A Phase Ib Multi-Cohort Study of MK-3475 in Subjects With Advanced Solid Tumors
Phase: PHASE1
Conditions: Cancer, Solid Tumor
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase Ib Multi-Cohort Study of MK-3475 in Subjects with 
Advanced Solid Tumors
11-Dec-2017
NCT01848834

Product:  MK-3475 (SCH 900475)
1
Protocol/Amendment No.: 012-05 
MK-3475-012-05 Final Protocol
11-Dec-2017
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.
TITLE:
A Phase Ib Multi-Cohort Study of MK-3475 in Subjects with Advanced Solid Tumors
IND NUMBER:  110,080
EudraCT NUMBER:  2012-005771-14
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
2.1
Trial Design ........................................................................................................... 14
2.2
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
3.1
Primary Objective(s) & Hypothesis(es) .............................................................. 16
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 17
3.3
Exploratory Objective .......................................................................................... 19
4.0
BACKGROUND & RATIONALE.......................................................................... 19
4.1
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 20
4.1.2
Ongoing Clinical Trials....................................................................................... 20
4.1.3
4.2
Rationale................................................................................................................ 20
Rationale for the Trial and Selected Subject Population .................................... 20
4.2.1
Rationale for Dose Selection/Regimen/Modification......................................... 21
4.2.2
Rationale for Endpoints ...................................................................................... 22
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 22
4.2.3.2
Safety Endpoints .......................................................................................... 23
4.2.3.3
Biomarker Research..................................................................................... 24
4.2.3.4
Future Biomedical Research........................................................................ 24
5.0
METHODOLOGY ................................................................................................... 25
5.1
Entry Criteria........................................................................................................ 25
Diagnosis/Condition for Entry into the Trial ...................................................... 25
5.1.1
Subject Inclusion Criteria.................................................................................... 25
5.1.2
Subject Exclusion Criteria .................................................................................. 27
5.1.3
5.2
Trial Treatments................................................................................................... 29
Dose Selection/Modification .............................................................................. 30
5.2.1
 
 
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5.2.1.1
Dose Selection ............................................................................................. 30
5.2.1.2
Dose Modification ....................................................................................... 30
Timing of Dose Administration.......................................................................... 34
5.2.2
Trial Blinding/Masking....................................................................................... 35
5.2.3
5.3
Randomization or Treatment Allocation............................................................ 36
5.4
Stratification.......................................................................................................... 36
5.5
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 36
Acceptable Concomitant Medications ................................................................ 36
5.5.1
Prohibited Concomitant Medications.................................................................. 36
5.5.2
5.6
Rescue Medications & Supportive Care............................................................. 37
Supportive Care Guidelines ................................................................................ 37
5.6.1
5.7
Diet/Activity/Other Considerations..................................................................... 41
Diet...................................................................................................................... 41
5.7.1
Contraception...................................................................................................... 41
5.7.2
Use in Pregnancy ................................................................................................ 42
5.7.3
Use in Nursing Women....................................................................................... 42
5.7.4
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 42
Discontinuation of Study Therapy after CR ....................................................... 44
5.8.1
5.9
Subject Replacement Strategy............................................................................. 44
5.10
Beginning and End of the Trial ........................................................................... 44
5.11
Clinical Criteria for Early Trial Termination ................................................... 44
6.0
TRIAL FLOW CHART ........................................................................................... 46
6.1
Study Flow Chart for Cohorts A, B, C and D (10 mg/kg Q2W dosing)........... 46
6.2
Study Flow Chart for Cohort B2 (200 mg Q3W dosing)................................... 50
6.3
Second Course Phase (Retreatment ONLY) for Cohorts A, B, C and D......... 53
6.4
Second Course Phase (Retreatment ONLY) for Cohort B2 ............................. 56
7.0
TRIAL PROCEDURES ........................................................................................... 58
7.1
Trial Procedures ................................................................................................... 58
Administrative Procedures.................................................................................. 58
7.1.1
7.1.1.1
Informed Consent......................................................................................... 58
7.1.1.1.1
General Informed Consent.................................................................... 58
 
