects 
approximately 30~45 PD-L1 strong positive subjects would be expected.
The study has 
approximately 92% to 99% power to demonstrate that the ORR >5% with a type I error rate 
of 1.25% if the 
Success for this 
hypothesis requires at least 6 responses out of 30~39 PD-L1 strong positive subjects, and at 
least 7 responses out of 40~45 PD-L1 strong positive subjects.  
Interim Analysis
8.1.4
No interim analyses are planned.
Statistical Analysis Plan
8.2
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as an open-label non-randomized single-arm clinical trial, i.e., 
subjects, investigators, and Sponsor personnel will be aware of subject treatment assignments 
after each subject is enrolled and treatment is assigned. The study team at the Sponsor 
consisting of clinical, statistical, scientific programming and data management personnel, 
will be blinded to individual-level PD-L1 biomarker results until the time that a study report 
is written. While the study team is blinded to the PD-L1 patient-level biomarker results, an 
unblinded Sponsor statistician and Sponsor statistical programmer who will have access to 
the PD-L1 results for the purpose of data review and cleaning and will have no other 
responsibilities associated with the study. Summary reports of biomarker prevalence may be 
provided to the study team at the Sponsor by the IVRS vendor, the unblinded Sponsor 
statistician, and/or an unblinded external statistician.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.  Allocation will be implemented in an interactive voice response 
system (IVRS).
 
 
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Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
8.2.3.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
The primary efficacy endpoint is objective response rate (ORR), defined as the proportion of 
subjects in the analysis population who have complete response (CR) or partial response 
(PR) using RECIST 1.1 criteria at any time during the study.  Response for the primary 
analyses will be determined by independent radiology review. ORR will be evaluated 
separately in all subjects and the subset of all PD-L1 strong positive subjects (defined as a 
PD-L1 tumor proportion score ≥50% by IHC).
Supportive analyses of ORR will be performed based on site assessments using RECIST 1.1.  
ORR in all subjects with any PD-L1 positive will be a key secondary efficacy endpoint. PD-
L1 positivity is defined as PD-L1 tumor proportion score >0% by IHC. Other key secondary 
efficacy endpoints that will be evaluated in all subjects, all PD-L1 positive subjects, and all 
PD-L1 strong positive subjects include: 
Duration of Response:  defined as time from first RECIST 1.1 response to disease 
progression in subjects who achieve a PR or better
ORR by modified RECIST 1.1:  defined as proportion of subjects with a CR or PR using 
modified RECSIT 1.1 criteria as defined in Section 4.2.3.1.
ORR among HPV positive subjects:  defined as the proportion of subjects with HPV 
positive tumor biopsy who achieve a CR or PR according to RECIST 1.1 criteria.
Progression-free survival (PFS):  defined as the time from allocation to the first 
documented disease progression according to RECIST 1.1 or death due to any cause, 
whichever occurs first.
Overall survival (OS):  defined as the time from allocation to death due to any cause.  
Additional exploratory endpoints include PFS by modified RECIST 1.1 criteria and 
ORR/PFS/OS by exploratory candidate biomarkers.
8.2.3.2
Safety Endpoints
A description of safety measures is provided in Section 4.2.3.2.  
The primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who have 
received pembrolizumab (MK-3475), including serious adverse events (SAEs) and events of 
 
 
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clinical interest (ECIs).  Immune-related ECIs, as described in Section 7.2.3.2 will be 
collected.  Other safety endpoints include laboratory safety assessments, ECOG performance 
status, vital signs and physical examinations.
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all subjects who:

Receive at least one dose of study treatment,

Have a baseline scan with measurable disease per RECIST 1.1 by independent
radiology review
A supportive analysis using the All Patients as Treated (APaT) population, defined as all 
enrolled subjects who receive at least one dose of study medication, will be performed for the 
primary efficacy endpoint(s).  Supportive analyses in the FAS population using the site 
radiology assessment will require baseline scan with measureable disease per RECIST 1.1 
using site radiology assessment.
Details on the approach to handling missing data are provided in Section 8.2.5 Statistical 
Methods.
8.2.4.2
Safety Analysis Populations
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
Statistical Methods
8.2.5
Statistical testing and inference for safety analyses are described in 8.2.5.2.   Efficacy results 
that will be considered to be statistically significant after consideration of the strategy for 
controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses as a measure of strength of association between 
the endpoint and the treatment effect rather than formal tests of hypotheses.  
8.2.5.1
Statistical Methods for Efficacy Analyses
For the primary efficacy endpoint independently reviewed ORR using RECIST 1.1, the point 
estimate, 97.5% confidence interval, and p-value for testing ORR is greater than the 
 
