Clinical trial NCT02611960
Conditions: Nasopharyngeal Neoplasms
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2016-04-18; Completion date: 2022-09-30
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study of pembrolizumab (MK-3475) versus standard treatment (capecitabine, gemcitabine, or docetaxel) for the treatment of recurrent or metastatic nasopharyngeal cancer (NPC). Participants will be randomly assigned to receive either pembrolizumab or Investigator's choice of standard treatment.

The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.

With Amendment 7 (effective 2-March-2022), upon study completion, participants will be discontinued and may be enrolled in an extension study.

Detailed description:

Arms: arm 1: Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 3-week cycle (Q3W) until progressive disease (PD) or unacceptable toxicity for a maximum of up to 35 cycles (up to approximately 2 years). Eligible participants who stop pembrolizumab with Stable Disease (SD) or better but progress after discontinuation may be able to initiate a second course of pembrolizumab 200 mg Q3W for up to 17 cycles (up to approximately 1 additional year). arm 2: Participants receive capecitabine 1000 mg/m\^2 orally (PO) twice each day (BID) on Days 1-14 of each 3-week cycle, or gemcitabine 1250 mg/m\^2 IV on Days 1 and 8 of each 3-week cycle, or docetaxel 75 mg/m\^2 IV on Day 1 of each 3-week cycle until PD or unacceptable toxicity.
Interventions: intervention 1: Pembrolizumab intervention 2: Capecitabine intervention 3: Gemcitabine intervention 4: Docetaxel
Intervention descriptions: intervention 1: IV infusion intervention 2: oral tablet intervention 3: IV infusion intervention 4: IV infusion

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Two-arm, Open-label, Randomized Phase III 
Study of Pembrolizumab (MK-3475) 
Monotherapy versus Standard Chemotherapy in 
Platinum Pre-treated, Recurrent or Metastatic 
Nasopharyngeal Cancer (NPC) (Keynote-122)
NCT02611960
02-Mar-2022


Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 122-07 
MK-3475-122-07 Final Protocol
02-Mar-2022
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 Two-arm, Open-label, Randomized Phase III Study of Pembrolizumab (MK-3475) 
Monotherapy versus Standard Chemotherapy in Platinum Pre-treated, Recurrent or 
Metastatic Nasopharyngeal Cancer (NPC) (Keynote-122)
IND NUMBER:  122325
EudraCT NUMBER:  Not Applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 12
SUMMARY OF CHANGES................................................................................................ 14
TRIAL SUMMARY.................................................................................................. 19
TRIAL DESIGN........................................................................................................ 20
Trial Design ........................................................................................................... 20
Trial Diagram........................................................................................................ 20
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 21
Primary Objective(s) & Hypothesis(es).............................................................. 21
Secondary Objective(s)......................................................................................... 21
Exploratory Objectives......................................................................................... 22
BACKGROUND & RATIONALE.......................................................................... 22
Background ........................................................................................................... 22
Pharmaceutical and Therapeutic Background .................................................... 22
Pre-clinical Studies ............................................................................................. 24
Ongoing Clinical Trials....................................................................................... 24
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
Pre-clinical Evidence for the Role of PD-1/PD-L1 in NPC ........................ 26
Preliminary Evidence That Anti-PD-L1 Blockade With Pembrolizumab 
(MK-3475) Monotherapy has Clinical Activity in Advanced and/or 
Metastatic NPC............................................................................................ 27
Current Therapies for Advanced and/or Metastatic NPC............................ 28
Quantification of Plasma EBV DNA in Patients With Advanced and/or 
Metastatic NPC............................................................................................ 30
Rationale for Evaluation of Interferon-γ Producing EBV-specific T 
Cells in Peripheral Blood............................................................................. 30
4.2.1.5.1
T-cell Responses Against EBV in NPC Patients.................................. 30
4.2.1.5.2
Evidence That EBV-specific T-cell Responses are Important for 
Survival From NPC .............................................................................. 31
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4.2.1.5.3
Evaluation of Interferon-γ Producing EBV-specific T Cells in 
Peripheral Blood of NPC Patients Receiving Anti-PD1 Therapy ........ 31
Rationale for Dose Selection/Regimen/Modification for Pembrolizumab 
(MK-3475) .......................................................................................................... 32
Rationale for Endpoints ...................................................................................... 32
Efficacy Endpoints....................................................................................... 32
4.2.3.1.1
Primary and Secondary Endpoints........................................................ 32
Immune-related RECIST................................................................ 33
Safety Endpoints.......................................................................................... 34
Patient-Reported Outcomes ......................................................................... 34
Planned Exploratory Biomarker Research................................................... 34
Future Biomedical Research........................................................................ 36
Benefit/Risk ........................................................................................................... 36
METHODOLOGY ................................................................................................... 37
Entry Criteria........................................................................................................ 37
Diagnosis/Condition for Entry into the Trial...................................................... 37
Subject Inclusion Criteria.................................................................................... 37
Optional Sub-study Additional Subject Inclusion Criteria (Appendix 
12.9)............................................................................................................. 40
Subject Exclusion Criteria .................................................................................. 40
Optional Sub-study Additional Subject Exclusion Criteria......................... 42
Trial Treatment(s) ................................................................................................ 42
Dose Selection/Modification for Pembrolizumab (MK-3475)........................... 44
Dose Selection (Preparation) ....................................................................... 44
Dose Modification (Escalation/Titration/Other).......................................... 44
5.2.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................... 44
Timing of Dose Administration.......................................................................... 48
Pembrolizumab (MK-3475) Administration................................................ 48
Standard of Care Administration ................................................................. 48
Dose Selection for Capecitabine (Preparation)............................................ 48
Dose Modification for Capecitabine............................................................ 49
Dose Selection for Gemcitabine (Preparation) ............................................ 50
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Dose Modification for Gemcitabine ............................................................ 50
Dose Selection for Docetaxel (Preparation) ................................................ 51
Dose Modification for Docetaxel................................................................. 51
Trial Blinding/Masking....................................................................................... 52
Treatment Allocation............................................................................................ 52
Stratification.......................................................................................................... 52
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 52
Acceptable Concomitant Medications ................................................................ 52
Prohibited Concomitant Medications.................................................................. 53
Prohibited Concomitant Medications for Pembrolizumab (MK-3475)....... 53
Prohibited Concomitant Medications for SOC............................................ 53
Rescue Medications & Supportive Care............................................................. 54
Supportive Care Guidelines for Pembrolizumab (MK-3475)............................. 54
Supportive Care Guidelines for Standard of Care Chemotherapy...................... 56
Growth Factor Support ................................................................................ 56
Prophylactic Steroid Administration............................................................ 56
Steroid Administration for Treatment of Adverse Events or Medical 
Conditions.................................................................................................... 56
Diet/Activity/Other Considerations..................................................................... 57
Diet...................................................................................................................... 57
Contraception...................................................................................................... 57
Subject Withdrawal/Discontinuation Criteria................................................... 57
Discontinuation of Trial Treatment After CR..................................................... 58
Subject Withdrawal/Discontinuation Criteria from the Optional Sub-Study ..... 59
Subject Replacement Strategy............................................................................. 59
Beginning and End of the Trial ........................................................................... 59
Clinical Criteria for Early Trial Termination ................................................... 59
TRIAL FLOW CHART ........................................................................................... 60
Initial Treatment Phase – Pembrolizumab (MK-3475) and SOC Arms ......... 60
Second Course Phase (Retreatment) – Pembrolizumab (MK-3475) Arm 
Only........................................................................................................................ 64
TRIAL PROCEDURES ........................................................................................... 66
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Trial Procedures ................................................................................................... 66
Administrative Procedures.................................................................................. 66
Informed Consent......................................................................................... 66
7.1.1.1.1
General Informed Consent.................................................................... 66
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 67
Inclusion/Exclusion Criteria ........................................................................ 67
7.1.1.2.1
Inclusion/Exclusion Criteria for Optional Participation in the Sub-
Study..................................................................................................... 67
Subject Identification Card .......................................................................... 67
Medical History ........................................................................................... 67
7.1.1.4.1
Disease Details...................................................................................... 67
Prior and Concomitant Medications Review............................................... 68
7.1.1.5.1
Prior Medications.................................................................................. 68
Prior Treatment Details for Nasopharyngeal Cancer ..................... 68
7.1.1.5.2
Concomitant Medications..................................................................... 68
7.1.1.5.3
Subsequent Anti-Cancer Therapy Status .............................................. 68
Assignment of Screening Number............................................................... 68
Assignment of Treatment/Randomization Number..................................... 68
Trial Compliance (Medication/Diet/Activity/Other)................................... 69
Survival Status ............................................................................................. 69
Clinical Procedures/Assessments........................................................................ 69
Adverse Event Monitoring........................................................................... 69
Electronic Patient-Reported Outcomes........................................................ 70
Physical Exam.............................................................................................. 70
7.1.2.3.1
Full Physical Exam ............................................................................... 70
7.1.2.3.2
Directed Physical Exam........................................................................ 70
Vital Signs.................................................................................................... 70
12-Lead Electrocardiogram ......................................................................... 70
Eastern Cooperative Oncology Group Performance Status......................... 70
Tumor Tissue Collection..................................................................................... 71
Epstein-Barr Virus Status ............................................................................ 71
PD-L1 Status................................................................................................ 71
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Laboratory Procedures/Assessments .................................................................. 71
Local Laboratory Evaluations...................................................................... 72
7.1.4.1.1
Pregnancy Testing................................................................................. 72
7.1.4.1.2
Hematology, Chemistry, Urinalysis, Other Labs and Coagulation 
Factors................................................................................................... 72
Central Laboratory Evaluations................................................................... 74
7.1.4.2.1
Plasma Epstein-Barr Virus DNA.......................................................... 74
7.1.4.2.2
Pharmacokinetic Evaluations................................................................ 74
Blood Collection for Serum Pembrolizumab (MK-3475).............. 74
Blood Collection for Anti-pembrolizumab (MK-3475) Antibodies
75
Planned Genetic Analysis Sample Collection.............................................. 75
Future Biomedical Research........................................................................ 75
Blood for Correlative and Biomarker Studies ............................................. 75
Blood for Participation in Optional Sub-Study............................................ 76
Efficacy Measurements....................................................................................... 76
Tumor Imaging and Assessment of Disease................................................ 76
7.1.5.1.1
Initial Tumor Imaging........................................................................... 76
7.1.5.1.2
On Study Tumor Imaging..................................................................... 77
7.1.5.1.3
End of Treatment and Follow-up Tumor Imaging................................ 78
7.1.5.1.4
Second Course (Retreatment) Tumor Imaging..................................... 78
7.1.5.1.5
RECIST 1.1 Assessment of Disease..................................................... 79
7.1.5.1.6
irRECIST Assessment of Disease......................................................... 79
Other Procedures................................................................................................. 84
Withdrawal/Discontinuation........................................................................ 84
7.1.6.1.1
Withdrawal From Future Biomedical Research ................................... 84
Blinding/Unblinding .................................................................................... 84
Calibration of Equipment............................................................................. 84
Visit Requirements.............................................................................................. 85
Screening...................................................................................................... 85
Treatment Period.......................................................................................... 86
7.1.7.2.1
Second Course Phase (Retreatment Period) ......................................... 86
Post-Treatment Visits................................................................................... 87
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7.1.7.3.1
Safety Follow-up Visit.......................................................................... 87
7.1.7.3.2
Efficacy Follow-up Visits..................................................................... 87
7.1.7.3.3
Survival Follow-up ............................................................................... 88
Survival Status ............................................................................................. 88
Assessing and Recording Adverse Events .......................................................... 88
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 89
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 90
Immediate Reporting of Adverse Events to the Sponsor.................................... 90
Serious Adverse Events ............................................................................... 90
Events of Clinical Interest............................................................................ 91
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 92
Evaluating Adverse Events................................................................................. 92
Sponsor Responsibility for Reporting Adverse Events ...................................... 95
TRIAL GOVERNANCE AND OVERSIGHT................................................... 95
Executive Oversight Committee......................................................................... 95
Data Monitoring Committee............................................................................... 95
STATISTICAL ANALYSIS PLAN ........................................................................ 95
Statistical Analysis Plan Summary ..................................................................... 96
Responsibility for Analyses/In-House Blinding ................................................. 98
Hypotheses/Estimation......................................................................................... 98
Analysis Endpoints ............................................................................................... 98
Efficacy Endpoints.............................................................................................. 98
Safety Endpoints ................................................................................................. 99
Analysis Populations............................................................................................. 99
Efficacy Analysis Populations ............................................................................ 99
Safety Analysis Populations ............................................................................. 100
Statistical Methods.............................................................................................. 100
Statistical Methods for Efficacy Analyses........................................................ 100
Overall Survival......................................................................................... 100
Progression-free Survival........................................................................... 100
Objective Response Rate ........................................................................... 102
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Duration of Response................................................................................. 102
Summary of Efficacy Analysis Methods................................................... 103
Statistical Methods for Safety Analyses ........................................................... 104
Summaries of Baseline Characteristics, and Demographics............................. 106
Interim Analyses ................................................................................................. 106
Efficacy Interim Analysis ................................................................................. 106
Safety Interim Analyses.................................................................................... 107
Multiplicity .......................................................................................................... 108
Multiplicity Control for Efficacy Interim Analyses.......................................... 108
Overall Survival......................................................................................... 108
Progression-Free Survival.......................................................................... 109
Objective Response Rate ........................................................................... 110
Multiplicity Control for Safety Interim Analyses............................................. 110
Sample Size and Power Calculations ................................................................ 110
Subgroup Analyses and Effect of Baseline Factors ......................................... 111
Compliance (Medication Adherence)................................................................ 111
Extent of Exposure.............................................................................................. 111
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 111
Investigational Product ...................................................................................... 111
Packaging and Labeling Information ............................................................... 112
Clinical Supplies Disclosure............................................................................... 112
Storage and Handling Requirements................................................................ 112
Discard/Destruction/Returns and Reconciliation ............................................ 113
Standard Policies................................................................................................. 113
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 113
Confidentiality..................................................................................................... 113
Confidentiality of Data ..................................................................................... 113
Confidentiality of Subject Records................................................................... 113
Confidentiality of Investigator Information...................................................... 114
Confidentiality of IRB/IEC Information........................................................... 114
Compliance with Financial Disclosure Requirements..................................... 114
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Compliance with Law, Audit and Debarment ................................................. 115
Compliance with Trial Registration and Results Posting Requirements...... 116
Quality Management System............................................................................. 117
Data Management............................................................................................... 117
Publications ......................................................................................................... 117
LIST OF REFERENCES....................................................................................... 118
APPENDICES......................................................................................................... 126
Merck Code of Conduct for Clinical Trials...................................................... 126
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 129
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs
and 
Investigational Site Staff .................................................................................... 133
Abbreviations ...................................................................................................... 144
ECOG Performance Status................................................................................ 147
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 148
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 149
List of Strong CYP3A4 Inhibitors..................................................................... 150
Optional Sub-Study Trial................................................................................... 151
Optional Sub-Study Trial Diagram................................................................... 151
Optional Sub-Study Trial Flow Chart............................................................... 152
Contraceptive Guidance..................................................................................... 153
Definitions ................................................................................................. 153
Contraception Requirements...................................................................... 154
SIGNATURES......................................................................................................... 155
Sponsor's Representative ................................................................................... 155
Investigator.......................................................................................................... 155
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LIST OF TABLES
Table 1
Monotherapy Regimens Overview ....................................................................... 29
Table 2
Adequate Organ Function Laboratory Values...................................................... 38
Table 3
Trial Treatments.................................................................................................... 43
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations .................................................................... 45
Table 5
Dose Modification Guidelines for Capecitabine Drug-Related Events or 
(Drug-Related) Adverse Events............................................................................ 49
Table 6
Dose Modification Guidelines for Gemcitabine Hematologic Drug-Related 
Events or (Drug-Related) Adverse Events............................................................ 50
Table 7
Dose Modification for Docetaxel Drug-Related Events (or Drug-Related) 
Adverse Events).................................................................................................... 51
Table 8
Infusion Reaction Treatment Guidelines .............................................................. 55
Table 9
Laboratory Tests ................................................................................................... 73
Table 10
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.................................................................................................................. 82
Table 11
Evaluating Adverse Events................................................................................... 93
Table 12
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival............................................................................................................... 102
Table 13
Censoring Rules for Duration of Response ........................................................ 103
Table 14
Analysis Strategy for Key Efficacy Endpoints................................................... 104
Table 15
Analysis Strategy for Safety Parameters............................................................. 106
Table 16
Summary of Interim and Final Analyses Strategy for Efficacy.......................... 107
Table 17
Summary of Interim Analysis Strategy for Safety.............................................. 107
Table 18
Efficacy Boundaries and Properties for OS Analyses. ....................................... 109
Table 19
Efficacy Boundaries and Properties for PFS Analysis. ...................................... 109
Table 20
Possible Alpha-levels and Approximate ORR Difference Required to 
Demonstrate Efficacy for ORR........................................................................... 110
Table 21
Product Descriptions........................................................................................... 112
  