 
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 59
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 59
7.1.1.3
Subject Identification Card .......................................................................... 59
7.1.1.4
Medical History ........................................................................................... 59
7.1.1.5
Prior and Concomitant Medications Review ............................................... 59
7.1.1.5.1
Prior Medications.................................................................................. 59
7.1.1.5.2
Concomitant Medications..................................................................... 59
7.1.1.6
Disease Details and Treatments................................................................... 60
7.1.1.6.1
Disease Details...................................................................................... 60
7.1.1.6.2
Prior Treatment Details......................................................................... 60
7.1.1.6.3
Subsequent Anti-neoplastic Therapy Status ......................................... 60
7.1.1.7
Assignment of Screening Number............................................................... 60
7.1.1.8
Assignment of Randomization Number....................................................... 60
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other) ................................... 60
Clinical Procedures/Assessments........................................................................ 61
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 61
7.1.2.2
Physical Exam.............................................................................................. 61
7.1.2.2.1
Full Physical Exam ............................................................................... 61
7.1.2.2.2
Directed Physical Exam........................................................................ 61
7.1.2.3
Vital Signs.................................................................................................... 62
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 62
7.1.2.5
Tumor Imaging and Assessment of Disease................................................ 62
7.1.2.5.1
Assessment of Disease.......................................................................... 62
7.1.2.5.2
Initial Tumor Imaging........................................................................... 64
7.1.2.5.3
Tumor Imaging During Trial ................................................................ 64
7.1.2.6
Tumor Tissue Collection and Correlative Studies Blood Sampling............ 65
Laboratory Procedures/Assessments .................................................................. 66
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 66
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 68
7.1.3.2.1
Blood Collection for Serum MK-3475 ................................................. 68
7.1.3.2.2
Blood Collection for Anti-MK-3475 Antibodies.................................. 68
 
 
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7.1.3.3
Future Biomedical Research........................................................................ 68
Other Procedures................................................................................................. 68
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 68
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 69
7.1.4.2
Blinding/Unblinding .................................................................................... 69
Visit Requirements.............................................................................................. 69
7.1.5
7.1.5.1
Screening...................................................................................................... 69
7.1.5.1.1
Pre-screening Period............................................................................. 69
7.1.5.1.2
Screening Period................................................................................... 70
7.1.5.2
Treatment Period.......................................................................................... 70
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 70
7.1.5.3
Post-Treatment Visits................................................................................... 71
7.1.5.3.1
Safety Follow-Up Visit......................................................................... 71
7.1.5.4
Follow-up Visits........................................................................................... 72
7.1.5.4.1
Survival Follow-up ............................................................................... 72
7.1.5.5
Survival Status ............................................................................................. 72
7.2
Assessing and Recording Adverse Events .......................................................... 73
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 74
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 74
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 75
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 75
7.2.3.2
Events of Clinical Interest............................................................................ 76
7.2.3.3
Protocol-Specific Exceptions to Serious Event Reporting .......................... 77
Evaluating Adverse Events ................................................................................. 77
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 80
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 80
8.1
Statistical Analysis Plan Summary ..................................................................... 80
Efficacy Analyses ............................................................................................... 80
8.1.1
Safety Analyses................................................................................................... 82
8.1.2
Power and Sample Size....................................................................................... 82
8.1.3
Interim Analysis.................................................................................................. 83
8.1.4
 
 
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8.2
Statistical Analysis Plan ....................................................................................... 84
Responsibility for Analyses/In-House Blinding ................................................. 84
8.2.1
Hypotheses/Estimation ....................................................................................... 85
8.2.2
Analysis Endpoints ............................................................................................. 85
8.2.3
8.2.3.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints.............................. 85
8.2.3.2
Safety Endpoints .......................................................................................... 85
Analysis Populations........................................................................................... 86
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 86
8.2.4.2
Safety Analysis Populations ........................................................................ 86
Statistical Methods.............................................................................................. 86
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses ................................................... 87
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 88
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 88
8.2.5.3.1
Demographic and Baseline Characteristics .......................................... 88
Multiplicity ......................................................................................................... 88
8.2.6
Sample Size and Power Calculations.................................................................. 89
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 90
8.2.8
Interim Analyses ................................................................................................. 90
8.2.9
8.2.9.1
Efficacy Interim Analyses............................................................................ 90
8.2.9.2
Safety Interim Analyses............................................................................... 92
Compliance (Medication Adherence) ................................................................. 92
8.2.10
Extent of Exposure.............................................................................................. 92
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 93
9.1
Investigational Product ........................................................................................ 93
9.2
Packaging and Labeling Information ................................................................. 93
9.3
Clinical Supplies Disclosure................................................................................. 93
9.4
Storage and Handling Requirements.................................................................. 93
9.5
Returns and Reconciliation.................................................................................. 93
9.6
Standard Policies................................................................................................... 94
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 94
 