 
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historical control rate of 5% will be provided separately for all subjects and PD-L1 strong 
positive subjects using exact binomial distribution. Subjects in the primary analysis 
population (FAS) without response data will be counted as non-responder.
Efficacy for the key secondary endpoint of ORR among PD-L1 positive subjects, as well as 
other secondary analyses of ORR using modified RECIST 1.1 and ORR among subjects with 
HPV positive head and neck cancer will be evaluated in the same manner as in the primary 
analysis.  
For the secondary analyses of response duration, PFS and OS, Kaplan-Meier (KM) curves 
and median estimates from the KM curves will be provided as appropriate. Subjects without 
efficacy evaluation data or without survival data will be censored at Day 1.
The primary analysis for each hypothesis will be conducted after all subjects have at least 6 
months of follow-up.  The final analysis of OS will occur when <5% of patients remain on 
study drug.  
Table 10 summarizes the key efficacy analyses.
Table 10
Analysis Strategy for Key Efficacy Variables
Endpoint
Statistical Method
Analysis Population
Missing data 
approach
ORR

RECIST 1.1, 
independent 
radiology review
Exact test of 
binomial parameter
FAS in all below populations:

all-comers 

PD-L1 strong positive*

PD-L1 positive‡
Subjects with 
missing data are 
considered non-
responders
ORR

RECIST 1.1, 
independent 
radiology review

modified RECIST 
1.1, independent 
radiology review

modified RECIST 
1.1, investigator
Point estimate and 
exact  binomial CI║
FAS in all below populations:

all-comers 

PD-L1 strong positive*

PD-L1 positive‡

HPV positive
APaT in all below populations:

all-comers 

PD-L1 strong positive

PD-L1 any positive

HPV positive
Subjects with 
missing data are 
considered non-
responders
Response Duration

RECIST 1.1, 
independent 
radiology review 

modified RECIST 
1.1, investigator
Summary statistics 
using Kaplan-
Meier method
FAS in all below populations:

all-comers 

PD-L1 strong positive*

PD-L1 positive‡
APaT in all below populations:

all-comers 

PD-L1 strong positive

PD-L1 positive
Non-responders are 
excluded in analysis
 
 
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Endpoint
Statistical Method
Analysis Population
Missing data 
approach
PFS

RECIST 1.1, 
independent 
radiology review 

modified RECIST 
1.1, investigator
Summary statistics 
using Kaplan-
Meier method
FAS in all below populations:

all-comers 

PD-L1 strong positive*

PD-L1 positive‡
APaT in all below populations:

all-comers 

PD-L1 strong positive

PD-L1 positive
Censored at last 
assessment date
OS

RECIST 1.1, 
independent 
radiology review 

modified RECIST 
1.1, investigator
Summary statistics 
using Kaplan-
Meier method
FAS in all below populations:

all-comers 

PD-L1 strong positive*

PD-L1 positive‡
APaT in all below populations:

all-comers 

PD-L1 strong positive

PD-L1 positive
Censored at last 
assessment date
* PD-L1 strong positive is defined as PD-L1tumor proportion score ≥50% by IHC.
‡ PD-L1 positive is defined as PD-L1tumor proportion score exceeding 0% by IHC.
║ Exact Clopper-Pearson 95% CI will be provided.
Exploratory analyses of PFS using modified RECIST 1.1 criteria and PFS/OS by exploratory 
candidate biomarkers will also follow the same approach as for the secondary analyses of 
PFS and OS.  The exploratory analysis of ORR by PD-L1 combined positive score (CPS) and 
exploratory candidate biomarkers will be conducted using point estimate and exact binomial 
CI.
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, and vital signs. 
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate. The 95% confidence interval for the incidence rate of 
Grade 2 or higher adverse events with an immune etiology and the incidence rate of Grade 
4/5 AEs will be provided as appropriate.  
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.3.1
Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs.  No statistical 
hypothesis tests will be performed on these characteristics.  The number and percentage of 
subjects screened, randomized, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed.  Demographic variables (e.g., age, gender), 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized by treatment either by descriptive statistics or a categorical 
summary.
 
 
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8.2.5.3.2 Pharmacokinetic Analyses
Based on pharmacokinetic data obtained within this study, the exposure response relationship 
for MK-3475 and measures of antitumor activity/efficacy and pharmacodynamic biomarkers 
may be explored. The analysis, if performed, will be reported separately.
Multiplicity
8.2.6
The false positive rate for testing the primary efficacy hypotheses is controlled at 2.5% (1-
sided) with 1.25% allocated to all subjects and 1.25% allocated to PD-L1 strong positive 
subjects.  The key secondary efficacy hypothesis of ORR based on RECIST 1.1 assessed by 
independent radiology review in PD-L1 positive subjects will be tested at 1.25% (one-sided) 
if the primary efficacy hypothesis in PD-L1 strong positive subjects is rejected. If both the 
primary hypothesis for PD-L1 strong positive subjects and the key secondary efficacy 
hypothesis are rejected, the additional alpha level 1.25% will be allocated back to all subjects 
and the primary efficacy hypothesis for all subjects will be tested at 2.5% (Figure 2).
Figure 2
Multiplicity Strategy 
 