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LIST OF FIGURES
Figure 1
Trial Design .......................................................................................................... 21
Figure 2
Imaging and Treatment for Clinically Stable Subjects in Subjects Treated 
With Pembrolizumab (MK-3475) After First Radiologic Evidence of 
Progressive Disease Assessed by the Site............................................................. 83
Figure 3
Multiplicity Strategy........................................................................................... 108
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
07
02-MAR-2022
To add language to give ongoing study participants the option to discontinue this study 
and transition into a pembrolizumab extension study.
06
19-JUL-2021
To update the dose modification and toxicity management guidelines for irAEs in the 
MK-3475 Dose Modification Table, to allow site Investigators to follow the 
local/standard imaging schedule, to remove blood collection for Plasma EBV DNA 
beyond Cycle 80,
to remove blood collection for Correlative Studies at the 
Discontinuation Visit, to remove ePRO administration at the Discontinuation/EOT and 
30-Day Safety Follow-Up Visits, and to remove blood collection at time of progression 
after Cycle 80 for the sub-study.
05
06-JUN-2019
To primarily update the primary endpoint from dual primary endpoints of PFS and OS to 
a sole primary endpoint of OS, add newly available clinical trial data to support the 
update in endpoints, update duration of trial, and update Statistical Analysis Plan (i.e., 
multiplicity, interim analysis, and power).
04
17-JAN-2018
To primarily update the MK-3475 Dose Modification Table and survival follow-up 
language.
03
18-AUG-2017
To primarily increase the number of trial subjects, update trial phase number, update 
duration of trial, and update Statistical Analysis Plan (i.e., sample size, interim analysis, 
power).
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Document
Date of Issue
Overall Rationale
02
21-DEC-2016
To primarily include an optional sub-study, remove head/brain imaging requirements, 
update the MK-3475 Dose Modification Table, and update the Flow Chart for ePRO, 
tumor imaging, and Anti-pembrolizumab Antibodies.
01
05-JUL-2016
To primarily increase the number of trial subjects and to make updates to the following: 
capecitabine dose, gemcitabine dose, Statistical Analysis Plan (i.e., type I error, sample 
size, interim analysis, power), and Tables of Dose Modifications for Capecitabine, 
Gemcitabine and Docetaxel.
00
20-NOV-2015
Original Protocol
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1
2.1
5.8
5.10
7.1.1.7
7.1.7.2.1
7.1.7.3.3
Trial Summary
Trial Design
Subject 
Withdrawal/Discontinuation 
Criteria
Beginning and End of the Trial
Assignment of 
Treatment/Randomization 
Number
Second Course Phase 
(Retreatment Period)
Survival Follow-up
Added language to give ongoing study 
participants the option to discontinue this 
study and transition into a pembrolizumab 
extension study.
To transition ongoing study 
participants, who are either on 
active treatment or in post-
treatment follow-up, into a 
pembrolizumab 
extension 
study prior to close out of this 
study.
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number(s)
Section Title (s)
Description of Change (s)
Rationale
N/A
Document History
Reversed document order.
To ensure that the most 
recent amendment history is 
indicated first.
1
5.1.2
5.1.2.1
5.10
7.1.1.1
7.1.1.1.1
7.1.1.3
7.1.3.1
7.1.3.2
7.1.4.2.1
7.1.4.5
7.1.4.6
7.1.7.1
7.2
7.2.3.1
7.2.3.2
10.1.2
12.2
Trial Summary
Subject Inclusion Criteria
Optional Sub-study Additional Subject 
Inclusion Criteria (Appendix 12.9)
Beginning and End of the Trial
Informed Consent
General Informed Consent
Subject Identification Card
Epstein-Barr Virus Status
PD-L1 Status
Plasma Epstein-Barr Virus DNA
Blood for Correlative and Biomarker Studies
Blood for Participation in Optional Sub-Study
Screening
Assessing and Recording Adverse Events
Serious Adverse Events
Events of Clinical Interest
Confidentiality of Subject Records
Collection and Management of Specimens for 
Future Biomedical Research
Changed language regarding 
signing informed consent to 
providing 
documented 
informed consent.
To comply with updated 
protocol template.
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Section Number(s)
Section Title (s)
Description of Change (s)
Rationale
1.0
5.10
Trial Summary
Beginning and End of the Trial
Changed language regarding 
the last study-related phone 
call or visit to the last 
study-related contact.
To allow for flexibility and 
participant safety.
3.3
4.2.3.3
6.1
7.1.2.2
Exploratory Objectives
Patient Reported Outcomes
Initial Treatment Phase Pembrolizumab 
(MK-3475) and SOC Arms
Electronic Patient Reported Outcomes
Removed “European Quality 
of Life” in front of the 
EQ-5D questionnaire.
Incorrect label/heading.
4.2.3.4
Planned Exploratory Biomarker Research
Made minor text updates.
To 
ensure 
exploratory 
biomarker 
section 
allows 
flexibility 
and 
current 
treatment options.
5.1.3
Subject Exclusion Criteria
Updated 
Exclusion 
Criterion 11 to add interstitial 
lung disease.
To exclude participants with 
interstitial lung disease.
5.2
Trial Treatment(s)
Study intervention table was 
updated to add IMP/NIMP 
designations.
To comply with European 
Commission regulations.
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Section Number(s)
Section Title (s)
Description of Change (s)
Rationale
7.1.1.4
Medical History
Changed language regarding 
which conditions diagnosed 
within the prior 10 years need 
to be reported as medical 
history from those that are 
considered to be clinically 
significant to those that are 
considered to be clinically 
important.
To clarify text.
7.1.5.1.2
7.1.5.1.3
7.1.5.1.4
On Study Tumor Imaging
End of Treatment and Follow-up Tumor 
Imaging
Second Course (Retreatment) Tumor Imaging
Clarified language regarding 
tumor imaging and imaging 
discontinuation criteria.
To 
increase 
clarity 
and 
maintain 
consistency 
throughout the protocol.
7.1.6.1.1
12.2
Withdrawal From Future Biomedical Research
Collection and Management of Specimens for 
Future Biomedical Research
Updated 
clinical 
supplies 
email.
To 
provide 
accurate 
information.
10.3
Compliance with Law, Audit and Debarment
Corrected the name of the 
International 
Council 
for 
Harmonisation of Technical 
Requirements 
for 
Pharmaceuticals for Human 
Use.
To render accurate.
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Section Number(s)
Section Title (s)
Description of Change (s)
Rationale
12.1
Merck Code of Conduct for Clinical Trials
Made minor text updates.
It was updated on inclusion 
of 
diverse 
and 
underrepresented 
groups 
(age, race, ethnicity, gender, 
etc.)
in 
global 
clinical 
studies.
N/A
N/A
Made 
small 
grammatical/typographical 
corrections throughout.
To increase readability and 
clarity.
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TRIAL SUMMARY
Abbreviated Title
Ph III Trial of MK-3475 (Pembrolizumab) in Platinum Pre-treated, 
Recurrent/Metastatic Nasopharyngeal Cancer
Trial Phase
Phase III
Clinical Indication
Platinum Pre-treated, Recurrent, or Metastatic Nasopharyngeal Cancer
Trial Type
Interventional
Type of control
Standard of Care (SOC)
Route of administration
Intravenous, Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Arm 1:  MK-3475 (also known as pembrolizumab) 200 mg every
3 weeks (Q3W)
OR
Arm 2:  Investigator’s choice of the following SOC:

Capecitabine

Gemcitabine

Docetaxel
Number of trial subjects
Approximately 230 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 4.5 – 5 
years from the time the first subject provides documented informed 
consent until the last subject’s last study-related contact.
Duration of Participation
Each subject1 will participate in the trial from the time the subject 
provides documented informed consent through the final protocol-
specified contact.  After a screening phase of 30 days, eligible subjects
can be randomized to either pembrolizumab (MK-3475) (experimental 
arm) or SOC chemotherapy (control arm).  The chemotherapy to be used 
must be chosen before randomization.
Subjects will be randomized in a 1:1 fashion to standard chemotherapy 
per investigator’s choice or to pembrolizumab (MK-3475).  Treatment on 
study will continue until disease progression is radiographically 
documented and verified by blinded independent central review (BICR)
per RECIST 1.1 (for subjects treated with SOC chemotherapy) or 
confirmed by the site per immune-related Response Evaluation Criteria 
in Solid Tumors ([irRECIST] for subjects treated with pembrolizumab),
unacceptable adverse event (AEs), intercurrent illness that prevents 
further administration of treatment, investigator’s decision to withdraw 
the subject, noncompliance with trial treatment or procedures 
requirements or administrative reasons requiring cessation of treatment, 
or until the subject has received 35 administrations of pembrolizumab 
(approximately 2 years).  Subjects who stop trial treatment after 
receiving 35 administrations of pembrolizumab for reasons other than 
disease progression or intolerability, or subjects who attain a complete 
response (CR) and stop trial treatment may be eligible for up to 17 
additional administrations of pembrolizumab (approximately 1 year) 
upon experiencing disease progression (see Section 7.1.7.2.1).
After the end of treatment, each subject will be followed for the 
resolution of ongoing select AEs, the occurrence of AEs, OS, and 
spontaneously reported pregnancy as described in Section 7.2.2.
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Subjects who discontinue study treatment for reasons other than disease 
progression will have post-treatment follow-up for disease status until 
disease progression is documented radiographically and verified by 
BICR per RECIST 1.1 (subjects treated with SOC chemotherapy) or 
confirmed
by the site per irRECIST (subjects treated with 
pembrolizumab), 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 for 
survival follow-up, or the end of the study.
Upon study completion, participants are discontinued and may be 
enrolled in a pembrolizumab extension study, if available.
1The Sponsor has changed the terminology referring to individuals who take part in clinical 
trials as “Participant” from the previously used term “Subject.” For the purpose of any 
trial-related documents using the previous terminology, the term “Participant” is equivalent 
to “Subject.”
A list of abbreviations used in this document can be found in Appendix Section 12.4.
TRIAL DESIGN
Trial Design
This is a two-arm, multi-site, international, randomized, open-label, controlled trial of
pembrolizumab (MK-3475) monotherapy versus standard chemotherapy in subjects with
platinum pre-treated, recurrent, or metastatic nasopharyngeal cancer to be conducted in 
conformance with Good Clinical Practices (GCP).
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.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Trial Diagram
The trial design is depicted in Figure 1.
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Figure 1
Trial Design
Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, 
if available.
OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In subjects with recurrent and/or metastatic (R/M) nasopharyngeal cancer (NPC) treated with 
pembrolizumab (MK-3475) versus standard of care (SOC) chemotherapy:
(1) Objective:  To compare overall survival (OS).
Hypothesis: Single-agent pembrolizumab (MK-3475) prolongs OS compared to SOC
chemotherapy.
The study will be declared a success if OS is shown to be successful.
Secondary Objective(s)
In subjects with R/M NPC treated with pembrolizumab (MK-3475) versus SOC 
chemotherapy:
(1) Objective:  To compare progression-free survival (PFS) per response evaluation criteria 
in solid tumors (RECIST) 1.1 as determined by Blinded Independent Central Review
(BICR).
Hypothesis: Single-agent pembrolizumab (MK-3475) prolongs PFS per RECIST 1.1 as 
determined by BICR compared to SOC chemotherapy.
(2) Objective:  To compare objective response rate (ORR) per RECIST 1.1 as determined by 
BICR.
Hypothesis: Single-agent pembrolizumab (MK-3475) improves ORR per RECIST 1.1 
as determined by BICR compared to SOC chemotherapy.
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(3) Objective:  To evaluate duration of response (DOR) per RECIST 1.1 as determined by 
BICR.
(4) Objective: To evaluate survival proportion at 12 months and 24 months.
(5) Objective: To evaluate proportion PFS at 6 months and 12 months per RECIST 1.1 as 
determined by BICR.
(6) Objective:  To evaluate the safety and tolerability profiles of pembrolizumab
(MK-3475).
Exploratory Objectives
In subjects with R/M NPC treated with pembrolizumab (MK-3475) versus SOC 
chemotherapy:
(1) Objective: To evaluate progression-free survival 2 as defined in Section 8.4.1.
(2) Objective: To evaluate PFS per immune-related RECIST (irRECIST) determined by 
BICR.
(3) Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, 
and/or the mechanism of action of pembrolizumab and other treatments.
(4) Objective: To investigate the relationship between the response to pembrolizumab
(MK-3475) treatment and plasma circulating Epstein-Barr virus (EBV) DNA levels.
(5) Objective: To characterize the quality of life using the EQ-5D questionnaire.
(6) Objective:  To compare the effect of treatment on the level of interferon-producing 
EBV-specific CD8+ T cells in peripheral blood.
(7) Objective: To investigate the relationship between response to treatment (ORR, PFS and 
OS) and the increase in levels of interferon-γ producing EBV-specific CD8+ T cells in 
peripheral blood.
BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) and the approved labeling for detailed background 
information on pembrolizumab (MK-3475).
Pharmaceutical and Therapeutic Background
Pembrolizumab (MK-3475), previously known as SCH 9000475 is a potent and highly 
selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between programmed death 1 (PD-1) and its ligands, PD-L1 
and programmed death ligand 2 (PD-L2).
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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 immune system pathway hijacked by tumors 
to suppress immune activation.  The normal function of PD-1, expressed on the cell surface 
of activated T cells under healthy conditions, is to down-modulate unwanted or excessive 
immune responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is 
an Ig superfamily member related to CD28 and cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) which has been shown to negatively regulate antigen receptor signaling upon 
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 domain responsible for ligand 
binding and a cytoplasmic tail that 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 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, regulatory T cells and natural killer cells [15] [16].  
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T cells as well as subsets of macrophages and dendritic cells [17]
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors [1]
[14] [18] [19] [20].  Both ligands are type I transmembrane receptors containing both IgV-
and IgC-like domains in the extracellular region and contain short cytoplasmic regions with 
no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation 
triggered through the T-cell receptor.  PD-L1 is expressed at low levels on various non-
hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only 
detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments.  PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [14] Although healthy organs express little (if any) PD-L1, a variety of cancers were 
demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma [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.
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Pre-clinical Studies
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma 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 monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models (see the IB).
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, head and neck cancer, as well as a number of advanced solid tumor indications and 
hematologic malignancies.  For study details please refer to the IB.
Trials evaluating pembrolizumab (MK-3475) 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 (MK-3475) 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 (MK-3475).  Preliminary results of this cohort 
were reported at the Annual Meeting of the American Society of Clinical Oncology in 2014 
[28], showing an ORR (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 or 4 
drug-related adverse events (DRAEs).
In general, pembrolizumab (MK-3475) was well tolerated with 58.3% reporting a DRAE and 
16.7% reporting a Grade 3 to 5 DRAE.  The DRAEs 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 DRAEs, Grades 3 to 5 was seen in rash (2, 3.3%).  
The reported pre-specified adverse events (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%) [26].
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Rationale
Rationale for the Trial and Selected Subject Population
Nasopharyngeal cancer represents a unique malignancy with a distinct geographic 
distribution and greater tendency among head and neck cancers for metastasis [29]. 
Globally, NPC is a relatively rare cancer with approximately 87,000 cases reported and an 
associated mortality of 50,000 reported for 2012 [29].  While rare in the United States with 
approximately 3,200 cases expected to be diagnosed in 2015, NPC is endemic in indigenous 
populations of Southeast Asia, natives of the Arctic region, North Africa, and the Middle 
East.  Even within China, the incidence increases moving from Northern China to Southern 
China, where for example, in Hong Kong, approximately 1 in 40 people will be diagnosed 
with NPC before age 75 [30] [31] [32].
Among squamous cell carcinomas of the head and neck, NPC is also distinguished from 
other head and neck cancers as being an EBV-driven malignancy.  Unique among other head 
and neck cancers, EBV, a member of the herpes virus family, is implicated in the 
development of NPC.
Upon transmission to the host via saliva, EBV directly infects B lymphocytes of the 
oropharyngeal epithelium.  During the acute phase of infection, EBV causes cellular 
proliferation of B lymphocytes and induces an EBV-specific cytotoxic lymphocyte response.  
During this acute phase, integration of the viral genome into host DNA occurs, resulting in 
the transcription of EBV-encoded RNAs 1 and 2 (EBERs 1 and 2) as well as the expression 
of EBV nuclear proteins and 2 latent membrane proteins, LMP-1 and LMP-2 [33]. Acute 
infection is followed by a normal immune response in healthy individuals, resulting in the 
virus persisting in memory B cells.  In contrast, in chronic infection, so-called latent viral 
infection is associated with continuous expression of various EBV nuclear and latency genes, 
the specific combination of which is associated with specific malignancies.  NPC is 
distinguished by the type II latency pattern in which EBERs 1 and 2 and the LMP-1s and 
LMP-2s, are expressed, in addition to Epstein-Barr Nuclear Antigen (EBNA)-1 (but not the 
other EBNAs) and BARF0 which is expressed in all latency types [33].
EBERs 1 and 2 are nonpolyadenylated, uncapped, noncoding RNAs that are expressed in 
nearly all EBV-infected cells of NPC [34][35].  While not essential for malignant 
transformation, EBERS 1 and 2 are expressed in all forms of latency.
LMP-1 is most directly linked to oncogenesis based on its ability to activate multiple 
oncogenic signaling pathways such as nuclear factor-B (NF-B), c-Jun NH2-terminal 
kinase, p38 mitogen-activated protein kinase and Janus kinase/signal transducers and 
activators of transcription.  Chief among these diverse signaling pathways, NF-B is a key 
transcription factor that controls expression of several cytokines including lymphotoxin, an 
autocrine growth factor for EBV-transformed cells [36].  Additionally, LMP-1 is able to 
inhibit apoptosis by increasing levels of bcl-2 and a20 as well as by creating membrane 
aggregation which confers cellular immortalization.  The LMP-2 gene encodes 2 proteins 
(LMP-2A and LMP-2B) which have been demonstrated to drive EBV infection into latency, 
and is routinely expressed in NPC among other malignancies [37]
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Nearly all (>90%) of the population has experienced an acute EBV infection, most with 
subclinical symptoms; however, few develop chronic infection and subsequent EBV 
associated malignancy.  Although unconfirmed, multiple theories, including environmental 
exposure, dietary factors, as well as LMP-1 variants which may produce reduced cytotoxic 
T-cell response, have been postulated to account for what might cause an acute EBV 
infection to proceed into a chronic latent infection, primarily restricted to specific geographic 
regions of Southeast Asia [30].
Pre-clinical Evidence for the Role of PD-1/PD-L1 in NPC
More recently, evidence has emerged suggesting that prolonged exposure to antigen during 
chronic viral infections such as EBV result in irreversible functional impairment of memory 
CD8+ T cells, causing diminished immunity, a phenomenon known as T-cell exhaustion
[38].  A hallmark of the ability to fight infection is that normal differentiation of T cells 
results in memory CD8+ T cells that can persist in the absence of continuing antigen 
exposure, also known as antigen independent immunity.  In contrast to functional CD8+ T
cells in an acute infection, CD8+ T cells that were chronically exposed to antigen, such as is 
the case with chronic EBV infection, had impaired proliferation due to decreased cellular 
cytokine receptors necessary for T-cell proliferation.  Additionally, once altered, impaired 
memory T-cell function could not be restored by subsequent removal of the inciting antigen 
[38].
During chronic viral infection, PD-1 messenger RNA and protein levels were found to be 
upregulated, both on the exhausted CD8+ T cells as well as on the virally infected cells, 
implicating the immune checkpoint pathway in the development of this phenomenon.  Of 
note, upregulation of PD-1 was a specific response, as was consistent with other reports, and 
no upregulation of the CTLA-4 was seen [39] [40].  Importantly, anti-PD-L1 blockade 
restored both virus-specific CD8+ T-cell quantitative and qualitative responses as evidenced 
by increased cellular proliferation and increased ki-67 levels as well as restoration of 
cytokine production and lytic degranulation ability [39][40]..  Of note, PD-L1 blockade also 
resulted in substantial reduction of viral levels in the chronically infected host [39].
Given the association between EBV infection and EBV-associated malignancies including 
NPC, when EBV modulation of the PD-1/PD-L1 checkpoint pathway was further examined, 
EBV-induced LMP-1 protein was found to increase PD-L1 gene expression [41].  Compared 
with EBV-negative NPC cell lines, EBV-positive NPC cell lines were found to have 
increased levels of LMP-1, whether exogenous or endogenous, and EBV-positive NPC cell 
lines were able to induce PD-L1 expression, which could be abrogated by knocking down 
LMP1 in EBV-positive cell lines.  The differential expression of EBV-positive NPC cell 
lines (versus EBV-negative) to increase PD-L1 expression was further confirmed by 
flow-cytometry as well as by visual examination utilizing immunofluorescence.  When 
visually examined, both the cell membrane and cytoplasm of EBV-positive NPC cell lines 
showed strong PD-L1 fluorescence, while PD-L1 fluorescence within EBV-negative cell 
lines was significantly weaker.  For EBV-positive NPC, the relative expression of PD-L1 
correlated with EBV positivity [42]
Taken together, chronic EBV infection leads to increased viral EBV load.  This chronically 
increased virus load results in and correlates with increased expression of PD-1 on cytotoxic 
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memory T cells, leading to T-cell exhaustion with resultant decreased function and number 
of these cells.  This upregulation is specific for PD-1 as CTLA-4 levels were unaffected.  Of 
note, increased PD-1 expression also occurs in the virally affected host cells.  The relative 
quantitative and qualitative CD 8+ T-cell decrease leads to altered T-cell immunity, which 
prevents clearance of the EBV infection and allows further increase of viremia.  EBV-latent 
infection is associated with expression of LMP-1 protein which induces PD-L1 expression.  
Increased PD-1 and PD-L1 work together to suppress the immune system, leading to 
decreased EBV cellular immunity.  In the laboratory, anti-PD-L1 blockade was demonstrated 
to restore exhausted CD8+ T-cell function and decrease viral load.  This effect was specific 
for the PD-L1 as virally induced T-cell upregulation of PD-1 did not affect CTLA-4 levels 
and CTLA-4 blockade had no effect on either CD8+ T-cell function or viral control [39].  
Therefore, anti-PD-L1 blockade could be a worthwhile strategy to restore anti-EBV tumor 
CD-8 positive T cells, decrease viral load, and target NPC.
Preliminary Evidence That Anti-PD-L1 Blockade With Pembrolizumab 
(MK-3475) Monotherapy has Clinical Activity in Advanced and/or Metastatic 
NPC
KEYNOTE-028 is a global, non-randomized, multi-cohort trial that has enrolled subjects 
with a variety of advanced solid tumors in cohorts grouped by tumor type. PD-L1 positivity, 
defined as PD-L1 expression by immunohistochemistry (IHC) (≥1% PD-L1 membrane 
staining of tumor cells or stroma by a prototype assay performed at Qualtek CAP/CLIA 
laboratory), was required for study entry. Pembrolizumab (MK-3475) at a dose of 10 mg/kg 
intravenous (IV) was administered every 2 weeks as monotherapy until progression of 
disease.
An advanced NPC cohort that included subjects with metastatic NPC cancer not amenable to 
curative therapy and whose disease had progressed following at least 1 prior treatment was 
enrolled. Enrolled subjects were predominantly of Asian ethnicity (67%), male (77.8%), 
with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 (74%). Of 
note, approximately two-thirds had received 3 or more prior treatments for metastatic 
disease. All subjects had received prior platinum-based therapy for their disease. Similar to 
other reports of high PD-L1 expression among advanced NPC, 98% of screened and 100% of 
evaluable subjects that enrolled into the NPC cohort (46/47 and 27/27, respectively) were 
PD-L1 positive.
In this heavily pre-treated population, evidence of clinical activity by investigator assessment 
was demonstrated, as 22.2% (6/27) subjects had a confirmed ORR (0% CR + 22.2% PR), 
25.9% (7/27) had unconfirmed ORR, and 51.9% (14/27) had SD. Thus, only 6 of 27 (22.2%) 
subjects had progressive disease (PD) as their best response, with approximately 
three-quarters (75%) of all subjects deriving benefit from pembrolizumab (MK-3475). With 
a median follow-up of 7.8 months, the median PFS was 5.6 months (95% CI 3.6, 11.0), with 
a 6-month PFS rate of 49.7% and a 12-month PFS rate of 30.1%. Notably, a 6-month OS 
rate of 85.2% and 12-month OS rate of 66.7% was demonstrated. Median OS has not been 
reached at this time.
Of the 27 evaluable and treated subjects, all 27 reported at least 1 AE, with 70.4% (19/27) 
classifying it as a related AE. Nine subjects (9/27, 33.3%) experienced serious adverse 
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events (SAEs) and 3 subjects (3/27, 11.1%) experienced related SAEs. Overall AEs and 
related AEs lead to discontinuations in 11.1% (3/27) for both. Additionally, overall SAEs 
and related SAEs lead to treatment discontinuation in 7.4% (2/27) for both. Please refer to 
the IB for additional details.
Thus, encouraging evidence of robust clinical activity coupled with a favorable profile has 
been observed.
More recently, data from a randomized Phase 2 trial was reported at the American 
Association for Cancer Research meeting in March 2019. A global, randomized phase 2
study comparing spartalizumab, a humanized anti-PD-1 IgG4 mAb, was compared to the
investigator’s choice of therapy. In this open-label study, patients were randomized 2:1, to 
spartalizumab (400 mg every 4 weeks) vs any choice of chemotherapy. The primary endpoint 
was PFS by independent central review with secondary endpoints of OS, and ORR, and DOR 
based on independent central review. In total, 82 patients were randomized to spartalizumab
(42.7% ECOG PS 0, 54.9% ECOG PS 1) and 40 patients were randomized to chemotherapy
(22.5% ECOG PS 0, 75% ECOG PS 1) and the median age of enrolled subjects was 50-51 
years of age. Sixteen subjects (19.5%) treated with spartalizumab and 9 subjects (22.5%) in 
the chemotherapy control arm had received 1 line of prior therapy for the treatment of R/M 
NPC.  
The median PFS for spartalizumab was 1.9 months (95% CI 1.8, 3.6) vs 6.6 months (95% CI 
3.7, 9.3) in the chemotherapy arm, thus the primary endpoint was not met with hazard ratio
of 1.36 (95% CI 0.87, 2.12). ORR was 17.1% (95% CI 9.7, 27.0) and 35.0% (95% CI 20.6, 
51.7) for those treated with spartalizumab and chemotherapy respectively, and 25.9% (7/27) 
for those treated with monotherapy chemotherapy and 58.3% (7/12) for doublet or triplet 
chemotherapy regimens. Median DOR in the spartalizumab arm was 10.2 months (95% CI 
7.4, NE) compared with 5.7 months (95% CI 3.7, 7.4) for those randomized to 
chemotherapy. Of note, although the data and follow-up suggest that the OS data are 
immature, there appeared to be a trend towards superior OS for those randomized to 
spartalizumab with a median OS of 25.2 months (13.1, NE) compared to 15.5 months (95% 
CI 8.3 21.3) in the chemotherapy arm.
Of the 82 evaluable patients treated with spartalizumab, 79 (96.3%) reported at least 1 AE, 
with 72% (59/82) classifying it as a related AE. Twenty-seven subjects (32.9%) experienced 
SAEs and 8 subjects (9.8%) experienced related SAEs. AEs leading to discontinuation or to 
dose adjustment/interruption were 1.2% (1/82) and 14.6% (12/82), respectively [43]. 
Current Therapies for Advanced and/or Metastatic NPC
Due to the overall low prevalence of NPC, few randomized clinical trials have been 
conducted in this malignancy, and no randomized Phase III trials have been reported in the 
metastatic setting.  Initially, radiotherapy was viewed as the treatment of choice for NPC 
until a randomized trial, SWOG 099, reported by Al-Sarraf and colleagues, demonstrated that 
in the locally advanced population, platinum therapy with adjuvant cisplatin added 
concurrently to radiotherapy followed sequentially by combination cisplatin and infusional 
5-FU improved both disease-free survival and OS compared to adjuvant radiotherapy alone 
[44].
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Unfortunately, among head and neck cancers, NPC has a greater tendency for distant 
metastasis.  Once NPC recurs with incurable and/or metastatic disease, numerous treatments 
have demonstrated evidence of clinical activity, but with limited durability of response and 
no evidence of cure.  This evidence comes from multiple single-arm Phase II trials.  Several 
monotherapies have been associated with median ORRs ranging from 3% to 50%, and an 
approximate time to progression (TTP) of 4 months for those who have progressed following 
treatment with a platinum-containing regimen [45] [46] [47] [48] [49] [50] [51] [52] [53]
[54].
There is no approved agent for NPC, and following a platinum-based chemotherapy regimen, 
there is no recognized single regimen.  Therefore, clinical guidelines have emphasized 
balancing clinical benefit with tolerable toxicity.  Thus, monotherapy regimens are 
commonly employed following PD after platinum-based therapy.  Among the most 
commonly used monotherapy SOC regimens are gemcitabine, capecitabine, and docetaxel as 
in Table 1:
Table 1
Monotherapy Regimens Overview
Regimen
Line
Phase
N
ORR
PFS/TTP#
OS
Accrual
Gemcitabine[52]
2/3
II
27
48.1%
5.1#
10.5
1/99-11/99
Gemcitabine[45]
1+
II
32
43.8%
5.1#
16
Prior to 2004
Capecitabine[48]
2-4
II
17
23.5%
4.9#
7.6
3/00-2/02
Docetaxel[49]
2-4
II
30
36.7%
5.3
12.8
9/04-7/06
The ‘#’ denotes TTP.  The time unit for PFS, TTP and OS are all in months.
Keeping in mind that most of these clinical trial data were acquired and reported prior to the 
current RECIST assessment guidelines, and one of the higher response rates obtained with 
gemcitabine [46] included patients treated in the first-line metastatic setting, some of the 
response rates may represent an overestimation of the true ORR assessed in a contemporary 
platinum pre-treated metastatic population.
In the effort to increase ORR, several polychemotherapy regimens have been developed and 
demonstrated increased ORR of 60% to 74%, but with minimal improvement in durability of 
response with TTP and/or PFS of approximately 5 to 6 months.  Despite the addition of 
increasing numbers of cytotoxic therapies in treatment regimens, DOR was not significantly 
impacted, although toxicity was increased [55] [56] [57].  Therefore, despite the fact that 
NPC has historically been described as a radiosensitive and chemosensitive disease, over half 
of those diagnosed with NPC will ultimately die of their disease.
In summary, the overall low incidence coupled with the Southeast Asian geographic 
predominance has made it challenging to conduct large randomized clinical trials in patients 
with NPC.  Treatment guidelines refer to the SWOG 099 randomized trial above as the only 
randomized controlled clinical trial isolating the benefit of a cytotoxic therapy for NPC.  
Therefore, the inclusion of platinum therapy for locally advanced and/or metastatic 
recurrence can be taken to represent the SOC for NPC.  Following treatment with a 
platinum-containing regimen, multiple options exist, but without any regulatory approved 
therapy.
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Therefore, we propose to test the clinical activity of pembrolizumab (MK-3475) and compare 
it to commonly employed monotherapy regimens that might be used for this population.  We 
will seek to ensure that treatment with pembrolizumab (MK-3475) providing targeted PD-L1 
blockade is superior to SOC monotherapies in this EBV-driven PD-1/PD-L1 upregulated 
advanced metastatic NPC disease setting.
Quantification of Plasma EBV DNA in Patients With Advanced and/or 
Metastatic NPC
As noted above, in in vivo animal models, anti-PD-L1 blockade was associated with 
decreased EBV viral levels in addition to restoration of exhausted memory CD8+ T-cell
function [39].  Contemporaneous with this finding, several investigators sought to determine 
the clinical significance of circulating plasma concentrations of EBV DNA fragments in 
subjects with NPC.  In subjects with locally advanced NPC without evidence of distant 
disease, paired samples of EBV DNA obtained prior to and upon completion of definitive 
treatment with cisplatin and 5-fluouracil in conjunction with concurrent radiotherapy were 
able to be quantified.  Circulating EBV DNA from plasma was detectable in over 90% of 
tested subjects (90 of 94).  Importantly, these investigators were able to demonstrate that by 
genotyping both the plasma EBV DNA as well as the primary tumor samples, the circulating 
cell-free EBV DNA originated from the primary tumor.  Thus, plasma EBV DNA was 
demonstrated to be a surrogate marker for primary tumor.  Median concentrations of plasma 
EBV DNA increased with increasing stage of disease and disease burden.  In subjects who 
eventually relapsed during follow-up, plasma EBV DNA levels were found to be 
significantly higher than in those who did not relapse.  Additionally, those patients who had 
persistently detectable plasma EBV DNA were found to have significantly worse relapse-free 
survival (P<0.001) and OS (P<0.001) [58].
When evaluated in the recurrent and/or metastatic NPC setting, those subjects with either low 
pre-treatment or undetectable post-treatment levels of circulating plasma EBV DNA 
following palliative chemotherapy were found to have superior PFS and OS of 21.7% and 
50.6%, respectively [59].
Perhaps in response to these important results, an international collaboration to harmonize 
the quantitation of plasma EBV DNA assay for development of future biomarker-guided 
trials in NPC cancer is underway [60] and treatment guidelines for NPC have been updated 
to recommend quantification of EBV DNA during treatment of NPC [61].  Therefore, in this 
clinical trial, we propose to evaluate paired samples of plasma EBV DNA at baseline, on 
treatment, as well as at PD, to see if pre-treatment levels as well as post-treatment levels can 
predict response to anti-PD-L1 blockade with pembrolizumab (MK-3475).
Rationale for Evaluation of Interferon-γ Producing EBV-specific T Cells in 
Peripheral Blood
4.2.1.5.1 T-cell Responses Against EBV in NPC Patients
The levels of functional interferon-γ producing EBV-specific T cells are reduced in NPC 
patients and it is hypothesized that loss of EBV-specific CD8+ T-cell immune surveillance 
may be involved in the development or progression of NPC [62].  This is founded on the 
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observation that peripheral blood CD8+ T-cell responses for two of the EBV proteins found 
in tumor cells, EBNA-1 and LMP-2, are detected in EBV-positive healthy individuals but are 
decreased in NPC patients [62] [63].  These reduced EBV-specific CD8+ T-cell responses in 
NPC patients are not due to a lack of CD8+ T cells able to recognize the viral antigens, but 
rather that these cell have become unresponsive [63].  A number of mechanisms have been 
proposed to explain the limited effectiveness of these cells, as noted above. Additionally, a 
number of studies have reported increased regulatory T cells (Tregs) in the peripheral blood 
of NPC patients as potential suppressors of the CD8+ T-cell response [64] [65] [66].  
Alternatively the unresponsiveness of these cells could be due to the inhibitory PD-1-PD-L1 
interaction between CD8+ T cells and tumor cells.  Treatment with anti-PD-1 therapy could 
potentially relieve this inhibition and result in an increase in active interferon-γ producing 
EBV-specific T cells.
4.2.1.5.2 Evidence That EBV-specific T-cell Responses are Important for Survival 
From NPC
Compelling evidence that EBV-specific T cells are important for survival from NPC is 
provided by a number of clinical studies that treated advanced EBV-associated NPC with 
EBV-specific T cells. In these studies, autologous EBV-specific T cells were expanded in-
vitro and re-introduced into the patient. Prominent amongst these approaches is a phase II 
trial in untreated patients that received 6 doses of EBV-specific T cells following treatment 
with gemcitabine and carboplatin[67]
This combination demonstrated a response rate of 
71.4% with 3 complete and 22 partial responses. Furthermore, the authors concluded that the 
median overall survival of 29.9 months and the 2- and 3- year overall survival rates of 
62.9 % and 37 %, respectively, were significantly higher than those observed in historical 
controls receiving chemotherapy alone (11-22 months). A multicenter Phase III randomized 
control trial using this protocol is currently underway (NCT 02578641). Other studies with 
this approach reported response rates of 60% [68] (2 partial responses and 4 with stable 
disease) and 67% [69] (5 complete responses, 2 partial responses and 3 with stable disease).  
In the latter study, 8 additional patients were treated in their second or subsequent remission 
and 5 remained free of disease after 6 years. It is notable that in all these studies an 
association between measurable benefit of treatment with EBV-specific T cells and the 
presence of T cells specific for the EBV antigen LMP2 was observed [67] [68] [69].
4.2.1.5.3 Evaluation of Interferon-γ Producing EBV-specific T Cells in Peripheral 
Blood of NPC Patients Receiving Anti-PD1 Therapy
In this currently on-going, KEYNOTE-122, we propose in this sub-study to evaluate paired 
samples of PBMC from baseline (cycle 1) and after 1-, 2-, 3-, and 4- cycles, as well as at the 
time of disease progression, to see if levels of EBV-specific T cells are increased following 
treatment with pembrolizumab and SOC chemotherapy. We propose to evaluate whether 
increases in EBV-specific T-cell levels are predictive of response to treatment. A previous 
study in NSCLC identified a subject who demonstrated a > 40 fold increase in tumor-specific 
T-cell responses after a single cycle of anti-PD-1 therapy [70].  This response was 
maintained after a second cycle and returned to levels just above background in the 
subsequent months.  In this sub-study, patients, regardless of HLA type, will have 
cryopreserved peripheral blood mononuclear cells (PBMC) tested using EBV-specific T-cell 
biomarker assays that measure the T-cell interferon-γ response following stimulation with 
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peptides specific for EBV antigens.  Various approaches may be used for measuring the 
immune reactivity of these PBMCs to EBV antigens found in the tumor. Key questions that 
this sub-study will address include (1) Whether interferon-γ producing EBV-specific T cells 
can be measured in peripheral blood following anti-PD-1 therapy? (2) Whether interferon-γ 
producing EBV-specific T cells increase after anti-PD-1 therapy i.e., whether EBV-specific T
cells are more active following anti-PD-1 therapy? (3) Whether levels of interferon-γ 
producing EBV-specific T cells are increased in responsive patients (as compared to non-
responders)?
Rationale 
for 
Dose 
Selection/Regimen/Modification
for 
Pembrolizumab
(MK-3475)
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is an
appropriate dose of pembrolizumab for adults across all indications. As outlined below, this 
dose is justified by: 
•
Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer 
(NSCLC) indications demonstrating flat dose- and exposure- efficacy relationships 
from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) representing an approximate 
5- to 7-fold exposure range (refer to IB Section 5.2.2)
•
Population pharmacokinetic (PK) analysis showing that both fixed dosing and 
weight-based dosing provides similar control of PK variability with considerable 
overlap in the distributions of exposures, supporting suitability of 200 mg Q3W
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically based PK analysis) 
at 200 mg Q3W
Rationale for Endpoints
Efficacy Endpoints
4.2.3.1.1 Primary and Secondary Endpoints
Based on the recently presented spartalizumab data, where the primary PFS endpoint was not 
met for spartalizumab with a median PFS of 1.9 months vs 6.6 months with a hazard ratio of 
1.36 (95% CI 0.87, 2.12), we are amending the primary and efficacy endpoints from dual 
primary endpoints of PFS and OS to a single primary endpoint of OS. Of note, early data 
from the spartalizumab trial suggested a potential trend for superior OS with a median OS of 
25.2 months (13.1, NE) compared to 15.5 months (95% CI 8.3 
21.3) in the chemotherapy 
arm (HR not provided).
The primary efficacy objective to evaluate the anti-tumor activity of pembrolizumab 
(MK-3475) will be based on the primary endpoint of OS in this randomized, open-label trial.
To further support the robustness of the primary endpoint of OS, key secondary endpoints of 
PFS and ORR as assessed per RECIST 1.1 by the independent central review, blinded to 
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treatment assignment to minimize bias in the response assessments, will also be analyzed as 
part of a complete assessment of the anti-tumor and clinical utility of pembrolizumab (MK-
3475) compared to SOC chemotherapy in R/M NPC.
Because one of the key secondary efficacy objectives is ORR, measurable disease assessed 
by the site will be required at baseline for 
eligibility prior to treatment 
allocation/randomization. Retrospective confirmation of measurable disease will be assessed 
by central imaging vendor on a rolling basis. In addition, because PFS is an important 
supportive endpoint, final determination of radiologic PD will be based on the BICR of 
progression rather than local site investigator/radiology assessment. Expedited assessment 
by central imaging in instances of suspected radiologic progression identified at the site 
(verification of PD) will be communicated to the site study team. RECIST 1.1 will be used 
to determine the dates of progression as this methodology is accepted by regulatory 
authorities (see Appendix Section 12.7).
In order to more fully characterize the endpoints OS and PFS, secondary efficacy objective 
of DOR, as well as evaluation of progression-free survival proportion at 6- and 12-months 
per RECIST 1.1 and survival proportion at 12-and 24-months will be analyzed.
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) as below (see Section 4.2.3.1.1.1), and is referenced as 
irRECIST.
Immune-related RECIST
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 a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard RECIST 1.1 may, thus, not provide 
an accurate response assessment of immunotherapeutic agents such as pembrolizumab
(MK-3475). Based on an analysis of patients with melanoma enrolled in KEYNOTE-001, 
7% of evaluable patients experienced delayed or early tumor pseudoprogression. Of note, 
patients who had progressive disease by RECIST 1.1, but not by immune-related response 
criteria, had longer OS than patients with PD by both criteria. Additionally, the data suggest 
that RECIST 1.1 may underestimate the benefit of pembrolizumab (MK-3475) in 
approximately 15% of patients. These findings support the need to apply a modification to 
RECIST 1.1 that takes into account the unique patterns of atypical response in 
immunotherapy and enable treatment beyond initial radiographic progression.
Immune-related RECIST is RECIST 1.1 adapted to account for the unique tumor response 
seen with immunotherapeutics as described in Nishino et al.[71]. The assessment of 
unidimensional target lesions and response categories per irRECIST are identical to 
RECIST 1.1.
However, Merck has implemented an adaptation related to new lesions, 
non-target, and tumor burden assessment in order to confirm radiographic progression.
Immune-related RECIST will be used by local site investigators to assess tumor response and 
progression, and make treatment decisions (for subjects in treated with pembrolizumab
[MK-3475]) as well as by central imaging vendor in support of PFS endpoint.
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Safety Endpoints
The safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab (MK-3475) in subjects with R/M NPC. The safety analysis will be based on 
subjects who experience toxicities as defined by National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE) Version 4.0.
Safety will be assessed by 
summarizing the toxicities and grades experienced by subjects who have received 
pembrolizumab (MK-3475), including serious 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 ECIs as described 
in Section 7.2.3.2.
Patient-Reported Outcomes
The EQ-5D is not for pure efficacy or safety endpoint because it is affected by both disease 
progression and treatment tolerability.
The electronic EQ-5D (eEQ-5D) is a standardized instrument for use as a measure of health 
outcome. The eEQ-5D will provide data for use in economic models and analyses including 
developing health utilities or quality-adjusted life-years. The 5 health state dimensions in 
this instrument include the following: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression. 
Each dimension is rated on a 3-point scale from 1 (extreme 
problem) to 3 (no problem). The eEQ-5D also includes a graded (0 to 100) vertical visual 
analog scale on which the subject rates his or her general state of health at the time of the 
assessment. The eEQ-5D (or paper EQ-5D, if necessary) is to be completed at time points as 
specified in the Section 6.0 - Trial Flow Chart.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents.
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. 
Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy and other treatments 
administered, as well as determinants of AEs in the course of our clinical studies. These 
efforts may identify novel predictive/pharmacodynamic biomarkers and generate information 
that may better guide single-agent and combination therapy with immuno-oncology drugs. 
To identify novel biomarkers, biospecimens (i.e., blood components, tumor material) will be 
collected to support analyses of cellular components (e.g., protein, DNA, RNA, metabolites) 
and other circulating molecules. Investigations may include but are not limited to:
Germline (blood) genetic analyses (e.g., SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
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predict efficacy or adverse events, the data might inform optimal use of therapies in the 
patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations.  Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers 
(i.e., colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (i.e., mutations, 
methylation status, microsatellite instability). 
Key molecular changes of interest to 
immune-oncology drug development include the mutational burden of tumors and the 
clonality of T cells in the tumor microenvironment. Increased mutational burden (sometimes 
referred to as a ‘hyper-mutated’ state) may generate neo-antigen presentation in the tumor 
microenvironment.
To conduct this type of research, it is important to identify 
tumor-specific mutations that occur across all genes in the tumor genome. 
Thus, 
genome-wide approaches may be used for this effort. Note that in order to understand tumor-
specific mutations, it is necessary to compare the tumor genome with the germline genome. 
Microsatellite instability may also be evaluated as this is an important biomarker for some 
cancers (i.e., colorectal cancer). Circulating tumor DNA and/or RNA may also be evaluated 
from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. 
Specific immune-related gene sets (i.e., those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system may also be evaluated (e.g., IL-10). 
MicroRNA 
profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood and/or tumor
Tumor and/or blood samples from this study may undergo proteomic analyses (e.g., PD-L1 
IHC). PD L1 protein level in tumor sections, assessed by IHC, has been shown to correlate 
with response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) 
device has been developed for use with pembrolizumab in NSCLC. 
Preliminary data 
indicate that this association may also be true in additional cancer types (i.e., triple negative 
breast cancer, head and neck, and gastric). Additional tumor or blood-derived proteins may 
also correlate with response to pembrolizumab. Therefore, tumor tissue may be subjected to 
proteomic analyses using a variety of platforms that could include but are not limited to 
immunoassays and liquid chromatography/mass spectrometry. This approach could identify 
novel protein biomarkers that could aid in patient selection for pembrolizumab (MK-3475) 
therapy.
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Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor-derived proteins, RNA 
and/or DNA can be shed from tumor and released into the blood. 
Assays such as 
enzyme-linked immunoassay (ELISA) measure such proteins in serum, those assessing 
circulating tumor DNA, and/or RNA may also be evaluated from blood samples. Correlation 
of expression with response to pembrolizumab therapy may identify new approaches for 
predictive biomarkers in blood, representing a major advance from today’s reliance on 
assessing tumor biomarkers. This research would serve to develop such assays for future 
clinical use. 
Other molecular changes of interest include the subtype of T cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Induction of EBV antigen-specific T cells in peripheral blood in response to pembrolizumab 
(MK-3475) therapy.
PBMC isolated from peripheral blood will be assessed for antigen specificity using EBV-
specific T-cell biomarker assays following stimulation with overlapping pools of peptides 
from known EBV antigenic proteins. Various approaches for measuring immune reactivity 
of these PBMCs may be utilized.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research (FBR) on specimens for which 
consent was provided during this study. This research may include genetic analyses (DNA), 
gene expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of FBR research are presented in
Section 12.2 
Collection and Management of Specimens for FBR. Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
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METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male and female subjects with recurrent and/or metastatic nasopharyngeal carcinoma who
are ≥18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Provide documented informed consent for the trial. The subject may also provide 
consent for Future Biomedical Research. However, the subject may participate in the 
main trial without participating in Future Biomedical Research.
2. Be ≥18 years of age on day of providing documented informed consent.
3. Have histologically confirmed non-keratinizing differentiated NPC (World Health 
Organization [WHO] Type II) or undifferentiated NPC (WHO Type III).
4. Have locally or centrally determined EBV-positive NPC by EBV-encoded small 
RNA in situ hybridization (EBER in situ hybridization [ISH]) assay [72] If 
EBV-positive status has been previously determined by EBER ISH assay, then no 
re-testing is required.
Note: If EBV status by EBER ISH assay has not been previously determined and 
cannot be tested locally, tumor tissue from a newly obtained core or excisional 
biopsy or archival tissue may be submitted for central EBV determination.
5. Have metastatic disease defined as either disseminated disease and/or locally 
recurrent disease that is not amenable to curative treatment.
6. Subjects must have had prior receipt of platinum-containing regimen, either:
a.
For the treatment of recurrent or metastatic disease, or
b. Experienced progression of disease within 6 months following completion of 
a platinum-based combination therapy as part of (neo)adjuvant chemotherapy
Note: Patients who had only concurrent chemoradiation therapy without (neo)
adjuvant therapy and then recurred/metastasized must have progressed on at least 1
platinum-containing regimen for their recurrent/metastatic disease before study entry.
7. Have measurable disease based on RECIST 1.1 imaging criteria.
8. Have an ECOG performance status of 0 or 1.
9. Demonstrate adequate organ function as defined in Table 2.
Specimens must be 
collected within 10 days prior to the start of trial treatment.
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Table 2
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 (CrCl)
(Glomerular filtration rate [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 x ULN
AST 
(serum 
glutamic 
oxaloacetic 
transaminase 
[SGOT]) and
ALT (serum glutamic pyruvic transaminase [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 
and
PT,
partial 
thromboplastin time (PTT)
or INR is within 
therapeutic range of intended use of anticoagulants
Activated Partial Thromboplastin Time (aPTT)
≤1.5 x ULN 
unless 
subject 
is 
receiving 
anticoagulant therapy and PT, PTT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
a Creatinine clearance should be calculated per institutional standard.
10. Provide a tissue sample for PD-L1 biomarker analysis from a newly obtained core or 
excisional biopsy or archival tissue.
Note: If submitting unstained cut slides, freshly cut slides should be submitted to the 
testing laboratory within 14 days from when the slides are cut. See Section 7.1.3.2 
for further explanation.
11. Please refer to inclusion criterion number 12 for pregnancy testing of WOCBP.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
•
Is not a WOCBP
OR
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•
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-
term and persistent basis), as described in Section 12.10 
Contraceptive 
Guidance during the intervention period and for at least the time needed to 
eliminate each study intervention after the last dose of study intervention and 
agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use 
for the purpose of reproduction during this period. The length of time required to 
continue contraception for each study intervention is as follows:
-
MK-3475: at least 120 days
-
Chemotherapy: at least 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum as required by local regulations) within 24 hours for a urine test and 
72 hours for a serum test before the first dose of study intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.
-
Additional requirements for pregnancy testing during and after study 
intervention are in Section 7.1.4.1.1 Pregnancy Testing.
-
The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy.
-
Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies. If the contraception requirements in the local label for any of the 
study interventions is more stringent than the requirements above, the local 
label requirements are to be followed.
13. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study 
intervention after the last dose of study intervention. The length of time required to 
continue contraception for each study intervention is as follows: 
-
MK-3475: no contraception requirements
-
Chemotherapy: at least 95 days
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
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OR
•
Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Section 12.10 
Contraceptive 
Guidance]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile-vaginal penetration.
•
Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
14. Have a life expectancy of greater than 3 months.
Optional Sub-study Additional Subject Inclusion Criteria (Appendix 12.9)
1. Provide documented informed consent for this sub-study clinical trial. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial as well as the additional sub-study without participating in 
Future Biomedical Research.
2. In the Investigator’s assessment, be physically able and willing to donate the extra 
required tubes of whole blood throughout the course of this study. See Laboratory 
Manual or Procedures Manual for sub-study. 
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent.
2. Has a histological diagnosis of keratinizing squamous cell carcinoma (WHO Type I) 
or basaloid squamous cell nasopharyngeal carcinoma.
3. Patients who have received platinum therapy only as part of a concurrent 
chemoradiotherapy regimen (i.e., have not received platinum as part of (neo)adjuvant 
platinum-based combination therapy either prior to or following definitive concurrent 
chemoradiation, or as a platinum-containing regimen for the treatment of recurrent or 
metastatic disease) are excluded.
4. Patients previously treated in the recurrent/metastatic setting with any one of the 
3 SOC therapies in this trial (i.e., docetaxel, capecitabine, or gemcitabine) may not 
receive the same therapy if randomized to the SOC arm. Additionally, patients 
previously treated in the recurrent/metastatic setting with all 3 SOC therapies are 
excluded from this trial.
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5. Is currently participating in and receiving trial treatment or has participated in a study 
of an investigational agent and received trial treatment or used an investigational 
device within 4 weeks of the first dose of 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.
6. 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 peripheral 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.
7. Has had a diagnosed additional malignancy within 5 years prior to treatment 
allocation/randomization with the exception of curatively treated basal cell carcinoma 
of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ
cervical and/or breast cancers.
8. Has known active central nervous system 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 
4 weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment. This exception does not 
include carcinomatous meningitis, which is excluded regardless of clinical stability.
9. Has had a prior anti-cancer 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.
10. 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) is not considered a form of 
systemic treatment and is permitted.
11. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
12. Has an active infection requiring systemic therapy.
13. 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.
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14. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
15. Has known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or known 
active hepatitis C (e.g., hepatitis C virus RNA [qualitative] is detected; subjects who 
have been treated and now have a viral load that is undetectable are eligible).
16. 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.
17. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 180 days after 
the last dose of trial treatment for the chemotherapy arm or 120 days after the last 
dose of trial treatment for the pembrolizumab (MK-3475) arm.
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or has 
previously participated in Merck pembrolizumab (MK-3475) clinical trials.
20. Has received a live vaccine within 30 days of planned start of trial treatment.
Optional Sub-study Additional Subject Exclusion Criteria
1. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the sub-study, interfere with the subject’s 
participation for the full duration of the sub-study, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.
Trial Treatment(s)
The study drug dose and schedule to be used in this trial are outlined below in Table 3
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Table 3
Trial Treatments
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period
Use
IMP/ 
NIMP
Sourcing
Pembrolizumab
Experi
mental
Pembrolizumab
Drug
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Day 1 of each 3 week
cycle for up to 35 
cycles
Experimental
IMP
Provided 
centrally 
by the 
Sponsor
SOC
Active 
Comparator
Capecitabine
Drug
Tablet
Variable
1000 
mg/m2
See 
Note
Oral
Days 1 14 twice 
daily, followed by 
7 days with no dosing 
per 3 week cycle
Experimental
IMP
Provided 
centrally 
by the 
Sponsor or 
locally 
sourced
SOC
Active 
Comparator
Gemcitabine
Drug
Lyophilized 
Powder
Variable
1250 
mg/m2
IV Infusion
Days 1 and 8 per 
3 week cycle
Experimental
IMP
Provided 
centrally 
by the 
Sponsor or 
locally 
sourced
SOC
Active 
Comparator
Docetaxel
Drug
Solution for 
Infusion
Variable
75 
mg/m2
IV Infusion
Day 1 per 3 week 
cycle
Experimental
IMP
Provided 
centrally 
by the 
Sponsor or 
locally 
sourced
EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP=noninvestigational medicinal product; SOC=standard of care.
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Note: For capecitabine, based on labeling and local SOC, countries may increase the dose to 1250 mg/m2 from Cycle 2 onwards based upon tolerability and local practices.
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For Cycle 1, Day 1, trial treatment should be given on the day of treatment 
allocation/randomization, but up to 3 days after treatment allocation/randomization is 
permitted. For all subsequent cycles, +/-3 days of Day 1 are permitted.
All supplies indicated in Table 3 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
Per local guidelines, the trial site may be responsible for recording the lot number, 
manufacturer, and expiry date of any locally purchased product. If the same potency/strength 
of the SOC specified in the protocol is not available, then the potency/strength that is 
available may be used.
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 for Pembrolizumab (MK-3475)
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.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
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Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to trial treatment (e.g., elective surgery, unrelated medical events, subject
vacation, and/or holidays). If a subject interrupts the treatment plan for more than 3 weeks 
for a non-drug related reason, the site should consult with the Sponsor (see section 7.1.1.8). 
The reason for interruption should be documented in the subject’s study record.
Refer to Section 5.6.1 for management of infusion reactions for pembrolizumab (MK-3475).
Timing of Dose Administration
Pembrolizumab (MK-3475) Administration
Trial treatment of pembrolizumab (MK-3475) may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle due to administrative reasons (up to 3 days after
treatment allocation/randomization is permitted).
All trial treatments will be administered on an outpatient basis.
Trial treatment of pembrolizumab (MK-3475) should be administered on Day 1 of each cycle 
after all procedures/assessments have been completed as detailed in Section 6.0 - Trial Flow 
Chart. In general, the window for each visit is ± 3 days unless otherwise noted.
Pembrolizumab (MK-3475) 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 minutes/+10 minutes).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab (MK-3475) infusion fluid and administration of infusion solution.
Standard of Care Administration
Doses of SOC chemotherapy below should be based upon actual body weight, not ideal body 
weight. If the subject’s weight increases or decreases by >10% from baseline during the 
course of the study, the drug dose should be re-calculated.
Dose Selection for Capecitabine (Preparation)
The preparation and administration of capecitabine should follow local treatment guidelines. 
However, the following recommendations should be taken into account.
Capecitabine is administered at 1000 mg/m2 twice daily orally (i.e., total daily dose of 
2000 mg/m2), for 14 days continuously, followed by 7 days with no dosing in a 3-week cycle.
Dosage may need to be individualized to optimize patient management. Based on labeling 
and local SOC, countries may increase the dose to 1250 mg/m2 twice daily orally from 
Cycle 2 onwards. Capecitabine dosing is repeated for every 3-week cycle.
The morning dose of capecitabine should be taken with approximately 200 ml of water 
within 30 minutes after a meal.
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The evening dose of capecitabine should be taken approximately 12 hours after the morning 
dose and should be taken with food, or within 30 minutes after food/meal, with 
approximately 200 ml of water.
If a subject vomits after taking capecitabine, the subject should be instructed not to retake 
the dose. If vomiting persists, then the subject should notify the investigator. If the complete 
tablets are clearly visualized in the vomiting incident, follow local label instructions as per 
SOC.
Capecitabine can induce diarrhea, sometimes severe, including the rare reporting of 
necrotizing 
enterocolitis 
(typhlitis). 
Therefore, 
for 
subjects 
who 
experience 
capecitabine-associated diarrhea, aggressive supportive management with anti-diarrheals,
including loperamide and lomotil, according to local SOC treatment guidelines are indicated. 
Additional supportive measures should include aggressive hydration with electrolyte 
replacement as indicated, and could also include implementation of the American Dietetic 
Association BRAT diet as clinically indicated.
Dose Modification for Capecitabine
Table 5
Dose Modification Guidelines for Capecitabine Drug-Related Events or 
(Drug-Related) Adverse Events 
Toxicity Grades
During a Course of Therapy
Dose Adjustment for Next 
Treatment (% of starting dose)
Grade 1
Maintain dose level
Maintain dose level
Grade 2