 
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10.1
Confidentiality....................................................................................................... 94
Confidentiality of Data ....................................................................................... 94
10.1.1
Confidentiality of Subject Records ..................................................................... 94
10.1.2
Confidentiality of Investigator Information........................................................ 94
10.1.3
Confidentiality of IRB/IEC Information............................................................. 95
10.1.4
10.2
Compliance with Financial Disclosure Requirements....................................... 95
10.3
Compliance with Law, Audit and Debarment ................................................... 95
10.4
Compliance with Trial Registration and Results Posting Requirements ........ 97
10.5
Quality Management System............................................................................... 98
10.6
Data Management................................................................................................. 98
10.7
Publications ........................................................................................................... 98
11.0
LIST OF REFERENCES....................................................................................... 100
12.0
APPENDICES......................................................................................................... 104
12.1
Merck Code of Conduct for Clinical Trials...................................................... 104
12.2
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 106
12.3
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 112
12.4
ECOG Performance Status................................................................................ 123
12.5
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 124
12.6
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors .............................................................. 125
13.0
SIGNATURES......................................................................................................... 126
13.1
Sponsor's Representative ................................................................................... 126
13.2
Investigator.......................................................................................................... 126
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 27
Table 2
Trial Treatment ....................................................................................................... 29
Table 3  Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 31
Table 4
Imaging and Treatment After 1st Radiologic Evidence of PD............................... 35
Table 5
Infusion Reaction Treatment Guidelines................................................................ 40
Table 6
Imaging and Treatment after 1st radiologic evidence of PD.................................. 63
Table 7
Laboratory Tests ..................................................................................................... 67
Table 8
Evaluating Adverse Events..................................................................................... 78
Table 9
Primary Analysis Strategy for Efficacy Endpoints................................................. 81
Table 10 Summary of Interim Analysis Strategy.................................................................. 84
Table 11 Analysis Strategy for Key Efficacy Variables ....................................................... 87
Table 12 Operating Characteristics of Interim Analysis Rule for Triple Negative Breast 
Cancer – Pause Enrollment if ≤ 2/10 Subjects Respond........................................ 91
Table 13 Operating Characteristics of Interim Analysis Rule for Head/Neck Cancer 
(HPV negative) and Urothelial Cancer– Pause Enrollment if ≤ 1/10 subjects 
respond ................................................................................................................... 91
Table 14 Estimate of Incidence of Grade 4/5 events and 95% Upper Confidence Bound 
Based on Hypothetical Number of Subjects with Event Out of 10 Subjects 
Evaluated................................................................................................................ 92
Table 15 Product Descriptions .............................................................................................. 93
 