 
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Sample Size and Power Calculations
8.2.7
Assuming that approximately 135 of the 150 enrolled subjects with recurrent and/or 
metastatic head and neck cancer will be evaluable for the primary efficacy analysis in the 
FAS population, the study has approximately 85% power to demonstrate that the ORR is 
>5% with a type I error rate of 1.25%
  Success for this 
hypothesis requires at least 14/135 responses.  The null ORR rate of 5% was determined 
based on a prior randomized trial of methotrexate therapy vs. gefinitib in a second line 
population in which an ORR of 4% was observed in the methotrexate arm [28].
The proportion of subjects who are PD-L1 strong positive among the 150 subjects enrolled is 
not known but is estimated to be approximately 20%~30%, then 150 subjects would be 
expected to provide 30~45 PD-L1 strong positive subjects with recurrent and/or metastatic
head and neck cancer will be evaluable for the primary efficacy analysis in the FAS 
population.  Figure 3 shows the power curve ranging about 92% to 99% vs the sample size 
between 30 and 45, when the ORR>5% with a type I error rate of 1.25%
 
Success for this hypothesis requires at least 6
responses out of 30~39 subjects with PD-L1 strongly positive, and at least 7 responses out of
40~45 subjects with PD-L1 strongly positive.  The power may increase or decrease 
depending on the actual number of PD-L1 strong positive subjects who are enrolled in the 
study (Figure 3).
Figure 3
Power Curve vs Sample Size of PD-L1 Strong Positive Subjects
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.2.8
All efficacy endpoints will be evaluated by the following categories:  

HPV-positive and HPV-negative subjects

PD-L1 positive (> 0%) and PD-L1 negative subjects.

PD-L1 strong positive (≥50%) and PD-L1 not strong positive (0 to <50%).
In addition, subgroup analyses of efficacy (ORR, PFS and OS) by the following demographic 
factors will be performed.

Baseline ECOG status

Number of prior therapies
Interim Analyses
8.2.9
No interim analyses are planned in this trial.  
Compliance (Medication Adherence)
8.2.10
A day within the study will be considered an On-Therapy day if the subject receives the 
study medication infusion. The number of Days on Therapy is the total number of days from 
the first day of study medication to the date of the last dose of study medication. 
Summary statistics for the number of Days on Therapy will be provided by treatment group 
for the FAS population.
Extent of Exposure
8.2.11
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure for 
APaT population.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 11.
 
 
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Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab (MK-3475) 100 mg  / 4 mL
Solution for Infusion
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open label.  Pembrolizumab will be provided as non-kitted 
single vials or as single vials in a kit box.  
Clinical Supplies Disclosure
9.3
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
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
 
 
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Standard Policies
9.6
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
10.1
Confidentiality of Data
10.1.1
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
10.1.2
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
10.1.3
By signing this protocol, the investigator recognizes that certain personal identif ying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
 
 
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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
10.1.4
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
10.2
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.
Compliance with Law, Audit and Debarment
10.3
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.
 
 
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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 
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.  
 
 
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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
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the 
Sponsor of the trial is solely responsible for determining whether the trial and its results are 
subject
to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialregister.eu or other local registries. 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 FDAAA or the EMA clinical trials directive 
mandated trials. Information posted will allow subjects to identify potentially appropriate 
trials for their disease conditions and pursue participation by calling a central contact number 
for further information on appropriate trial locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
 
 
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Quality Management System
10.5
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
10.6
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
10.7
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, 
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.
 
 
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For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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11.0 LIST OF REFERENCES
1.
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-38.
2.
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.  
3.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
4.
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.  
5.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
6.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.  
7.
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.
8.
Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.  
9.
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-27.
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.  
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-64.  
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.  
 
 
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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.  
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-41.  
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.  
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.  
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic 
lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-
59.  
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-97.  
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-1506.  
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-
24.  
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.  
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.  
 
 
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25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R et al. Foxp3+ cell 
infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.  
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Ann Rev Immunol 
2005;23:515-48.  
28. 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. J Clin Oncol 2009;27(11):1864-71.
29. 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.
30. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al. 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Eng J Med 
2012;366(26):2443-54.
31. 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):106-11.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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
12.2
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 tissue 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 tissue
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 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
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 patient 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.
 
 
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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. 
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. 
 
 
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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 
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 
 
 
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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 
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 patient 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.
 
 
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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 
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. 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 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Abbreviations
12.4
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
APaT
All Patients 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
DNA
Deoxyribonucleic acid
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Forms
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
Electronic Patient Reported Outcomes
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
 
 
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Abbreviation/Term
Definition
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
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
ORST
Oncologic Response-Solid Tumor
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
 
 
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Abbreviation/Term
Definition
SOC
Standard of Care
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
12.5
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 self care but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited self care; confined to bed or chair more than 50% of waking 
hours
4
Completely disabled; cannot carry on any self care; 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)
12.6
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 
12.7
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
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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