1st appearance
Interrupt until resolved to Grade 0-1
100%

2nd appearance
75%

3rd appearance
Interrupt treatment 
50%

4th appearance
Discontinue treatment permanently
-
Grade 3

1st appearance
Interrupt until resolved to Grade 0-1
75%

2nd appearance
50%

3rd appearance
Discontinue treatment permanently
-
Grade 4

1st appearance
Discontinue permanently
OR
If physician deems it to be in the patient’s 
best interest to continue, interrupt until 
resolved to Grade 0-1
50%
For additional guidance regarding treatment modification of capecitabine, please refer to the 
United States package insert (or local prescribing information) for dose modifications for 
hematologic and other non-hematologic toxicities.
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Drug-induced Liver Injury
If the AE of elevated liver enzymes (i.e., ALT, AST or total bilirubin) meets the following
laboratory criteria for potential Drug-induced Liver Injury (DILI) as defined below, the event 
must be reported as a DILI as well as an ECI:

An elevated ALT or AST lab value that is greater than or equal to three times (3X) 
the upper limit of normal (ULN) and

An elevated total bilirubin lab value that is greater than or equal to two times (2X) 
ULN and

At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 

As a result of within-protocol-specific testing or unscheduled testing.
For capecitabine-related diarrhea supportive care guidelines, please see Section 5.6.2
Supportive Guidelines for SOC Chemotherapy.
Dose Selection for Gemcitabine (Preparation)
The preparation and administration of gemcitabine should follow local treatment guidelines. 
However, the following recommendations should be taken into account.
Gemcitabine is administered by IV infusion at a dose of 1250 mg/m2 over 30 minutes on 
Days 1 and 8, of a 3-week cycle.
Pre-medication with steroids prior to IV infusion is 
permitted as per local SOC.
Dose Modification for Gemcitabine
Table 6
Dose Modification Guidelines for Gemcitabine Hematologic Drug-Related Events 
or (Drug-Related) Adverse Events
Absolute neutrophil count 
(x 106/L)
Platelet count
% of Full Dose
>1000
and
>100,000
100%
500 999
or
50,000 99,000
75%
<500
or
<50,000
Hold until resolves to Grade 0 1
Dose Modification Guidelines for Gemcitabine Non-Hematologic Drug-Related Events or 
(Drug-Related) Adverse Events

Withhold gemcitabine or reduce dose by 50% of full dose for other severe (Grade 3 or 4) 
non-hematologic toxicities until resolved to Grade 0-1.

No dose modifications are recommended for alopecia, nausea, or vomiting.