 
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LIST OF FIGURES
Figure 1
Trial Design ........................................................................................................ 16
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2
Dose Modification 
(Escalation/Titration/Other)
The dose modification guidelines are 
expanded to cover supportive care, 
monitoring, and follow-up.  Myocarditis 
is added.
To provide current, comprehensive 
guidelines for management of immune-
related adverse events.
6.1
Study Flow Chart for 
Cohorts A, B, C and D (10 
mg/kg Q2W dosing)
Survival status activities are shown 
taking place throughout the trial.
The frequency of telephone contacts 
during the survival follow-up phase is 
changed from every 12 weeks to 
approximately every 12 weeks.
To allow flexibility of survival status 
activities and ensure that current, complete 
survival data are available at the time of 
database locks
To allow flexibility of survival status 
activities
6.2
Study Flow Chart for 
Cohort B2 (200 mg Q3W 
dosing)
Survival status activities are shown 
taking place throughout the trial.
The frequency of telephone contacts 
during the survival follow-up phase is 
changed from every 12 weeks to 
approximately every 12 weeks.
ORST (Oncologic Response-Solid 
Tumor) is defined.
To allow flexibility of survival status 
activities and ensure that current, complete 
survival data are available at the time of 
database locks
To allow flexibility of survival status 
activities
To provide definition of this term
6.3
Second Course Phase 
(Retreatment ONLY) for 
Cohorts A, B, C and D 
6.4
Second Course Phase 
(Retreatment ONLY) for 
Cohort B2 
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.5.4.1
Survival Follow-up
The frequency of telephone contacts 
during the survival follow-up phase is 
changed from every 12 weeks to 
approximately every 12 weeks.
To allow flexibility of survival status 
activities
7.1.5.5
Survival Status
This section is added to state that the 
Sponsor may request updated survival 
data during the course of the trial.
To allow flexibility of survival status 
activities and ensure that current, complete 
survival data are available at the time of 
database locks
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
1.0
Trial Summary
Once subjects have achieved the trial 
objective or the trial has ended, subjects 
are discontinued from this trial and will 
be enrolled in an extension trial to 
continue protocol-defined assessments 
and treatment.
This trial has been identified to roll over 
into an extension trial.
2.2
Trial Diagram
The pembrolizumab extension trial after 
survival follow-up is added.
5.10
Beginning and End of the 
Trial
Upon trial completion, subjects are 
discontinued and enrolled in a 
pembrolizumab extension trial. 
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.1
Study Flow Chart for 
Cohorts A, B, C and D (10 
mg/kg Q2W dosing
Text was added to allow flexibility 
around the imaging schedule for subjects 
in follow-up.
To maintain subject retention and the 
collection of survival status for every 
subject enrolled
6.2
Study Flow Chart for 
Cohort B2 (200 mg Q3W 
dosing)
6.3
Second Course Phase 
(Retreatment ONLY) for 
Cohorts A, B, C and D
6.4
Second Course Phase 
(Retreatment ONLY) for 
Cohort B2
7.1.2.5.1
Assessment of Disease
7.1.5.4
Follow-up Visits
5.6.1
Supportive Care
Reference to the ECI (events of clinical 
interest) guidance document is removed.
This guidance document has been retired.
7.1.2.1
Adverse Event (AE) 
Monitoring
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase Ib Multicohort Study of MK-3475 in Subjects with Advanced 
Solid Tumors
Trial Phase
Ib
Clinical Indication
The treatment of subjects with triple negative breast cancer, head/neck 
cancer, urothelial tract cancer, or gastric cancer.  
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups 
MK-3475 10 mg/kg every 2 weeks (Cohort A, B, C and D)
MK-3475 200 mg every 3 weeks (Cohort B2)
Number of trial subjects
Approximately 114 subjects originally planned for enrollment into 
Cohorts A, B, C, and D, plus 110 additional H/N expansion (Cohort 
B2) subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 42
months from the time the first subject signs the informed consent until 
the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact.  After a screening phase of 28 days, eligible subjects will 
receive treatment on Day 1 of each 2-week dosing cycle (Cohorts A, 
B, C, and D) or 3-week dosing cycle (Cohort B2).  Treatment with 
MK-3475 will continue until documented confirmed disease 
progression, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdraws consent, pregnancy of the 
subject, 
noncompliance 
with 
trial 
treatment 
or 
procedure 
requirements, subject receives 24 months of study medication, or 
administrative reasons.  Subjects who attain a complete response may 
consider stopping trial treatment if they meet criteria for holding
therapy.  Subjects who stop trial treatment after receiving 24 months 
of study medication for reasons other than disease progression or 
intolerability or who attain a complete response and stop trial 
treatment may be eligible for up to one year of retreatment after 
experiencing disease progression.  The decision to retreat will be at 
the discretion of the investigator only if they meet the criteria for 
retreatment and the trial is ongoing.  After the end of treatment, each 
subject will be followed for 30 days for adverse event monitoring 
(serious adverse events will be collected for 90 days after the end of 
treatment or 30 days after the end of treatment if the subject initiates 
new anticancer therapy, whichever is earlier).  Subjects who 
discontinue for reasons other than disease progression will have post-
treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up.  All subjects will be followed by 
telephone for overall survival until death, withdrawal of consent, or 
the end of the study.  Once subjects have achieved the trial objective 
or the trial has ended, subjects are discontinued from this trial and will 
be enrolled in an extension trial to continue protocol-defined 
assessments and treatment.
 
 
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2.0 TRIAL DESIGN
2.1
Trial Design
This is a multicenter, nonrandomized, multi-cohort trial of MK-3475 in subjects with
advanced solid tumors.  Subjects will be enrolled into Cohort A for triple negative breast 
cancer (TNBC), Cohort B for the initial head and neck (H/N) cancer cohort and Cohort B2 
for the H/N cancer expansion cohort, Cohort C for urothelial tract cancer, or Cohort D for 
gastric cancer. Only subjects with PD-L1 positive tumors will be enrolled in Cohorts A, B, C 
and D.  Subjects in Cohort B2 may be enrolled regardless of PD-L1 status.  Approximately 
114 subjects were planned to be enrolled in Cohorts A, B, C and D of this trial to examine 
the safety and efficacy of MK-3475 in these populations.  Approximately 110 subjects will 
be enrolled into Cohort B2 of the study to further explore the safety and efficacy in the head 
and neck cancer population at a different dose and schedule of MK-3475 and including both 
PD-L1 positive and negative subjects.  Subjects enrolled in Cohorts A, B, C and D will 
receive 10 mg/kg of MK-3475 administered every 2 weeks.  Subjects enrolled in Cohort B2
will receive 200 mg of MK-3475 administered every 3 weeks.  Subjects will be evaluated 
every 8 weeks (56 days ± 7 days) with radiographic imaging to assess response to treatment.  
RECIST 1.1 response rate as assessed by independent central radiology review will be used 
as the primary efficacy endpoint for Cohorts A, B, C and D.  RECIST 1.1 response rate as 
assessed by independent central radiology review will be used as the primary efficacy 
endpoint for Cohort B2.  RECIST 1.1 will be adapted as described in Section 4.2.3.1 to 
accommodate for the tumor response patterns seen with MK-3475 treatment (e.g., tumor 
flare), and this adapted RECIST will be used by the sites for treatment decisions in all 
cohorts.  Adverse events will be monitored throughout the trial and graded in severity 
according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0.  Treatment with MK-3475 will continue until documented 
disease progression, unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, completion of 24 months of treatment with MK-3475, or 
administrative reasons. Subjects who attain an investigator-determined confirmed complete 
response (CR) may consider stopping trial treatment after receiving at least 24 weeks of 
treatment.  Subjects who discontinue after at least 24 months of therapy for reasons other 
than disease progression or intolerability or who discontinue after attaining a CR may be 
eligible for up to one year of retreatment after they have experienced radiographic disease 
progression.  The decision to retreat will be at the discretion of the investigator only if no 
cancer treatment was administered since the last dose of MK-3475, the subject still meets the 
safety parameters listed in the Inclusion/Exclusion criteria and the trial remains open (refer to 
Section 7.1.5.2.1 for further details).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment or 30 days after the end of treatment if the subject 
initiates new anticancer therapy, whichever is earlier).  Subjects who discontinue treatment 
for reasons other than disease progression will have post-treatment follow-up for disease 
status until disease progression, initiating a non-study cancer treatment, withdrawing consent, 
 
 
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or becoming lost to follow-up.  All subjects will be followed by telephone contact for overall 
survival until death, withdrawal of consent or the end of the study, whichever comes first.
The primary objectives of the trial are to determine the safety, tolerability, and anti-tumor 
activity of MK-3475 in subjects with advanced solid tumors receiving either the 10 mg/kg 
Q2W dose (Cohorts A, B, C and D) or the 200 mg Q3W dose (Cohort B2).  Secondary 
objectives include progression-free survival (PFS), overall survival (OS) and response 
duration in subjects with advanced solid tumors.  In addition, the anti-tumor activity of MK-
3475 in subjects with PD-L1 positive advanced human papillomavirus (HPV) positive 
head/neck cancer will be evaluated as a secondary objective.  The relationship between 
candidate efficacy/resistance biomarkers (including PD-L1 expression in the tumor and its 
microenvironment) and anti-tumor activity of MK-3475 will also be investigated as a 
secondary objective.  The pharmacokinetic (PK) properties of MK-3475 in the advanced 
solid tumor population will be investigated as an exploratory objective.  
Participation in this trial will be dependent upon supplying tissue from an archival tissue 
sample or newly obtained biopsy of a tumor lesion not previously irradiated (subjects in the 
H/N cohort may submit tissue from a previously-irradiated lesion).  This specimen will be 
evaluated at a central laboratory for expression status of PD-L1 by immunohistochemistry
(IHC).  Only subjects with PD-L1 positive tumors will be enrolled into Cohorts A, B, C and 
D of the trial.  Both PD-L1 positive and negative subjects will be enrolled into Cohort B2, 
and the clinical activity in both subsets will be evaluated. 
This study will be conducted in conformance with Good Clinical Practices.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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2.2
Trial Diagram
The trial design is depicted in Figure 1 below.
Figure 1
Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
(1) Objective:  To determine the safety and tolerability of the 10 mg/kg Q2W dose of MK-
3475 in subjects with PD-L1 positive advanced solid tumors enrolled into Cohorts A, B, 
C, and D.
Hypothesis:  Intravenous administration of the single agent 10 mg/kg Q2W dose of MK-
3475 is sufficiently well-tolerated to permit continued clinical investigation.  
Pembrolizumab extension trial
 