Permanently discontinue gemcitabine for the following:

Unexplained dyspnea or other evidence of severe pulmonary toxicity

Severe hepatic toxicity

Hemolytic-uremic syndrome

Capillary leak syndrome
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
Posterior reversible encephalopathy syndrome
For additional guidance regarding treatment modification of gemcitabine, please refer to the 
United States package insert (or local prescribing information) for dose modifications for 
hematologic and other non-hematologic toxicities.
Dose Selection for Docetaxel (Preparation)
The preparation and administration of docetaxel should follow local treatment guidelines. 
However, the following recommendations should be taken into account.
Docetaxel is administered by IV infusion over 1 hour every 3 weeks at a dose of 75 mg/m2.
Corticosteroid Use with Docetaxel
In order to reduce the incidence and severity of fluid retention as well as the severity of 
hypersensitivity reactions, all patients should be premedicated with oral corticosteroids such 
as dexamethasone 16 mg per day (e.g., 8 mg BID) for 3 days, starting 1 day prior to 
docetaxel administration.
Growth Factor Support Use with Docetaxel
For docetaxel, pegfilgrastim 6 mg subcutaneous (SQ) on Day 2 of each treatment cycle or 
filgrastim 5 µg/kg SQ on Days 2 through 11 of each treatment cycle may be used according 
to local treatment standards; however, discontinue for ANC >10,000/mm3. 
See also 
Section 5.6.2
Supportive Guidelines for SOC Chemotherapy.
Docetaxel should not be given to subjects with bilirubin >1 x ULN, or to subjects with AST
and/or ALT >1.5 x ULN with concomitant ALP >2.5 x ULN as subjects with laboratory 
values above these limits are at increased risk of SAEs (refer to local product label).
Dose Modification for Docetaxel
Table 7
Dose Modification for Docetaxel Drug-Related Events (or Drug-Related) Adverse 
Events)
Toxicity
Grade
Occurrence
Hold Treatment
Dose Modification
Treatment 
Discontinuation
Liver 
dysfunction
AST/ALT >2.5 to 
≤5 × ULN and AP 
≤2.5 × ULN, or 
AST/ALT >1.5 to 
≤5 × ULN and AP 
>2.5 to ≤5 × ULN
Yes
Restart treatment at 
60 mg/m2
N/A
AST/ALT 
>5 
× 
ULN and/or AP >5 
× ULN
Yes
N/A
Discontinue 
upon onset
Peripheral 
Neuropathy
Grade 3, 4
Yes
N/A
Discontinue 
upon onset
Oral Mucositis
Grade 3, 4
1st,2nd
occurrence
Hold until resolved
55 mg/m2
Note: Patients who develop >Grade 3 peripheral neuropathy should have docetaxel treatment 
permanently discontinued.
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For additional guidance regarding treatment modification of docetaxel, please refer to the 
United States package insert (or local prescribing information) for dose modifications for 
hematologic and other non-hematologic toxicities as recommended for monotherapy with 
docetaxel in patients with non-small cell lung cancer).
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS). There are 2 treatment arms; subjects 
will be assigned randomly in a 1:1 ratio to pembrolizumab (MK-3475) or SOC, respectively. 
The choice of SOC for a subject must be identified and documented prior to randomization. 
The choice of the SOC therapy will be input in the IVRS/IWRS prior to the randomized 
allocation schedule generation. Patients randomized to SOC therapy who discontinue will 
not be crossed-over to pembrolizumab (MK-3475).
Stratification
Randomization will be stratified according to the presence or absence of liver metastasis(es) 
(presence of any liver metastasis versus absence of all liver metastasis).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy 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 schedule requires the mutual agreement of the investigator, the 
Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.
If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
All concomitant medications taken by the subject from the date of first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.
Concomitant 
medications administered >30 days after the last dose of trial treatment should be recorded 
for SAEs and ECIs as defined in Section 7.2
Assessing and Recording AEs.
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Bisphosphonate or denosumab therapy is allowed as long as it is begun at least 2 weeks prior 
to randomization. If started after randomization, it will be determined to be consistent with 
symptomatic progression of disease and clinical progression will be declared at that time 
followed by discontinuation of study treatment.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol (with the exception of denosumab as 
noted above in Section 5.5.1)

Investigational agents other than pembrolizumab (MK-3475)

Radiation therapy

Live or live attenuated vaccines within 30 days prior to the first dose of trial treatment 
and while participating in the trial. Note: Killed vaccines are allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines.  These vaccines will be treated just as any other 
concomitant therapy. Investigational vaccines (i.e., those not licensed or approved for 
Emergency Use) are not allowed.
Prohibited Concomitant Medications for Pembrolizumab (MK-3475)

Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of 
asthma/chronic obstructive pulmonary disease are permitted) for any purpose other 
than to modulate symptoms from an AE.
The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. Additionally, a 
short, limited course of steroids may be used to treat medical conditions and/or AEs 
during the study after Sponsor notification and consultation (Sponsor consultation is 
not required for topical steroid administration or for any other non-parenteral steroid 
administration).
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., IV contrast 
dye) is permitted.
Prohibited Concomitant Medications for SOC 

For subjects receiving docetaxel, strong inhibitors of the CYP3A4 enzymes (a 
common list of such agents may be found in Section 12.8 for subjects receiving 
docetaxel)
Note: For subjects randomized to the standard treatment arm that require treatment 
with a strong inhibitor of CYP3A4, docetaxel may not be chosen as the standard 
treatment.
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
For subjects receiving capecitabine, rare, unexpected severe toxicity (e.g., stomatitis, 
diarrhea, neutropenia, and neurotoxicity) associated with 5-fluorouracil has been 
attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link 
between decreased levels of DPD and increased, potentially fatal toxic effects of 
5-fluorouracil/capecitabine therefore, cannot be excluded. Therefore, capecitabine 
may not be chosen as the standard treatment for any subject with a known DPD 
deficiency.

For subjects being treated with warfarin, capecitabine may not be chosen as the 
standard treatment.
Note: Concomitant treatment with low-molecular weight heparin therapy may be 
instituted instead.
Subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describe other medications that are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab (MK-3475)
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are outlined in Section 5.2.1.2 (Table 4).
Where 
appropriate, these guidelines include the use of oral or IV treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with administration 
of corticosteroids.
Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab (MK-3475).
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined in Section 5.2.1.2; Table 4).
It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Management of Infusion Reactions:
Pembrolizumab (MK-3475) may cause severe or life threatening infusion-reactions including 
severe hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion of
infusion.
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Dose modification and toxicity management guidelines on pembrolizumab (MK-3475)
associated infusion reaction are shown in Table 8.
Table 8
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption 
but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
non steroidal 
anti inflammatory 
drugs 
[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 1 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 to 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.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Note: Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
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Supportive Care Guidelines for Standard of Care Chemotherapy
Growth Factor Support
Docetaxel should not be given to subjects with neutrophil counts of <1500 without growth 
factor support.

For docetaxel, pegfilgrastim 6 mg SQ on Day 2 of each treatment cycle or filgrastim
5 µg/kg SQ on Days 2 through 11 of each treatment cycle may be used according to 
local treatment standards; however, discontinue for ANC >10,000/mm3.

For gemcitabine, filgrastim 5 µg/kg SQ on Days 2 through 5 following each infusion, 
may be used according to local treatment standards; however, discontinue for ANC 
>10,000/mm3.
Prophylactic Steroid Administration
For subjects randomized to gemcitabine:
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, 
and adult respiratory distress syndrome, have been reported rarely following 1 or more doses 
of gemcitabine administered to patients with various malignancies. 
Some patients 
experienced the onset of pulmonary symptoms up to 2 weeks after the last gemcitabine dose. 
Respiratory failure and death occurred very rarely in some patients despite discontinuation of 
therapy. Therefore, prophylactic steroids may be administered prior to gemcitabine infusions 
as per the local treatment standards.
For subjects randomized to docetaxel:
Hypersensitivity reactions, especially during the first and second infusions, as well as severe 
fluid retention, have been reported following docetaxel infusions. Severe hypersensitivity 
reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, as 
well as very rarely, fatal anaphylaxis, have been reported.
Therefore, in order to reduce the incidence and severity of fluid retention as well as the 
severity of hypersensitivity reaction, all subjects randomized to receive docetaxel must be 
premedicated with oral corticosteroids such as dexamethasone 16 mg per day (e.g., 8 mg 
BID) for 3 days starting 1 day prior to docetaxel administration.
Steroid Administration for Treatment of Adverse Events or Medical 
Conditions
A short course of steroids may be used as concomitant medication for either treatment of an 
adverse event or medical condition with Sponsor approval (Sponsor consultation is not 
required for topical steroid administration or for any other non-parenteral steroid 
administration).
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Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Capecitabine can induce diarrhea, sometimes severe, including the rare reporting of 
necrotizing 
enterocolitis 
(typhlitis). 
Therefore, 
for 
subjects 
who 
experience 
capecitabine-associated diarrhea, aggressive supportive management with anti-diarrheals,
including loperamide and lomotil, according to local SOC treatment guidelines are indicated. 
Additional supportive measures should include aggressive hydration with electrolyte 
replacement as indicated, and could also include implementation of the American Dietetic 
Association BRAT diet as clinically indicated.
Contraception
Details regarding contraception are outlined in Section 5.1.2 - Subject Inclusion Criteria and 
Section 12.10 - Contraceptive Guidance.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.6
Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue in the study in survival 
follow-up, 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, as outlined in Section 7.1.7.2.1.
A subject must be withdrawn from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) requests to 
discontinue treatment

Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if 
the Sponsor approves treatment continuation).
Note: For unconfirmed radiographic disease progression, please see Section 7.1.5.1.6.

Unacceptable AEs as described in Section 7.2
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
Any progression or recurrence of any malignancy, or occurrence of another 
malignancy that requires active treatment

Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment

Any study treatment-related toxicity specified as a reason for permanent 
discontinuation as defined in Section 5.2.1.2.1

Investigator’s decision to discontinue treatment for the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 35 administrations of pembrolizumab (MK-3475) (approximately 2 years)
Note: Subjects who stop pembrolizumab (MK-3475) after 35 administrations 
(approximately 2 years) may be eligible for up to 17 additional administrations of 
pembrolizumab (MK-3475) (approximately 1 year) if they progress after stopping 
trial treatment provided they meet the requirements detailed in Section 7.1.7.2.1.

Administrative reasons
The End of Treatment and Follow-up Visit procedures are listed in Section 6.0
Trial Flow 
Chart and Section 7.1.7
Visit Requirements. After the end of treatment, each subject will 
be followed for the occurrence of AEs and spontaneously reported pregnancy as described in 
Section 7.2. See Section 7.2.2 for complete details of reporting requirements of AEs and 
pregnancy/lactation.
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up. After documented disease progression,
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Discontinuation of Trial Treatment After CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have received at least 8 administrations of pembrolizumab (MK-3475) and had at 
least 2 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 17 additional administrations of pembrolizumab (MK-3475) (approximately 1 year) 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 as at the time of initial discontinuation.
Additional details are provided in 
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Section 7.1.7.2.1.
Response or progression in this Second Course Phase will not count 
towards the ORR and PFS of the key secondary endpoint in this trial.
Subject Withdrawal/Discontinuation Criteria from the Optional Sub-Study
Subjects may withdraw consent at any time for any reason or discontinue from this sub-study
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 sub-study is 
inappropriate, the sub-study plan is violated, or for administrative and/or other safety 
reasons.  Subjects may withdraw from the sub-study without withdrawing from the main 
study.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall study begins when the first participant provides documented informed consent. 
The overall study ends when the last participant completes the last study-related contact, 
withdraws consent or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
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.
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Trial Period
Screening Phase
Treatment Cycles (3 Week Cycles)
End of 
Treatment
Post Treatment Visits
Treatment Cycle/Title:
Screening (Visit 1)
1
2
3
4
To be repeated 
beyond 6 cyclesr
Discon
Safety 
Follow up
Efficacy 
Follow upp
Survival 
Follow upa
5
6
Scheduling Window (Days)b:
30 to 1
+3
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks post 
discon 
Every 
12 weeks
a. After documented disease progression, or the start of new anti cancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested by 
the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor 
defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded). The investigator should make every attempt to follow the 
subject’s AE(s) during the Survival Follow Up Phase if the AE is in the reporting timeframe. See Section 7.1.7.3.3 for details.
b. In general, the window for each visit is ± 3 days unless otherwise noted.
c. Height will be measured at visit 1 only.
d. ECOG and laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.
e. For women of reproductive potential, a urine pregnancy test should be performed within 24 hours or a serum pregnancy test should be performed within 72 hours prior to first dose of 
trial treatment and repeated at every cycle, at the time of treatment discontinuation, at the safety follow up visit, and at least 120 days after the last dose of pembrolizumab or at least 180 
days after the last dose of chemotherapy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Monthly pregnancy testing should be 
conducted as per local regulations where applicable.
f. After Cycle 1, Hematology and Chemistry lab samples can be collected up to 3 days prior to Day 1 of every cycle for all treatment groups and additionally up to 3 days prior to Day 8 for 
subjects assigned to gemcitabine. Urinalysis is only required at Day 1 of Cycle 2 and then Day 1 of every other cycle after Cycle 2, for all treatment groups, and additionally on Day 8 of 
every other cycle for subjects assigned to gemcitabine.  For Urinalysis, samples can be obtained up to 3 days prior to the scheduled time points.
g. To be repeated every other cycle after Cycle 6.
h. Pre dose trough PK and anti pembrolizumab (MK 3475) antibody samples will be collected at Cycles 1, 2, 4, 6 and 8. All pre dose trough samples should be drawn within 24 hours 
before infusion of pembrolizumab (MK 3475).
i. To be repeated every 4 cycles after Cycle 8, until discontinuation of study drug (or until the subject starts new anti cancer therapy).
j. Details for collection can be found in Section 7.1.4, Laboratory Procedures/Assessments.
k. Tumor imaging assessments are to be every 6 weeks as per Section 7.1.5.1. After 1 year in the treatment period, imaging should be performed every 9 weeks (63 days ± 7 days).  After 
Year 1, it will be at the site Investigator’s discretion to follow the protocol specified imaging schedule or to follow the imaging schedule per local/standard practice.
l. If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory. Refer to Section 7.1.5.1.3 for details.
m. It is a best practice and strongly recommended that ePROs are administered to randomized subjects prior to drug administration, AE evaluation, and disease status notification. The 
EQ 5D is to be performed prior to dosing on only Day 1 of Cycle 1, Cycle 2, Cycle 3 and every 2 cycles thereafter (e.g., Cycle 5, Cycle 7, Cycle 9) up to 1 year from treatment initiation 
(i.e., Cycle 17). If the subject does not complete the EQ 5D for any reason, the Miss Mode form must be completed to capture the reason the assessment was not performed.
n. Plasma EBV DNA to be collected weekly during Cycle 1, and then up to 3 days prior to dosing at all subsequent cycles. Plasma EBV DNA should not be collected beyond Cycle 80 Day 
1.
o. After Cycle 1, lab samples can be collected up to 3 days prior to the scheduled time point. Note: weekly collection of Serum human chorionic gonadotropin (hCG) is not required for any 
subject. See footnote e regarding pregnancy test requirements.
p. In subjects who discontinue trial treatment without documented disease progression, every effort should be made to continue monitoring disease status by radiologic imaging using the 
same imaging schedule used while on treatment (every 6 weeks in Year 1 and every 9 weeks after Year 1) until (1) the start of new anti cancer treatment, (2) disease progression, (3) 
pregnancy, (4) death, (5) withdrawal of consent, or (6) the end of the study, whichever occurs first.  Follow up visits may be adjusted to coincide with the Follow up imaging schedule.
After Year 1, it will be at the site Investigator’s discretion to follow the protocol specified imaging schedule or to follow the imaging schedule per local/standard practice.
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Trial Period
Screening Phase
Treatment Cycles (3 Week Cycles)
End of 
Treatment
Post Treatment Visits
Treatment Cycle/Title:
Screening (Visit 1)
1
2
3
4
To be repeated 
beyond 6 cyclesr
Discon
Safety 
Follow up
Efficacy 
Follow upp
Survival 
Follow upa
5
6
Scheduling Window (Days)b:
30 to 1
+3
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks post 
discon 
Every 
12 weeks
q. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  PTT may be performed if the local lab is unable to perform aPTT.  Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
r. Subjects on the SOC arm may continue study treatment beyond Cycle 35 until they meet a discontinuation criterion. For subjects on the SOC arm who are dosed beyond Cycle 35, 
procedures (i.e., imaging) should continue.
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Trial Period:
Treatment Cycles (3 Week Cycles)
End of 
Treatment
Post Treatment Visits
Treatment Cycle/Title:
1
2
3
4
To be repeated 
beyond 6 cycles
Discon
Safety 
Follow up
Efficacy 
Follow upi
Survival 
Follow upa
5
6
Scheduling Window (Days)b:
+ 3
± 3
± 3
± 3
± 3
± 3
At time of 
discon
30 days 
post last 
dose
Every 
6 weeks post 
discon
Every 
12 weeks
d. After Cycle 1, Hematology and Chemistry lab samples can be collected up to 3 days prior to Day 1 of every cycle at the scheduled time point. Urinalysis is only required at Day 1 of 
every other cycle after Cycle 1. Urinalysis samples can be scheduled up to 3 days prior to the scheduled time point.
e. Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab (MK 3475).
f. To be repeated every other cycle after Cycle 5.
g. A scan must be performed within 30 days prior to restarting treatment with pembrolizumab (MK 3475). Subjects who obtain a confirmation scan for CR, PR, or disease progression do 
not need to undergo scheduled tumor imaging if it is <4 weeks later and may wait until the next scheduled imaging time point, unless clinical disease progression is suspected or subject 
is deemed to be clinically unstable. In the Re treatment phase tumor assessments are to be every 6 weeks/every 3 cycles as outlined in Section 7.1.5.1.4. Subjects who discontinue 
without documented disease progression will continue scans every 6 weeks for the first year and every 9 weeks in Year 2. After Year 1, it will be at the site Investigator’s discretion to 
follow the protocol specified imaging schedule or to follow the imaging schedule per local/standard practice.
h. After Cycle 1, lab samples can be collected up to 3 days prior to the scheduled time point. Note: weekly collection of Serum human chorionic gonadotropin (hCG) is not required for any 
subject. See footnote c for pregnancy test requirements.
i. In subjects who discontinue trial treatment without documented disease progression, every effort should be made to continue monitoring disease status by radiologic imaging using the 
same imaging schedule used while on treatment (every 6 weeks in Year 1 and every 9 weeks after Year 1) until (1) the start of new anti cancer treatment, (2) disease progression, (3)
pregnancy, (4) death, (5) withdrawal of consent, or (6) the end of the study, whichever occurs first. Follow up visits may be adjusted to coincide with the Follow up imaging schedule.
After Year 1, it will be at the site Investigator’s discretion to follow the protocol specified imaging schedule or to follow the imaging schedule per local/standard practice.
j. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  PTT may be performed if the local lab is unable to perform aPTT.  Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
The optional sub-study flow chart can be found in Section 12.9.
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TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential subject or their legally acceptable 
representative prior to participating in this clinical trial or Future Biomedical Research. If 
there are changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
7.1.1.1.1 General Informed Consent
Informed consent given by the subject or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the subject (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the subject (or 
their legally acceptable representative) before participation in the trial.
The initial informed consent form, any subsequent revised 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 or the subject’s legally acceptable 
representative’s dated signature.
Specifics about the trial and the trial population are to be included in the study informed 
consent form.  
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 medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.2.1 Inclusion/Exclusion Criteria for Optional Participation in the Sub-Study
All additional inclusion and exclusion criteria as noted in Sections 5.1.2.1 and 5.1.3.1 will be 
reviewed by the investigator or qualified designee to ensure that the subject qualifies for the 
trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides documented informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
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 important by the investigator. Details regarding the subject’s 
nasopharyngeal cancer will be recorded separately and not listed as medical history.
Please note that if the subject has lost at least 15 lbs. (6.8 kg) over the 3 months prior to 
screening, “weight loss” should be entered as an active condition on the Medical History. In 
addition, any autoimmune disorders, feeding tube placement, and tracheotomy, regardless of 
onset date, should be recorded.
7.1.1.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding the 
subject’s nasopharyngeal cancer.
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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 
during the screening period (Day -30 through Day -1 of trial treatment start).
Prior 
anti-cancer treatment for NPC will be recorded separately and not listed as a prior 
medication.
Prior Treatment Details for Nasopharyngeal Cancer
The investigator or qualified designee will review and record all prior anti-cancer treatments 
including systemic treatments, radiation, and surgeries, regardless of the time prior to first 
dose of trial treatment.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
from the date of first dose of trial treatment through the Safety Follow-up visit.  In addition, 
new medications started during the Second Course through the Second Course Safety 
Follow-up Visit should be recorded. All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 7.2
Assessing and Recording Adverse Events.
Additionally, please see Section 5.5.1
Acceptable Concomitant Medications and Section 
5.5.2
Prohibited Concomitant Medications.
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up Visit must occur before the 
first dose of the new therapy. Once new anti-cancer therapy has been initiated, the subject 
will move into Survival Follow-up.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.7.1.
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
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occurring after treatment allocation/randomization.  Once a treatment/randomization number 
is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
In a situation where reallocation/rerandomization of participants is planned (eg, study 
extension 
periods), 
the 
reallocation/rerandomization will 
be 
based 
on 
a 
new 
allocation/randomization schedule; however, each participant will retain his/her original 
treatment/randomization number. Only the study intervention regimen associated with the 
reallocation/rerandomization period or phase may change.
Trial Compliance (Medication/Diet/Activity/Other)
Details regarding administration of trial treatment are outlined in Section 5.2 
Trial 
Treatment.
Interruptions from the protocol specified treatment plan for greater than 3 weeks between 
pembrolizumab (MK-3475) doses for non-drug-related or administrative reasons (see 
Section 5.2.1.2 for drug-related modifications) require consultation between the investigator 
and the Sponsor and written documentation of the collaborative decision on subject 
management.
Administration of trial treatment will be monitored 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 with each dose of pembrolizumab
(MK-3475)
administered.
The instructions for preparing and administering pembrolizumab (MK-3475) will be 
provided in the Pharmacy Manual.
Survival Status
Details regarding survival status follow-up are outlined in Section 7.1.7.3.3
Survival 
Follow-up and Section 7.1.7.4 Survival Status.
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject weekly during the first 
4 cycles, followed by Day 1 of each subsequent cycle to evaluate for potential new or 
worsening AEs, and more frequently if clinically indicated. Adverse events will be graded 
and recorded throughout the study and during the Follow-up Period according to NCI 
CTCAE Version 4.0 (see Section 12.6). Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.
For subjects receiving treatment with pembrolizumab (MK-3475), all AEs of unknown 
etiology associated with pembrolizumab (MK-3475) exposure should be evaluated to 
determine if it is possibly an ECI of a potentially irAE; see Section 7.2.3.2 regarding the 
identification, evaluation and management of potential irAEs.
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Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Electronic Patient-Reported Outcomes
The EQ-5D questionnaire will be administered by trained site personnel and completed 
electronically (eEQ-5D) or by paper (EQ-5D), if necessary, by subjects at the time points 
specified in the Trial Flow Chart. It is a best practice and strongly recommended that 
electronic patient-reported outcomes (ePROs) are administered to randomized subjects prior 
to drug administration, AE evaluation, and disease status notification.
Physical Exam
7.1.2.3.1 Full Physical Exam
The investigator or clinical designee will perform a complete physician exam during the 
screening period and at the time of treatment discontinuation.
Clinically significant 
abnormal findings should be recorded as medical history. A full physical exam should be 
performed as specified in Section 6.0 - Trial Flow Chart.
After the first dose of trial 
treatment, new clinically significant abnormal findings should be recorded as AEs.
7.1.2.3.2 Directed Physical Exam
The investigator or qualified designee will perform a directed physical exam weekly for the 
first 4 cycles in the Initial Treatment Phase only and prior to all dosing visits. On dosing 
visits, the directed physical exam will be performed prior to dosing ± 3 days of Day 1 of each 
treatment cycle.
For subjects assigned to gemcitabine with dosing visits on Day 1 and 
Day 8 of each cycle, a directed physical exam will be performed prior to dosing ± 3 days of 
Day 1 and ± 3 days of Day 8.
New clinically significant abnormal findings should be 
recorded as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at screening, weekly for the first 
4 cycles in the Initial Treatment Phase only, and ± 3 days of Day 1 of each subsequent 
treatment cycle, as well as at treatment discontinuation as specified in the Trial Flow Chart.
For subjects assigned to gemcitabine with dosing visits on Day 1 and Day 8 of each cycle, 
vital signs will be taken prior to dosing ± 3 days of Day 1 and ± 3 days of Day 8. Vital signs 
should include temperature, pulse, respiratory rate, weight and blood pressure. Height will 
be measured at screening only.
12-Lead Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening. Clinically significant abnormal findings should be recorded as 
medical history. Additional ECGs may be performed as clinically necessary.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.5) at 
screening, weekly for the first 4 cycles in the Initial Treatment Phase only, prior to dosing 
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± 3 days of Day 1 of each treatment cycle, and at discontinuation of trial treatment as 
specified in the Trial Flow Chart. For subjects assigned to gemcitabine with dosing visits on 
Day 1 and Day 8 of each cycle, ECOG will be assessed prior to dosing ± 3 days of Day 1 and 
± 3 days of Day 8.
Tumor Tissue Collection
Epstein-Barr Virus Status
All subjects must have assessment of EBV status from tumor tissue prior to treatment 
allocation/randomization (see Section 5.1.2). Baseline tumor tissue from an archival tissue 
sample or newly obtained core or excisional biopsy (fine needle aspirate [FNA] not adequate
for archival and new tissue samples) must be evaluated for EBV status (if EBV status is not 
already known) by local assessment by means of EBER ISH testing.
If EBV status has 
previously been tested using EBER ISH, no retesting is required.
Note: Subjects without available local EBER ISH testing results may submit tumor tissue for 
central EBER ISH testing.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Laboratory Manual or Procedures Manual.
If the subject provides documented informed consent for Future Biomedical Research, any 
leftover samples that would ordinarily be discarded at the end of the main study will be 
retained for Future Biomedical Research.
PD-L1 Status
All subjects should submit either a newly obtained core or excisional biopsy or archival 
tissue (FNA not adequate for both archival and new tissue samples) to a central lab for 
characterization of PD-L1 status prior to treatment allocation/randomization.
Note: Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory within 14 days from site slide section date, otherwise a new specimen will 
be requested.
If the sample is determined to be non-evaluable by the central lab, a new sample should be 
submitted if available. This may include additional cut slides that are outside of the 14-day 
window noted above.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Laboratory Manual or Procedures Manual.
If the subject provides documented informed consent for Future Biomedical Research, any 
leftover samples that would ordinarily be discarded at the end of the main study will be 
retained for Future Biomedical Research.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
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the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject, can be found in the Laboratory 
Manual or Procedures Manual.
Local Laboratory Evaluations 
7.1.4.1.1 Pregnancy Testing
Details regarding pregnancy testing are outlined in Section 5.1.2 - Subject Inclusion Criteria, 
Section 7.1.7.1 - Screening and Section 7.1.4.1.2 - Hematology, Chemistry, Urinalysis and 
Other Labs.
Pregnancy tests are required within 24 hours for a urine pregnancy test and within 72 hours 
for a serum pregnancy test prior to each cycle.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.2.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted for the time required to eliminate systemic exposure after the last dose 
of each study intervention(s) as noted in Section 5.1.2. The length of time 
required to continue pregnancy testing for each study intervention is as follows:
◦
MK-3475: at least 120 days
◦
Chemotherapy: at least 180 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study.
7.1.4.1.2 Hematology, Chemistry, Urinalysis, Other Labs and Coagulation Factors
All required laboratory tests are specified in Table 9.
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Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Coagulation
Factors 
(Hemostatic Tests)
Hematocrit
Albumin
Blood
Highly 
sensitive 
serum 
human 
chorionic 
gonadotropin 
(hCG)c
PT (INR)
Hemoglobin
Alkaline 
phosphatase
Glucose
aPTT or PTT
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
White Blood Cell 
Count (WBC) (total 
and differential)
Aspartate 
aminotransferase
(AST)
Specific gravity 
Total 
triiodothyronine 
(T3) or Free T3 
(FT3)d
Red 
Blood 
Cell 
Count (RBC)
Carbon 
dioxide 
(CO2
or 
bicarbonate)b
Microscopic exam, 
if abnormal results 
are noted
Free 
thyroxine 
(FT4)
Absolute 
Neutrophil Counta
Calcium
Urine 
pregnancy 
testc
Thyroid stimulating 
hormone (TSH)
Absolute 
Lymphocyte Count
Chloride
Creatinine
Glucose
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if 
total 
bilirubin 
is 
elevated above the 
upper 
limit 
of 
normal
Total protein 
Blood Urea 
Nitrogen or Ureae
Lactate 
dehydrogenase 
(LDH)
Uric acid
a Absolute is required, % is considered optional.
b If these tests are not done as part of standard of care in your region, then these tests do not need to be performed.
c As needed for women of childbearing potential.  Serum pregnancy test is preferred but urine test can be considered if 
serum not appropriate.
d T3 or FT3 can be assayed based on local standards.
e 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 (hematology and chemistry) 
must be conducted up to 3 days prior to Day 1 of each cycle.
In addition, laboratory 
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procedures must be performed within 3 days prior to Day 8 dosing for all subjects assigned to 
gemcitabine.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening 
procedures for all subjects.  PTT may be performed if the local lab is unable to perform 
aPTT.  Any subject receiving anticoagulant therapy should have coagulation factors 
monitored closely throughout the trial.
After screening, urinalysis and thyroid function tests should be performed within 3 days prior 
to Day 1 of every other cycle (e.g., Cycles 2, 4, 6, 8).
Note: Weekly collection of Serum hCG is not required for any subject.
With the exception of thyroid tests that are obtained after the baseline testing, laboratory 
results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment. Unresolved abnormal labs that are DRAEs should be 
followed until resolution. Labs do not need to be repeated after the end of treatment if labs 
are within normal range.
Central Laboratory Evaluations 
7.1.4.2.1 Plasma Epstein-Barr Virus DNA
Blood for plasma EBV DNA analysis is to be drawn weekly during Cycle 1, and then up to
3 days prior to dosing at all subsequent cycles. Plasma EBV DNA should not be collected 
beyond Cycle 80 Day 1.  Hence, there will be 3 collections for plasma EBV DNA analysis in 
Cycle 1 and 1 collection in all subsequent cycles. All samples are to be submitted for central 
testing. Collection, storage, and shipment instructions for this sample will be provided in the 
Laboratory Manual or Procedures Manual.
If the subject provides documented informed consent for Future Biomedical Research, any 
leftover samples that would ordinarily be discarded at the end of the main study will be 
retained for Future Biomedical Research.
7.1.4.2.2 Pharmacokinetic Evaluations
To further evaluate pembrolizumab (MK-3475) immunogenicity and pembrolizumab
(MK-3475) exposure in this indication, and also to evaluate exposure of the 200 mg fixed
dosing regimen, sample collections for analysis of anti-drug antibodies (ADA) and PK are 
currently planned as shown in the Trial Flow chart (Section 6.1).
Blood samples will be 
obtained to measure PK of serum pembrolizumab (MK-3475) as monotherapy.
Blood 
samples for PK and ADA collected will be stored and analysis will be performed only if 
required. If ongoing ADA and/or PK results continue to be consistent with existing ADA 
and/or PK data from other pembrolizumab (MK-3475) clinical trials, it may be decided to 
discontinue or reduce further sample collection in this study.
Blood Collection for Serum Pembrolizumab (MK-3475)
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Manual or Procedures Manual. PK samples should be drawn according to the 
PK collection schedule for subjects who receive pembrolizumab (MK-3475).
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Blood Collection for Anti-pembrolizumab (MK-3475) Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Manual or Procedures Manual. Anti-pembrolizumab (MK-3475) antibody 
samples should be drawn according to the ADA collection schedule for subjects who receive 
pembrolizumab (MK-3475). Simultaneous PK sampling is required for interpretation of 
ADA analysis.
Planned Genetic Analysis Sample Collection
A sample should be drawn at the Cycle 1 Visit for planned analysis of the association 
between genetic variants in DNA and drug response. If there is either a documented law or 
regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the 
sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the 
participant provides documented informed consent for Future Biomedical Research. If the 
planned genetic analysis is not approved, but Future Biomedical Research is approved and 
consent is given, this sample will be collected for the purpose of Future Biomedical 
Research.
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Laboratory Manual or Procedures Manual.
Future Biomedical Research
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:

Leftover DNA for future research

Leftover main study tumor tissue for future research

Leftover main study plasma from EBV DNA analyses stored for future research

Leftover DNA and RNA from correlative studies

Leftover plasma and serum from biomarker studies
Detailed instructions for the collection and management of specimens for Future Biomedical 
Research are provided in the Laboratory Manual or Procedures Manual and Section 12.2
Collection and Management of Specimens for Future Biomedical Research.
Blood for Correlative and Biomarker Studies
Blood for correlative studies (RNA and DNA) should be collected pre-dose for each of the 
following: Day 1, Cycle 1; Day 1, Cycle 2; Day 1, Cycle 3. Blood for biomarker studies
(plasma and serum) should be collected pre-dose on Day 1, Cycle 1 only.
Detailed 
instructions with specific time points per sample are provided in the Laboratory Manual or 
Procedures Manual. Any leftover samples from the correlative and biomarker studies will be 
stored for future biomedical research if the subject provides documented informed consent 
for Future Biomedical Research.
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Blood for Participation in Optional Sub-Study
Blood for this translational sub-study should be collected pre-dose for each of the following: 
baseline sample obtained prior to or on Day 1, Cycle 1. Additional samples will also be 
collected prior to Day 1 of Cycle 2, Day 1 of Cycle 3, Day 1 of Cycle 4, Day 1 of Cycle 5,
and at the time of disease progression. If disease progression occurs after Cycle 80 Day 1, a 
sample should not be collected at the time of disease progression. Detailed instructions are 
provided in the Procedures Manual.
Please see Appendix 12.9 for details. Any leftover 
samples from the optional sub-study will be stored for future biomedical research if the 
subject provides documented informed consent for FBR.
Efficacy Measurements
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual.
Tumor imaging should be acquired by computed 
tomography (CT) (strongly preferred). Magnetic resonance imaging (MRI) should only be 
used when CT is contraindicated or for imaging of the brain. The same imaging technique 
regarding modality and use of contrast should be used in a subject throughout the trial to 
optimize the visualization of existing and new tumor burden.
Imaging should include the neck, chest, and abdomen at all time points specified in 
Section 6.0 
Trial Flow Chart. Imaging of the pelvis is considered optional, and should be 
acquired if clinically indicated. A CT from the vertex of the head or a brain CT is preferred
but not required. A soft tissue neck CT (starting from orbital line) plus CT of chest and 
abdomen are required. For an individual subject, imaging should be consistent at all time 
points (i.e., follow-up scans should image the same area as the baseline area, using the same 
imaging modality).
A dedicated brain MRI is only needed at baseline to document stability in subjects with 
previously treated brain metastasis (see Section 5.1.3).
A dedicated brain MRI is to be 
acquired at follow-up only if there is clinical suspicion of brain metastasis. This imaging 
should be submitted to the central imaging vendor.
Confirmation of measurable disease based on RECIST 1.1 by central imaging vendor at 
screening will be reviewed retrospectively on a rolling basis. All scheduled images from the 
sites should be submitted to the central imaging vendor for evaluation and should be 
submitted in a timely fashion. In addition, additional imaging (including other modalities) 
that are obtained at an unscheduled time point to determine disease progression, as well as 
imaging obtained for other reasons but captures radiologic progression, should be submitted 
to the central imaging vendor as well.
7.1.5.1.1 Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 30 days prior to the date of
treatment allocation/randomization. The site study team must review screening images to 
confirm the subject has measurable disease per RECIST 1.1. The screening images must be 
submitted immediately to the central imaging vendor for retrospective confirmation of 
measurable disease per RECIST 1.1. Subject eligibility will be based on the site assessment.
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Scans performed as part of routine clinical management are acceptable for use as initial 
tumor imaging if they are of diagnostic quality and performed within 30 days prior to the 
date of treatment allocation/randomization and can be assessed by the central imaging 
vendor.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e., without evidence of progression by imaging: confirmed by MRI if MRI 
was used at prior imaging, or by CT imaging if CT used at prior imaging for at least 4 weeks 
prior to the first dose of trial treatment. Any neurologic symptoms must have returned to 
baseline and subjects must have no evidence of new or enlarging brain metastases, and have 
not used steroids for brain metastases for at least 7 days prior to trial initiation as per local 
site assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
7.1.5.1.2 On Study Tumor Imaging
The first on study imaging assessment should be performed at 6 weeks (42 days ± 7 days) 
after the date of first dose regardless of treatment delays. Subsequent tumor imaging should 
be performed every 6 weeks up to the first year of treatment (42 days ± 7 days), or more 
frequently if clinically indicated. After 1 year, subjects who remain on treatment will have 
imaging performed every 9 weeks up to completion of the second year of treatment (63 days 
± 7 days), or more frequently if clinically indicated.
After Year 1, it will be at the site 
Investigator’s discretion to follow the protocol-specified imaging schedule or to follow the 
imaging schedule per local/standard practice. Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until the start of new anti-cancer treatment, disease progression (unless site PI 
elects to continue treatment and follow irRECIST), pregnancy, death, withdrawal of consent, 
or the end of the study, whichever occurs first. All supplemental imaging must be submitted 
to the central imaging vendor.
Per RECIST 1.1, PR or CR should be confirmed by a repeat tumor imaging assessment not 
less than 4 weeks from the date the response was first documented. The tumor imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan, whichever is clinically indicated. Subjects will then 
return to regularly scheduled imaging every 6 weeks in the first year (42 days ± 7 days), or 
every 9 weeks after 1 Year (63 days ± 7 days), depending on weeks from date of first dose,
starting with the next scheduled imaging time point. After Year 1, it will be at the site 
Investigator’s discretion to follow the protocol-specified imaging schedule or to follow the 
imaging schedule per local/standard practice. Subjects who obtain a confirmation scan do 
not need to undergo scheduled tumor imaging if it is <4 weeks later and may wait until the 
next scheduled imaging time point.
Per irRECIST (Section 7.1.5.1.6), disease progression in subjects treated with 
pembrolizumab (MK-3475) should be confirmed by the site at least 4 weeks after central 
verification of site-assessed first radiologic evidence of PD in clinically stable subjects.
Subjects who have unconfirmed disease progression may continue on treatment at the 
discretion of the site investigator until progression is confirmed by the site provided they 
have met the conditions detailed in Section 7.1.5.1.6
irRECIST Assessment of Disease.
Subjects who obtain a confirmation scan do not need to undergo the next scheduled tumor 
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imaging if it is <4 weeks later; tumor imaging may resume at the subsequent scheduled 
imaging time point if clinically stable. Subjects who have confirmed disease progression as 
assessed by the site will discontinue the treatment. 
Exceptions are detailed in 
Section 7.1.5.1.6
irRECIST Assessment of Disease.
7.1.5.1.3 End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window). If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory.
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring disease status by radiographic imaging using 
the same imaging schedule used while on treatment (every 6 weeks in Year 1 and 9 weeks
after Year 1) until (1) the start of new anti-cancer treatment, (2) disease progression, (3) 
pregnancy, (4) death, (5) withdrawal of consent, or (6) the end of the study, whichever occurs 
first.  After Year 1, it will be at the site Investigator’s discretion to follow the protocol-
specified imaging schedule or to follow the imaging schedule per local/standard practice.
For subjects who stopped treatment prior to the maximum time of 2 years/35 treatments due 
to confirmed CR or who completed 2 years/35 treatments of treatment, a less frequent 
imaging schedule of 12 weeks can be considered with Sponsor approval; this applies only to 
subjects prior to initiation of second course (retreatment).
7.1.5.1.4 Second Course (Retreatment) Tumor Imaging
A scan must be performed within 30 days prior to restarting treatment with pembrolizumab
(MK-3475). Local reading (investigator assessment with site radiology reading) will be used 
to determine eligibility.
Imaging should be submitted to the central imaging vendor for 
retrospective verification.
The first on study imaging assessment should be performed at 6 weeks (42 days ± 7 days) 
after the restart of treatment. Subsequent tumor imaging should be performed every 6 weeks 
(42 days ± 7 days) or more frequently if clinically indicated. After Year 1, it will be at the 
site Investigator’s discretion to follow the protocol-specified imaging schedule or to follow 
the imaging schedule per local/standard practice. 
Per RECIST 1.1, PR or CR should be confirmed by a repeat tumor imaging assessment not 
less than 4 weeks from the date the response was first documented. The tumor imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan, whichever is clinically indicated. Subjects will then 
return to regular scheduled imaging every 6 weeks (42 days ± 7 days), starting with the next 
scheduled imaging time point. Subjects who obtain a confirmation scan do not need to 
undergo scheduled tumor imaging if it is <4 weeks later and may wait until the next 
scheduled imaging time point. After Year 1, it will be at the site Investigator’s discretion to 
follow the protocol-specified imaging schedule or to follow the imaging schedule per 
local/standard practice. 
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Per irRECIST (Section 7.1.5.1.6), if tumor imaging shows initial PD in subjects treated with 
pembrolizumab (MK-3475), tumor assessment should be repeated ≥ 4 weeks later in order to 
confirm PD with the option of continuing treatment while awaiting radiologic confirmation 
of progression. Subjects who obtain a confirmation scan do not need to undergo scheduled 
tumor imaging if it is <4 weeks later and may wait until the next scheduled imaging time 
point if clinically stable.
Imaging should continue to be performed until the start of new anti-cancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever 
occurs first. Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating progressive disease in clinically stable subjects.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window).
If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t 
mandatory.
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring disease status by radiologic imaging using the 
same imaging schedule used while on treatment (every 6 weeks in Year 1 and 9 weeks after 
Year 1) until (1) the start of new anti-cancer treatment, (2) disease progression, (3) 
pregnancy, (4) death, (5) withdrawal of consent, or (6) the end of the study, whichever occurs 
first. After Year 1, it will be at the site Investigator’s discretion to follow the protocol-
specified imaging schedule or to follow the imaging schedule per local/standard practice. 
7.1.5.1.5 RECIST 1.1 Assessment of Disease
RECIST 1.1 (Section 12.7) will be applied by the central imaging vendor as the primary 
measure for assessment of tumor response, date of disease progression, and as a basis for all 
protocol guidelines related to disease status (e.g., discontinuation of trial treatment). 
Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this 
protocol allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant 
to enable a broader sampling of tumor burden.
For subjects treated with pembrolizumab (MK-3475) or SOC chemotherapy, initial tumor 
imaging showing site-assessed PD should be submitted to the central imaging vendor 
immediately.
The site will be notified if the central imaging vendor verifies progressive 
disease (PD) using RECIST 1.1. Figure 2 illustrates the imaging flow involving verification 
of PD for clinically stable subjects.
7.1.5.1.6 irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic
drugs. 
irRECIST
will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively.
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When feasible, subjects treated with pembrolizumab (MK-3475) should not be discontinued 
until progression is confirmed by the local site investigator/radiology assessment.
This 
allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and then experience subsequent disease response. Subjects that 
are deemed clinically unstable are not required to have repeat tumor imaging for 
confirmation of PD. Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects treated with pembrolizumab (MK-3475) who have shown initial evidence of 
radiological PD by RECIST 1.1 as verified by central imaging vendor, it is at the discretion 
of the PI whether to continue a subject on study treatment until repeat imaging is obtained 
(using irRECIST for subject management, see Table 10 and Figure 2).
This clinical 
judgment decision by the site investigator should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Subjects 
may receive study treatment and tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD by irRECIST per site assessment. Clinical stability is defined as the 
following:
1) Absence of symptoms and signs indicating clinically significant progression of
disease, including worsening of laboratory values
2) No decline in ECOG performance status
3) Absence of rapid progression of disease
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Any subject deemed clinically unstable should be discontinued from trial treatment at central 
verification of site-assessed first radiologic evidence of PD and is not required to have repeat 
imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST,
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST include:

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved

No incremental new lesion(s) since last evaluation
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
No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule.
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by 
irRECIST include:

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
Note: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks apart 
demonstrating progressive disease) per irRECIST, but the subject is achieving a clinically 
meaningful benefit and there is no further increase in the tumor burden at the confirmatory 
tumor imaging, an exception to continue treatment may be considered following consultation 
with the Sponsor. In this case, if treatment is continued, tumor imaging should continue to 
be performed following the intervals as outlined in Section 6.0
Trial Flowchart and be 
submitted to the central imaging vendor.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1 1 and 
irRECIST.
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Table 10
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Tumor Imaging
Treatment
Tumor Imaging
Treatment
1st
radiologic
evidence of PD
by RECIST 1.1 
which has been 
verified by the 
central 
imaging 
vendor
Repeat imaging at 
>4weeks at site to 
confirm PD
May continue study
treatment at the site 
Investigator’s 
discretion 
while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST
Repeat imaging at 
>4 weeks to confirm 
PD per physician 
discretion only
Discontinue treatment
Repeat 
tumor 
imaging confirms
PD by irRECIST 
at the local site
No 
additional 
tumor 
imaging
required
Discontinue 
treatment*
No additional tumor 
imaging required
N/A
Repeat 
tumor 
imaging 
shows
SD, PR or CR by 
irRECIST at the 
local site
Continue regularly
scheduled 
tumor 
imaging 
assessments
Continue 
study
treatment 
at 
the 
Investigator’s 
discretion
Continue 
regularly
scheduled
tumor 
imaging assessments
May 
restart 
study
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion
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Figure 2
Imaging and Treatment for Clinically Stable Subjects in Subjects Treated With 
Pembrolizumab (MK-3475) After First Radiologic Evidence of Progressive Disease
Assessed by the Site
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Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue from study treatment prior to completion of the treatment regimen
should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the 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 1) attain a CR or 2) complete 35 administrations of 
pembrolizumab (MK-3475) (approximately 2 years) may discontinue treatment with the 
option of restarting treatment if they meet the criteria specified in Section 7.1.7.2.1
Second 
Course Phase (Retreatment Period). After discontinuing treatment following assessment of 
CR or 35 administrations of pembrolizumab (MK-3475), these subjects should return to the 
site for a Safety Follow-up Visit (described in Section 7.1.7.3.1) and then proceed to the 
Follow-up Period of the study (described in Section 7.1.7.3.2).
7.1.6.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible.  
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Documentation of equipment calibration must be retained as source documentation at the 
trial site.
Equipment for this study includes:

Laboratory equipment, as required for inclusion labs and trial assessments

Imaging equipment, as required for study objectives
See protocol-specified guidance in the Administrative Binder,
Laboratory Manual, 
Procedures Manual, and Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Approximately 30 days prior to allocation/randomization number assignment, potential 
subjects will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5.1
Entry Criteria.
Visit requirements are outlined in Section 6.0
Trial Flow 
Chart. Screening procedures may be repeated.
Visit requirements for the Optional Sub-Study are outlined in Appendix 12.9
Trial Flow 
Chart for participation in the Optional Sub-Study. During screening procedures ongoing for 
the main trial, potential subjects will be identified and evaluated for additional entry 
requirements as set forth in Sections 5.1.2.1 and 5.1.3.1. 
Results of a test performed prior to the subject providing documented informed consent as 
part of routine clinical management are acceptable in lieu of a screening test if performed 
within the specified time frame (i.e., within 30 days prior to the date of treatment
allocation/randomization).
Screening procedures are to be completed within 30 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests and ECOG Performance Scale 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 within 24 hours 
prior to the first dose of trial treatment may be considered if serum test is not 
appropriate.
Note: A pregnancy test must be repeated at time points post screening if required by 
local guidelines.

Archival tumor collection is not required to be obtained within 30 days prior to the 
first dose of trial treatment. Newly obtained tumor tissue may be obtained within 
30 days of treatment allocation/randomization.
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 
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of a repeat screening test if performed within the specified time frame and the
inclusion/exclusion criteria are met.
Study personnel will access IVRS/IWRS to obtain the allocation/randomization number and 
study drug assignment.
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.
7.1.7.2.1 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab (MK-3475) with SD, PR or CR, may be eligible for up to 
1 year of additional pembrolizumab (MK-3475) therapy if they progress after stopping trial
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

Stopped initial treatment with pembrolizumab (MK-3475) after attaining an 
investigator-determined confirmed CR according to RECIST 1.1

Was treated for at least 8 administrations of pembrolizumab (MK-3475)
before discontinuing therapy

Received at least 2 treatments with pembrolizumab (MK-3475) beyond the 
date when the initial CR was declared
OR

Had SD, PR or CR and stopped pembrolizumab (MK-3475) treatment after 
35 administrations (approximately 2 years) 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
Subject Inclusion 
Criteria

WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours for a urine test and 72 hours for a 
serum test prior to receiving retreatment with study medication.
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If a urine pregnancy test cannot be confirmed as negative (e.g., an ambiguous result), 
a serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive.
Additional requirements for pregnancy testing are in Section 7.1.4.1.1 
Pregnancy 
Testing.

Female subject of childbearing potential should be willing to follow contraception 
requirements in Section 5.1.2 
Subject Inclusion Criteria and Section 12.10 
Contraceptive Requirements.

Male subjects should agree to follow contraception requirements in Section 5.1.2 
Subject Inclusion Criteria and Section 12.10 Contraceptive Requirements.

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 17 additional 
administrations (approximately 1 year).
Visit requirements are outlined in Section 6.0
Trial Flow Chart.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Post-Treatment Visits
7.1.7.3.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.
All AEs that occur prior to the Safety Follow-Up Visit should be recorded.
Subjects with an AE of Grade >1 will be followed until the resolution of the AE to 
Grade 0 or 1 or until the beginning of a new anti-cancer therapy, whichever occurs first.
Each subject will be followed for the occurrence of SAEs and ECIs for 90 days after the end 
of treatment, or 30 days following cessation of treatment if the subject initiates new 
anti-cancer therapy, whichever is earlier.
The Discontinuation and 30-day Safety Follow-up visits may be performed simultaneously if 
the Discontinuation visit is conducted at least 3 weeks after last dose or if the subject starts 
new anti-cancer therapy shortly after the End of Treatment.
Subjects who are eligible for retreatment with pembrolizumab (MK-3475) (as described in 
Section 7.1.7.2.1) may have up to 2 safety follow-up visits, 1 after the Initial Treatment or 
First Course and 1 after the Second Course.
7.1.7.3.2 Efficacy Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
begin the Efficacy Follow-Up and should be assessed radiographically every 6 weeks in 
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Year 1 and every 9 weeks after Year 1 to monitor disease status.  After Year 1, it will be at 
the site Investigator’s discretion to follow the protocol-specified imaging schedule or to 
follow the imaging schedule per local/standard practice. Follow-up visits may be adjusted to 
coincide with the Follow-up imaging schedule.  The Sponsor may request survival status to 
be assessed at additional time points during the course of the study (not to exceed
approximately 12 weeks).  Every effort should be made to collect information regarding 
disease status in the follow-up period (see Section 7.1.5.1.3) until the start of new anti-cancer
therapy, disease progression, death, end of study, or if the subject begins retreatment with 
pembrolizumab (MK-3475) as detailed in Section 7.1.7.2.1
Second Course Phase 
(Retreatment Period).
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.
Subjects who are eligible to receive retreatment with pembrolizumab (MK-3475) according 
to the criteria in Section 7.1.7.2.1
Second Course Phase (Retreatment Period) will move 
from the Efficacy Follow-Up Phase to the Second Course Phase when they experience 
disease progression. Details are provided in Section 6.0
Trial Flow Chart for retreatment 
with pembrolizumab (MK-3475).
7.1.7.3.3 Survival Follow-up
Once a subject experiences disease progression as determined by the site per RECIST 1.1 or
irRECIST or starts a new anti-cancer therapy, the subject moves into the Survival Follow-Up 
Phase and should be contacted by telephone approximately every 12 weeks to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first. The investigator should make every attempt to follow the subject’s AE(s) during the 
Survival Follow-Up Phase if the AE is in the reporting timeframe. If the AE occurred prior 
to the Safety Follow-Up Visit, subjects with an AE of Grade > 1 should be followed until the 
resolution of the AE to Grade 0 or 1 or until the beginning of a new anti-cancer therapy, 
whichever occurs first.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor.  For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.  Upon Sponsor 
notification, all subjects who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
subjects that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
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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 to be an adverse event.
All adverse events that occur after the subject provides documented informed consent but 
before treatment allocation/randomization must be reported by the investigator if they cause 
the subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. From the time of treatment allocation/randomization through 30
days following cessation of treatment, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  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 electronic data capture (EDC) data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
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If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product, 
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 meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent)
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
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●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 11 for additional details regarding each of the above criteria.
For the time period beginning when documented informed consent is provided until 
treatment allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 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/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
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 documented informed consent is provided until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
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initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3
Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); o
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre existing condition that has not 
worsened is not a serious adverse event.  A pre existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or (3) the trial is a single dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED 
BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's product 
is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
This trial was developed in collaboration with both Sponsor and non-Sponsor scientific 
experts who provided input with respect to the trial design, interpretation of trial results and 
subsequent peer-reviewed scientific publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an eDMC will monitor 
the interim data from this trial. The voting members of the committee are external to the 
Sponsor. The members of the eDMC must not be involved with the trial in any other way 
(e.g., they cannot be trial investigators) and must have no competing interests that could 
affect their roles with respect to the trial.
The eDMC will make recommendations to the EOC regarding steps to ensure subject safety, 
efficacy, and continued ethical integrity of the trial. The eDMC will be convened twice a 
year to monitor subject safety in this trial.
Specific details regarding composition, responsibilities, governance, including the roles and 
responsibilities of the various members and the Sponsor protocol team; meeting facilitation; 
the trial governance structure; and requirements for and proper documentation of eDMC 
reports, minutes and recommendations will be described in a separate charter that is reviewed 
and approved by the eDMC. The eDMC will monitor the trial at an appropriate frequency 
and described in the detailed eDMC charter. The eDMC will also make recommendations to 
the Sponsor protocol team regarding steps to ensure subject safety, efficacy, and the 
continued ethical integrity of the trial.
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after 
the study has begun, but prior to the conduct of any analysis, changes made to primary and/or 
key secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to 
unblinding, will be documented in a supplemental Statistical Analysis Plan (sSAP) and 
referenced in the Clinical Study Report (CSR) for the study (this includes the exploratory 
analyses for the Optional Sub-Study protocol which will also be documented in a separate 
sSAP). Post hoc exploratory analyses will be clearly identified in the CSR.
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2
Responsibility for Analyses/In-House Blinding
to 
Section 8.12
Extent of Exposure.
Study Design Overview
A Phase III
Study of Pembrolizumab (MK-3475) vs. Standard 
Chemotherapy in Subjects with Platinum Pre-treated, Recurrent or 
Metastatic Nasopharyngeal Cancer (KEYNOTE-122)
Treatment Assignment
This is an open-label study.
Approximately 230 subjects will be randomized in a 1:1 ratio to receive 
pembrolizumab (MK-3475) or one of the 3 standard of care (SOC)
treatments.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint
Overall Survival (OS)
Key Secondary Endpoint(s)
Progression-free Survival (PFS) per RECIST 1.1 by BICR
Objective Response Rate (ORR) per RECIST 1.1 by BICR
Statistical Methods for Key 
Efficacy Analyses
The primary hypothesis for OS will be evaluated by comparing 
pembrolizumab (MK-3475) to SOC using a stratified log-rank test. 
Estimation of the hazard ratio will be performed using a stratified Cox 
regression model. Event rates over time will be estimated within each 
treatment group using the non-parametric Kaplan-Meier method.
The same approach will be applied to the secondary hypothesis for PFS 
per RECIST 1.1 by BICR.
The secondary hypothesis for ORR per RECIST 1.1 by BICR will be 
evaluated by comparing pembrolizumab (MK-3475) to SOC using 
Stratified Miettinen and Nurminen method.
The same stratification factors used for randomization (see Section 5.4) 
will be applied to the stratified log-rank test, stratified Cox model and the 
stratified Miettinen and Nurminen method.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. There are no 
events of interest that warrant elevation as Tier 1 event in this study.  Point 
estimates and 95% CIs for between-treatment comparisons via the 
Miettinen and Nurminen method will be provided for Tier 2 safety 
endpoints; only point estimates by treatment group will be provided for 
Tier 3 safety endpoints.
Interim Analyses
Efficacy
One IA will be performed in this study.  Results will be reviewed by an 
external data monitoring committee.  The IA and final analysis (FA) are 
summarized below.  Details are provided in Section 8.7. 

IA: 
o Timing:
OS events and all subjects have been followed up for
at least 
months (estimated to be approximately
months 
after the first subject is randomized). If OS events accrue slower 
than expected and fewer than
events are observed 
months after the first participant is randomized, then the Sponsor 
may conduct the interim analysis at that time.
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o Testing: Inferential analyses for OS will be provided. If superiority 
of OS is declared, then inferential analysis for PFS will be 
conducted. Furthermore, if superiority of PFS is also declared then 
inferential analysis for ORR will be conducted.

FA:
o Timing:
OS events and all subjects have been followed up for 
at least 
months (estimated to be approximately 
months 
after the first subject is randomized). If OS events accrue slower 
than expected and fewer than 
events are observed 
months after the first participant is randomized, then the Sponsor 
may conduct the final analysis at that time. The efficacy 
boundaries will be adjusted accordingly in such a situation.
o
Testing: Inferential analysis for OS will be provided if superiority 
is not declared at the IA.
Note: If superiority of OS is declared at the FA, and not at the IA, the test 
statistics computed for PFS at the IA will be used to conduct inferential 
analysis.  Similarly, the test statistics computed for ORR at the IA will be 
used to conduct inferential analysis if superiority of both OS and PFS is 
declared at the FA and not at the IA. 
Safety:
Every 6 months since first subject is randomized.
Multiplicity
The type I error rate for this study is strongly controlled at 2.5% 
(one-sided) with full alpha allocated to the OS hypothesis. A group 
sequential approach will be used to allocate alpha between the interim 
and final analyses of OS. The study will be declared a success if OS is 
shown to be successful.
If the statistical criterion for success in OS hypothesis is met at an interim 
analysis or final analysis, the key secondary endpoint of PFS will be 
tested at the alpha level determined by the alpha shifting schema that 
follow the graphical approach of Maurer and Bretz (2013) [73] as 
described in Section 8.8. Similarly, if the PFS hypothesis is successful, 
alpha will be shifted to the key secondary endpoint of ORR using the 
same graphical approach of Maurer and Bretz.
Sample Size and Power 
The planned sample size is approximately 230 subjects.
For the primary endpoint OS, the trial provides approximately
power to demonstrate that pembrolizumab (MK-3475) is superior to SOC
at a one-sided
alpha-level, if the true underlying hazard ratio of OS 
is
For the key secondary endpoint PFS, the trial provides approximately 
power to demonstrate that pembrolizumab (MK-3475) is superior 
to SOC at a one-sided 
alpha-level, if the true underlying hazard 
ratio of PFS is
For the secondary endpoint ORR, the trial provides approximately 
power to demonstrate that pembrolizumab (MK-3475) is superior to SOC 
at a one-sided
alpha-level, assuming response rate in the SOC arm 
is 
and
true treatment difference between two arms.
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Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IVRS. Although 
the trial is open label, analyses or summaries generated by randomized treatment assignment, 
or actual treatment received will be limited and documented. Further documentation will be 
provided in the sSAP. In addition, the independent radiologist(s) will perform the central 
imaging review without knowledge of treatment group assignment.
Planned IA is described in Section 8.7. The results of the IA will not be shared with the 
investigator prior to the completion of the study. Subject-level unblinding will be restricted 
to the external unblinded statistician and scientific programmer performing the IA, who will 
have no other responsibilities associated with the study.  
Treatment-level results of the IA will be provided by the external unblinded statistician to the 
eDMC. The eDMC will serve as the primary reviewer of the treatment-level results and will 
make recommendations for discontinuation of the study or modification to an Executive 
Oversight Committee of the SPONSOR. Depending on the recommendation of the eDMC, 
the Sponsor may prepare a regulatory submission. If the eDMC recommends modifications 
to the design of the protocol or discontinuation of the study, this executive oversight 
committee may be unblinded to results at the treatment level in order to act on these 
recommendations. 
Additional logistical details, revisions to the above plan and data 
monitoring guidance will be provided in the eDMC Charter.
Prior to final study unblinding, the external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the IA.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0
Objectives and 
Hypotheses.
The study will be declared a success if the primary endpoint OS is shown to be successful.
Analysis Endpoints
Efficacy Endpoints
Primary

Overall Survival
Overall Survival is defined as the time from randomization to death due to any cause.
Subjects without documented death at the time of analysis will be censored at the date of 
last known contact.
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Secondary

Progression-free Survival – RECIST 1.1 by BICR
Progression-free survival is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on BICR or death due to any 
cause, whichever occurs earlier.
See Section 8.6.1
Statistical Methods for Efficacy 
Analyses for definition of censoring.

Objective Response Rate – RECIST 1.1 by BICR
Objective response rate is defined as the proportion of the subjects in the analysis 
population who have a confirmed CR or PR.

Duration of Response – RECIST 1.1 by BICR
For subjects who demonstrated confirmed CR or PR, response duration is defined as the 
time from the date of first response (CR or PR) until the date of first documented disease 
progression or death. Duration of response for subjects who have not progressed or died 
at the time of analysis will be censored at the date of their last tumor assessment.

Survival Proportion at 12 Months and 24 Months
The survival proportion at 12 months and at 24 months is defined as the Kaplan-Meier 
estimate of the survival function for OS at 12 months and 24 months respectively.