 
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(2) Objective: To evaluate anti-tumor activity of the 10 mg/kg Q2W dose of MK-3475 in 
subjects with PD-L1 positive advanced solid tumors enrolled into Cohorts A, B, C, and D 
based on RECIST 1.1 assessed by independent central radiology review.   
a.
Hypothesis: Intravenous administration of single agent MK-3475 10 mg/kg Q2W to 
subjects with PD-L1 positive triple negative advanced breast cancer (Cohort A) will 
result in a clinically meaningful overall response rate (ORR) based on RECIST 1.1.
b. Hypothesis: Intravenous administration of single agent MK-3475 10 mg/kg Q2W to 
subjects with PD-L1 positive HPV negative advanced head and neck cancer (Cohort 
B) will result in a clinically meaningful overall response rate (ORR) based on 
RECIST 1.1.
c.
Hypothesis: Intravenous administration of single agent MK-3475 10 mg/kg Q2W to 
subjects with PD-L1 positive advanced urothelial tract cancer (Cohort C) will result 
in a clinically meaningful overall response rate (ORR) based on RECIST 1.1.
d. Hypothesis: Intravenous administration of single agent MK-3475 10 mg/kg Q2W to 
subjects with PD-L1 positive advanced gastric cancer (Cohort D) will result in a 
clinically meaningful overall response rate (ORR) based on RECIST 1.1.
(3) Objective:  To determine the safety and tolerability of the 200 mg Q3W dose of MK-
3475 in subjects with advanced head and neck cancer enrolled into Cohort B2.
Hypothesis:  Intravenous administration of single agent MK-3475 200 mg Q3W in 
subjects with advanced head and neck cancer is sufficiently well-tolerated to permit 
continued clinical investigation.
(4) Objective:  To evaluate anti-tumor activity of MK-3475 200 mg Q3W (Cohort B2) in 
subjects with advanced head and neck cancer enrolled into Cohort B2 based on RECIST 
1.1 assessed by independent central radiology review .
Hypothesis:  Intravenous administration of the single agent 200 mg Q3W dose of MK-
3475 to subjects with advanced head and neck cancer (Cohort B2) will result in a 
clinically meaningful overall response rate (ORR) based on RECIST 1.1 assessed by 
independent central radiology review.
3.2
Secondary Objective(s) & Hypothesis(es)
(1) Objective:  To evaluate the anti-tumor activity of MK-3475 in subjects with PD-L1 
positive advanced HPV positive head/neck cancer in Cohort B as determined by 
independent central radiology review.
Hypothesis:  Intravenous administration of single agent MK-3475 to subjects with PD-
L1 positive HPV positive advanced head and neck cancer enrolled into Cohort B will 
result in a clinically meaningful overall response rate (ORR) based on RECIST 1.1 as 
assessed by independent central radiology review.
 
 
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(2) Objective:  To evaluate the anti-tumor activity of MK-3475 in subjects with PD-L1 
positive advanced gastric cancer in the Asia Pacific region as assessed by independent 
central radiology review.
Hypothesis:  Intravenous administration of single agent MK-3475 to subjects with PD-
L1 positive advanced gastric cancer in the Asia Pacific region will result in a clinically 
meaningful overall response rate (ORR) based on RECIST 1.1 as assessed by 
independent central radiology review.
(3) Objective:  To evaluate the anti-tumor activity of MK-3475 in subjects with advanced 
head and neck cancer previously treated with cetuximab and platinum enrolled in Cohort 
B or Cohort B2 based on RECIST 1.1 as assessed by independent central radiology 
review.
Hypothesis:  Intravenous administration of single agent MK-3475 in subjects with 
advanced head and neck cancer previously treated with cetuximab and platinum enrolled 
in Cohort B or Cohort B2 will result in a clinically meaningful overall response rate 
(ORR) based on RECIST 1.1 as assessed by independent central radiology review.
(4) Objective:  To evaluate the anti-tumor activity of MK-3475 in subjects with PD-L1 
positive advanced solid tumors based on RECIST 1.1 as determined by the Investigator
(Cohorts A, B, C and D)
(5) Objective: To evaluate the anti-tumor activity of MK-3475 at 200 mg Q3W in subjects 
with advanced head and neck cancer (Cohort B2) based on RECIST 1.1 as assessed by 
the Investigator. 
(6) Objective: To investigate the correlation between PD-L1 expression and anti-tumor 
activity of pembrolizumab in subjects with advanced head and neck cancer enrolled into 
Cohort B2.
(7) Objective:
To investigate the relationship between candidate efficacy/resistance 
biomarkers and anti-tumor activity of pembrolizumab utilizing pre- and post-treatment
tumor biopsies and blood sampling.
(8) Objective: To evaluate the progression-free survival (PFS) in subjects with advanced 
solid tumors receiving MK-3475.
(9) Objective:  To evaluate the overall survival (OS) in subjects with advanced solid tumors
receiving MK-3475.
(10) Objective: To evaluate the response duration in subjects with advanced solid tumors
receiving MK-3475.
 
 
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3.3
Exploratory Objective
(1)
Objective:
To explore the PK profile of MK-3475 in the advanced solid tumor 
population.
4.0 BACKGROUND & RATIONALE
4.1
Background
Pharmaceutical and Therapeutic Background
4.1.1
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 
8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type 
I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [13; 14].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [15; 16].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17]   The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [18; 19; 20; 13].  Both ligands are type I transmembrane receptors 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 
 
 
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chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL)
[21].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.  
Pre-clinical and Clinical Trials
4.1.2
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [22; 23; 24; 25; 26; 27].  Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
Ongoing Clinical Trials
4.1.3
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of advanced solid tumor indications and hematologic malignancies.  For 
study details please refer to the Investigator’s Brochure.
4.2
Rationale
Rationale for the Trial and Selected Subject Population
4.2.1
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents.
This is a multicenter, nonrandomized, multi-cohort trial of MK-3475 in subjects with 
advanced solid tumors.  Subjects with PD-L1 positive tumors will be enrolled into Cohort A 
for TNBC, Cohort B for H/N cancer, Cohort C for urothelial tract cancer or Cohort D for 
gastric cancer.  Subjects with advanced head and neck cancer will be enrolled into Cohort B2
irrespective of PD-L1 expression (including subjects whose tumors do not express PD-L1).    
 
 
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Participation in this trial will be dependent upon supplying tissue from an archival tissue 
sample or newly obtained core or excisional biopsy of a tumor lesion not previously 
irradiated (subjects in the H/N cohort may provide tissue from a previously irradiated lesion) 
to evaluate for PD-L1 expression by IHC.  For Cohorts A, B, C or D, if an archival specimen 
is PD-L1 negative but a newly obtained biopsy is positive, the subject would be eligible.  The 
specimen will be evaluated at a central laboratory for expression status of PD-L1.  Only 
subjects with PD-L1 positive tumors will be enrolled into Cohorts A, B, C and D of the trial. 
The hypothesis that PD-L1 may predict potential response to anti-PD-1 therapy is based on 
the results from Topalian et al [30] who examined PD-L1 expression in the archival 
specimens of 42 of the 296 subjects treated with the PD-1 inhibitor nivolumab.  Of those 17 
subjects whose tumor cells did not stain positive for PD-L1 using a 5% threshold of tumor 
cell surface expression, no objective response by RECIST 1.1 was observed.  But among the 
25 subjects whose tumor cells were considered positive for PD-L1, 9 responded (36%).  
Further, data from MK-3475 in patients with non-small cell lung cancer (NSCLC) showed 
that pretreatment tumor PD-L1 expression was a statistically significant predictor of 
response. In patients with evaluable tumor PD-L1 expression, confirmed responses by 
RECIST v1.1 (and irRC) occurred in patients with tumors strongly positive for PD-L1 [42].  
Therefore, PD-L1 may be a predictive biomarker of anti-PD-1 activity, and will be tested in 
this study as an enrollment criterion for select cohorts A, B, C, and D.
A subset of head and neck cancer is caused by infection with HPV.  It is hypothesized that 
virally induced tumors may have enhanced immunogenicity and PD-L1 expression [31].  
Therefore, additional subjects that are HPV positive will be enrolled into the initial H/N 
cohort (Cohort B).  Cetuximab and platinum are commonly used therapies for head and neck 
patients in the recurrent and metastatic setting.  Understanding the response rate of 
pembrolizumab in patients who have received these standard treatments is of interest. A 
subset of patients with prior cetuximab and platinum treatment will be analyzed to further 
characterize clinical response in head and neck cancer patients exposed to cetuximab and
platinum therapy.
Rationale for Dose Selection/Regimen/Modification
4.2.2
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose -
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity.  Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity [43].  To further 
investigate this hypothesis subjects in Cohort B2 will be dosed at 200 mg Q3W.  
 