Proportion Progression-free survival at 6 Months and 12 Months – RECIST 1.1 by 
BICR
The proportion progression free survival at 6 months and at 12 months is defined as the 
Kaplan-Meier estimate of the survival function for PFS at 6 months and 12 months, 
respectively. The progression-free status is based on BICR per RECIST 1.1.
Safety Endpoints
Safety measurements are described in Section 4.2.3.2
Safety Endpoints.
Analysis Populations
Efficacy Analysis Populations
The Intention-to-Treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized subjects will be included in this population. Subjects will be 
included in the treatment group to which they are randomized. The ITT population consists 
of all randomized subjects whether or not treatment was administered. Any subject who 
receives a treatment randomization number will be considered to have been randomized.
Details on the approach to handling missing data are provided in Section 8.6 
Statistical 
Methods.
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Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all randomized subjects who received at least 
1 dose of study treatment. Subjects will be included in the treatment group corresponding to 
the study treatment they actually received for the analysis of safety data using the ASaT 
population. For most subjects this will be the treatment group to which they are randomized.
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received. Any subject who 
receives the incorrect study medication for 1 cycle but receives the correct treatment for all 
other cycles will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the subject is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 8.8 Multiplicity.
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron's method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., hazard ratio) between the treatment arms. The 
hazard ratio and its 95% confidence interval from the stratified Cox model with Efron's 
method of tie handling and with a single treatment covariate will be reported. 
The 
stratification factors used for randomization (see Section 5.4) will be applied to both the 
stratified log-rank test and the stratified Cox model.
Since subjects in the SOC arm are expected to discontinue treatment earlier compared to 
subjects in the pembrolizumab arm, and they may switch to another anti PD-1 treatment 
following confirmation of PD, adjustment for the effect of crossover on OS may be 
performed based on recognized methods,
based on an 
examination of the appropriateness of the data to the assumptions required by the methods
[74].
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
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used to assess the magnitude of the treatment difference (i.e., hazard ratio) between the 
treatment arms. The hazard ratio and its 95% confidence interval from the stratified Cox 
model with Efron's method of tie handling and with a single treatment covariate will be 
reported. The stratification factors used for randomization (see Section 5.4) will be applied 
to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, PD can occur anytime in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 by BICR, regardless of discontinuation of study 
drug. Death is always considered as a confirmed PD event. Sensitivity analyses will be 
performed for comparison of PFS based on investigator's assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 
2 sensitivity analyses with a different set of censoring rules will be performed. The first 
sensitivity analysis is the same as the primary analysis except that the data for any subject 
who misses more than 1 disease assessment (with or without a subsequent death or 
progression) are censored at the last disease assessment prior to missing visits. The second 
sensitivity analysis is the same as the primary analysis except that it considers 
discontinuation of treatment or initiation of an anti-cancer treatment subsequent to 
discontinuation of study-specified treatments, whichever occurs later, to be a PD event for 
subjects without documented PD or death. If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied. The censoring rules for primary 
and sensitivity analyses are summarized in Table 12.
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Table 12
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented after 
≤1 missed disease assessment, 
and before new anti-cancer 
therapy, if any
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed 
at 
date 
of 
documented PD or death
PD 
or 
death 
documented 
immediately
after 
≥2 
consecutive 
missed 
disease 
assessments or after new anti-
cancer therapy, if any
Censored 
at 
last 
disease 
assessment 
prior to the
earlier 
date 
of 
≥2 
consecutive 
missed 
disease 
assessment
and new anti-cancer 
therapy, if any
Progressed at date of 
documented PD or 
death
Progressed 
at 
date 
of 
documented PD or death
No PD and no death; and new 
anti-cancer treatment is not 
initiated
Censored 
at 
last 
disease assessment 
Censored 
at 
last 
disease assessment 
Progressed 
at 
treatment 
discontinuation 
due 
to 
reasons other than complete 
response; 
otherwise
censored at last disease 
assessment if still on study 
or 
completed 
study 
treatment.
No PD and no death; new anti-
cancer treatment is initiated
Censored 
at 
last 
disease 
assessment 
before 
new 
anti-
cancer treatment
Censored 
at 
last 
disease assessment 
Progressed at date of new 
anti-cancer treatment
Further details of sensitivity analyses will be described in the sSAP.
Objective Response Rate
Stratified Miettinen and Nurminen’s method will be used for comparison of the ORR 
between 2 treatment groups. The difference in ORR and its 95% confidence interval from 
the stratified Miettinen and Nurminen’s method with strata weighting by sample size will be 
reported. The stratification factors used for randomization (see Section 5.4) will be applied to 
the analysis.
Duration of Response
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first.
Censoring rules for DOR are summarized in Table 13.
For each DOR analysis, a corresponding summary of the reasons responding subjects are 
censored will also be provided.
Subjects who are alive, have not progressed, have not 
initiated new anti-cancer treatment, have not been determined to be lost to follow-up, and 
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have had a disease assessment within ~5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a subject meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied.
Table 13
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anti-cancer therapy initiated
Last adequate disease assessment
Censor (non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment 
before 
new 
anti-cancer
therapy 
initiated
Censor (non-event)
Death or progression immediately
after ≥2 consecutive missed disease 
assessments or after new anti-cancer 
therapy, if any
Earlier date of last adequate disease 
assessment 
prior 
to 
≥2 
missed 
adequate disease assessments and new 
anti-cancer therapy, if any
Censor (non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anti-cancer therapy, if any
PD or death
End of response(event)
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Summary of Efficacy Analysis Methods
Table 14 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, and 
interim analyses is described in Section 8.7 
Interim Analyses and in Section 8.8
Multiplicity.
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Table 14
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Primary Endpoint
OS
Test: Stratified log-rank test 
Estimation: 
Stratified 
Cox 
model 
with 
Efron’s 
tie 
handling method
ITT 
Censored at last known 
alive date
Key Secondary Endpoints
PFS per RECIST 1.1 by 
BICR
Test: Stratified log-rank test 
Estimation: 
Stratified 
Cox 
model 
with 
Efron’s 
tie 
handling method
ITT
Primary 
censoring 
rule‡
Sensitivity analysis 1‡
Sensitivity analysis 2‡
ORR per RECIST 1.1 by 
BICR
Stratified 
Miettinen 
and 
Nurminen method
ITT
Subjects with missing 
data are considered as 
non-responders.
Response 
duration 
per 
RECIST 1.1 by BICR
Summary 
statistics 
using 
Kaplan-Meier method
All responders
in ITT
Non-responders are
excluded in analysis
† Statistical models are described in further detail in the text.
‡ Additional details are located in Table 12
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
Adverse Events
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped system organ class. 
AEs will be graded by the 
investigator according to the CTCAE, version 4.0.
The analysis of safety results will follow a tiered approach (Table 15). The tiers differ with 
respect to the analyses that will be performed. Adverse experiences (specific terms as well as 
system organ class terms) that are not pre-specified as Tier 1 endpoints will be classified as 
belonging to "Tier 2" or "Tier 3", based on the number of events observed. 
Tier 1 Events
Safety parameters or adverse events of interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance. For this 
protocol, there are no Tier 1 events as acceptable and manageable safety/tolerability profile 
of pembrolizumab monotherapy has been established. 
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Tier 2 Events
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for differences 
in the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [75].
Membership in Tier 2 requires that at least 10% of subjects in any treatment group exhibit a 
specific AE; all other AEs will belong to Tier 3. The threshold of at least 10% of subjects 
was chosen for Tier 2 events because the population enrolled in this study is in critical 
condition and usually experiences various AEs of similar types regardless of treatment; 
events reported less frequently than 10% of subjects would obscure the assessment of the 
overall safety profile and add little to the interpretation of potentially meaningful treatment 
differences. In addition, specific Grade 3 to 5 AEs (≥5% of subjects in 1 of the treatment 
groups) and specific SAEs (≥5% of subjects in 1 of the treatment groups) will be considered 
Tier 2 endpoints. Because many 95% confidence intervals may be provided without 
adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse experiences.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad 
clinical and laboratory AE categories consisting of the percentage of subjects with any AE, 
any DRAE, any Grade 3 through 5 AE, any serious AE, any AE which is both drug-related 
and Grade 3 through 5, any AE that is both serious and drug-related, due to AE, discontinued 
due to an AE, and death that are not pre-specified as Tier 1 endpoints will be considered Tier 
3 endpoints. Laboratory test toxicity grade shift from baseline is considered a Tier 3 event. 
Only point estimates by treatment group are provided for Tier 3 safety parameters.
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Table 15
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific Grade 3-5 AEs (incidence ≥5% of subjects in one 
of the treatment groups)
X
X
Specific serious AEs (incidence ≥5% of subjects in one of 
the treatment groups)
X
X
Specific AEs (incidence ≥10% of subjects in one of the 
treatment groups)
X
X
Tier 3
Any AE
X
Any SAE 
X
Any Grade 3-5 AE
X
Any DRAE
X
Any Serious and DRAE
X
Any Grade 3-5 and DRAE
X 
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence >0% of subjects in all of 
the treatment groups)
X
Change from Baseline Results (lab toxicity grade)
X
Abbreviations:  AE = adverse event; CI = confidence interval; DRAE = drug-related adverse event; SAE = 
serious adverse event; SOC = System Organ Class; X = results will be provided
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
Summaries of Baseline Characteristics, and Demographics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. 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), baseline characteristics, primary and secondary diagnoses, 
and prior and concomitant therapies will be summarized by treatment either by descriptive 
statistics or categorical tables.
Interim Analyses
Efficacy Interim Analysis
There will be 1 IA for efficacy.  The endpoints, timing, and purpose of the interim and final 
analyses are summarized in Table 16.
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Multiplicity
Multiplicity Control for Efficacy Interim Analyses
The study uses the graphical method of Maurer and Bretz (2013) [73] to provide strong 
multiplicity control for multiple hypotheses.  Figure 3 shows the initial one-sided α-
allocation for each hypothesis in the ellipse representing the hypothesis. The weights for 
reallocation from each hypothesis to the others are represented in the boxes on the lines 
connecting hypotheses. This is further explained below.
Figure 3
Multiplicity Strategy
Overall Survival
The OS hypothesis will be tested at the interim and the final analyses. The OS hypothesis 
will be tested at α 0.025. Table 18 below, demonstrates the bounds and boundary properties 
for OS hypothesis testing which were derived using a Lan-DeMets O’Brien-Fleming α 
spending function. The nominal α for testing is shown in the rows labeled “p (1-sided)”.  The 
approximate hazard ratio required to reach an efficacy bound is in the row labeled “HR at 
bound”.  The probability of crossing a bound is shown under the null hypothesis “P(Cross if 
HR=1)” and alternative hypothesis 
 Note that at the final analysis, 
these are the probabilities of crossing either at the interim or final analysis; e.g., the final row 
indicates that the total power to reject the null hypothesis for OS is
if the α -level for 
testing is 0.025.  If the actual number of events at the OS analyses differ from those specified 
in the table, the bounds will be adjusted using the Lan-DeMets O’Brien-Fleming spending 
CCI
CCI
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function accordingly.  If the OS hypothesis is rejected at any analysis, the corresponding 
(1-sided) will be rolled over to the PFS test.
Abbreviations: HR=hazard ratio; IA=interim analysis.
Progression-Free Survival
The PFS hypothesis will be tested only once at the interim analysis.  Note that if superiority 
of OS is declared at the final analysis and not at the interim analysis, the test statistics 
computed for PFS at the interim analysis will be used to conduct inferential analysis.
The PFS hypothesis will be tested at α=0.025 (if the OS null hypothesis is rejected). Table 19
below, analogous to the OS table explained above, shows the bound and boundary properties 
for the analysis of PFS.  If the actual number of events at the PFS analysis differs from that
specified in the table, the bound will be adjusted accordingly.  If the PFS hypothesis is 
rejected, the α=0.025 level (1-sided) will be rolled over to the ORR hypothesis testing.
CCI
CCI
CCI
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Objective Response Rate
ORR will be tested only once at the interim analysis. Note that, if superiority of OS is 
declared at the final analysis and not at the interim analysis, and furthermore superiority of 
PFS is also declared, the test statistics computed for ORR at the interim analysis will be used 
to conduct inferential analysis.
The ORR null hypothesis will be tested at α=0.025 (if both the PFS and OS null hypotheses 
are rejected).  Power, as well as the approximate treatment difference required to reach the 
bound (ΔORR), are shown in Table 20, assuming underlying 15% and 35% response rates in 
the SOC and pembrolizumab arms, respectively.
Abbreviations: ORR = Objective response rate
Multiplicity Control for Safety Interim Analyses
To account for any multiplicity concerns raised by the DMC review of unplanned efficacy 
data when prompted by safety concerns, a sensitivity analysis for OS will be pre-specified in 
the sSAP.  This analysis will be performed if requested by the DMC.  However, DMC review 
of OS data beyond the planned efficacy analysis to assess the overall risk/benefit to study 
participants will not require multiplicity assessment typically associated with a planned 
efficacy IA because these analyses are not to declare a positive efficacy finding.
Sample Size and Power Calculations
Enrollment of approximately
subjects will occur over
The OS hypothesis testing was designed for
to detect a hazard 
ratio of 
at the final analysis. The duration of OS in the SOC arm is 
assumed to follow an exponential distribution with a median of 12 months based on historical 
data. 
The assumed follow-up time after last participant enrolled is 30 months. 
An 
exponential dropout rate of 6% per year is assumed.
The PFS hypothesis testing was designed for
to detect a hazard 
ratio of 
The duration of PFS in the SOC arm is assumed to 
follow an exponential distribution with a median of 5 months based on historical data. The 
assumed follow-up time after last subject enrolled is 18 months. An exponential dropout rate 
of 10% per year is assumed.
The sample size of 
ORR testing at the
power to detect a 
difference from an underlying 
response rate in the SOC arm to 
in the 
pembrolizumab arm.  
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, if 
appropriate, the between-group treatment effect (with a nominal 95% CI) will be estimated 
and plotted within each category of the following classification variables:

Age category (<65 versus ≥65 years)

PD-L1 expression levels (CPS<10 vs. CPS ≥ 10)

Liver metastasis(es): Present versus Absent

Pembrolizumab (MK-3475) versus comparator therapies. Subjects will be analyzed 
according to the comparator identified by the site prior to randomization.
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.  In addition, a Forest plot will be 
produced, which provides the estimated point estimates and CIs for the treatment effect 
across the categories of subgroups listed above.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives
the study medication infusion. Summary statistics will be provided on Extent of Exposure
for ASaT population.
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 21.
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Table 21
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab (MK-3475) 
50 mg
Lyophilized powder for IV
injection/infusion
Provided centrally by the Sponsor 
Pembrolizumab (MK-3475) 
100 mg/4 mL
Solution for infusion
Provided centrally by the Sponsor; 
however, solution will not be 
supplied at initiation of the trial. It 
is considered a backup formulation.
Capecitabine 150 mg and 
500 mg
Tablets
Provided centrally by the Sponsor or 
locally by the trial site, subsidiary, 
or designee.
Gemcitabine 1000 mg
Lyophilized powder for IV 
infusion
Provided centrally by the Sponsor or 
locally by the trial site, subsidiary, 
or designee.
Docetaxel 80 mg/4 mL
Solution for infusion
Provided centrally by the Sponsor or 
locally by the trial site, subsidiary, 
or designee.
IV  intravenous
Note: If the standard of care is locally sourced, the potency/strength that is available may be used 
All supplies indicated in Table 21 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 21 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial site personnel will have access to a central electronic 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.
ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By providing documented informed 
consent, 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.
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Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor. 
The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and 
other generally accepted standards of good clinical practice); and all applicable federal, state 
and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
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period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
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the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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phase II study of cetuximab in combination with carboplatin in patients with 
recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol. 2005 May 
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of pazopanib in Asian patients with recurrent/metastatic nasopharyngeal 
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gemcitabine-vinorelbine chemotherapy in patients with metastatic nasopharyngeal 
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II study of capecitabine combined with nedaplatin for recurrent and metastatic 
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Cancer Chemother Pharmacol. 2013 Aug;72(2):323-8.
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carcinoma. N Engl J Med. 2004 Jun 10;350(24):2461-70.
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APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, Merck clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki. 
B. Scope
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 and shall respect the data protection rights of all participants, trial site staff and, where applicable, third 
parties.  All trial protocols are and will be assessed for the need and capability to enroll underrepresented groups.  
Research subjects must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
Merck’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors.  Merck 
selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations.  Prior to trial initiation, sites are 
evaluated by Merck personnel (or individuals acting on behalf of Merck) to assess the ability to successfully 
conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, Merck will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities.  Merck will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study.  Merck will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). 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 potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.. 
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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. 
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, as well as all applicable 
data protection rights.  Unless required by law, only the investigator, sponsor (or individuals acting on behalf of 
Merck), ethics committee, 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). 
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V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 7.1.4.4 
Future Biomedical Research will be used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways with which drugs/vaccines may interact
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Documentation of informed 
consent by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact 
the 
Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
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will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
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identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent. 
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National 
Cancer 
Institute 
[Internet]: 
Available 
from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid 45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding 
Categories. 
Available 
from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry 
Pharmacogenomics 
Working 
Group 
[Internet]: 
Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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Abbreviations
Abbreviation/Term
Definition
AE
adverse event
ADA
anti-drug antibodies
ADL
activities of daily living
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APaT
all patients as treated
aPTT
activated partial thromboplastin time
ASaT
all subjects as treated
AST
aspartate aminotransferase
BID
twice daily
BRAT
bananas, rice, apple sauce, and toast
BUN
blood urea nitrogen
CFR
Code of Federal Regulations 
CI
confidence interval
CIV
central imaging vendor
CR
complete response
CRF
case report form
CrCl
calculated creatinine clearance
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
DILI
drug-induced liver injury
DKA
diabetic ketoacidosis
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DOR
duration of response
DPD
dihydropyrimidine dehydrogenase
DRAE
drug-related adverse event
eCRF
electronic case report form
EBER 
Epstein-Barr encoded small RNA
EBNA
Epstein-Barr nuclear antigen
EBV
Epstein-Barr virus
ECI
events of clinical interest
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eDMC
external Data Monitoring Committee
EOC
Executive Oversight Committee
ePRO
electronic patient-reported outcome
EQ-5D
European Quality of Life Five Dimension
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
FFPE
formalin-fixed, paraffin-embedded
FNA
fine needle aspirate
FSH
follicle-stimulating hormone
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Abbreviation/Term
Definition
FT4
free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HLA
human leukocyte antigens
HPV
human papillomavirus
HR
hazard ratio
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IHC
immunohistochemistry
INR
international normalized ratio
IO
immuno-oncology
irAEs
immune-related adverse events
IRB
Institutional Review Board
irRECIST
immune-related RECIST
ISH
in situ hybridization
ITSM
immunoreceptor tyrosine-based switch motif
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
LDH
lactate dehydrogenase
LMP
latent membrane protein
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NCI
National Cancer Institute
NPC
nasopharyngeal cancer
NPV
negative predictive value
NSAID
non-steroidal anti-inflammatory drug
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PD
progressive disease
PD-1
programmed death 1 
PD-L1
programmed death ligand 1
PD-L2
programmed death ligand 2
PFS
progression-free survival
PGt
pharmacogenetic
PI
Principal Investigator
PIN
Personal Identification Number
PK
pharmacokinetic
PO
by mouth
PPV
positive predictive value
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QW
every week
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Abbreviation/Term
Definition
Q2W
every 2 weeks
Q3W
every 3 weeks
RBC
red blood cell
R/M
recurrent or metastatic
RECIST
response evaluation criteria in solid tumors
RNA
ribonucleic acid
SAE
serious adverse event
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedures
SQ
subcutaneous
sSAP
supplemental statistical analysis plan
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
TIL
tumor-infiltrating lymphocyte
TSH
thyroid-stimulating hormone
TTP
time to progression
ULN
upper limit of normal
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. 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
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649 655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair.
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov).
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. Although 
RECIST 1.1 references to maximum of 5 target lesions in total and 2 per organ, Merck 
allows maximum of 10 target lesions in total and 5 per organ. After initial disease 
progression, tumor response assessment will be per irRECIST (see Section 7.1.5.1.6).
While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging 
modality in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
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List of Strong CYP3A4 Inhibitors
For subjects receiving docetaxel, avoid using concomitant strong CYP3A4 inhibitors (e.g.,
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir,
ritonavir, saquinavir, telithromycin and voriconazole).
Taxotere (docetaxel) Prescribing Information, 12/2013.
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Optional Sub-Study Trial 
Optional Sub-Study Trial Diagram
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Contraceptive Guidance
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantb,c
IUSc,d
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    Male condoms must be used in addition to female participant hormonal contraception.
d    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0
TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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