 
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PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.  
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of MK-
3475 in subjects with advanced solid tumors.  Response rates per RECIST 1.1 and volumetric 
analysis will be evaluated.
RECIST 1.1[32] as assessed by the independent central radiology vendor will be used as the 
primary response rate efficacy endpoint for Cohorts A, B, C and D.  RECIST 1.1 [32] as 
assessed by independent central radiology review will be used as the primary response rate 
efficacy endpoint for Cohort B2.  
RECIST 1.1 will also be used by the local site to determine eligibility and make treatment 
decisions.  For this purpose RECIST 1.1 will be adapted to account for the unique tumor 
response profile seen with treatment of MK-3475.
Immunotherapeutic agents such as MK-3475 may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses which may be functionally anergic.  The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST criteria 
may not provide a complete response assessment of immunotherapeutic agents such as MK -
3475.  Therefore, RECIST 1.1 will be used with the following adaptation:
 
 
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If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  If repeat imaging shows a reduction in the tumor 
burden compared to the initial scan demonstrating PD, treatment may be continued as per 
treatment calendar.  If repeat imaging confirms progressive disease, subjects will be 
discontinued from study therapy (exception noted in Section 7.1.2.5.1).  In determining 
whether or not the tumor burden has increased or decreased, Investigators should consider all 
target lesions as well as non-target lesions (please refer to the Site Imaging Manual).
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained a 
minimum of 4 weeks later.  This decision should be based on the clinical judgment of the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria:

Absence of signs and symptoms indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, but with subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease.  Retrospective independent central radiology review of all imaging time points will 
be performed for this study using RECIST 1.1 and volumetric analysis.  Additional 
information is included in the Site Imaging Manual.    
4.2.3.2
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of MK-
3475 in subjects with advanced solid tumors.  The primary safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE criteria.  Safety will be assessed 
by quantifying the toxicities and grades experienced by subjects who have received MK-
3475, including serious adverse events (SAEs) and events of clinical interest (ECIs).  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.2.3.2.
 
 
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4.2.3.3
Biomarker Research
Additional biomarker research to identify factors important for MK-3475 therapy may also 
be pursued.  For example, pre- and post-dose tumor and blood samples from this study may
undergo proteomic, genomic and transcriptional analyses.  Additional research may evaluate 
factors important for predicting responsiveness or resistance to MK-3475 therapy and other 
immunologic targets.
Assays may include but are not be limited to:
Multiparametric (Two-Color) IHC
Spatial association of PD-1+ tumor infiltrating lymphocytes (TILs) and PD-L1+ cells (tumor 
and myeloid cells) suggests “induction” of PD-L1.  Interferon-gamma production by antigen-
specific PD-1+ CD8+ T cells is hypothesized to drive local intratumoral upregulation of PD-
L1 on adjacent tumor and myeloid cells, leading to a “stalled CTL” response which may be 
predictive of response to MK-3475 therapy.  By assessing both of the required elements, i.e. 
PD-L1 positive cells and PD-1+ T cells, a two-color IHC assay may be a better predictor of 
response than PD-L1 positivity alone.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material will be completed to 
assess expression of approximately 400 genes and attempt to define a gene set critical for 
clinical response to MK-3475.  The hypothesis to be tested is that MK-3475 responders will 
exhibit a “stalled Cytotoxic T Lymphocyte (CTL)” response within the tumor reflected in the 
physical proximity between PD-1 and PD-L1 expression and the presence of an aborted  
(e.g., weak but discernible) interferon-gamma transcriptional program will be detectable by 
profiling analyses.  Global profiling will also be pursued.
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., IL-10).
Gene Sequencing
New data are emerging that suggest we can define certain tumor types as being 
‘hypermutated’.  There is a potential that this hypermutated state may correlate with response 
to MK-3475 therapy, and/or that the converse, ‘hypomutated’ state may correlate with non-
response.  
4.2.3.4
Future Biomedical Research
Merck will conduct Future Biomedical Research on blood and tumor tissue specimens 
collected during this clinical trial.  This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes.
 
 
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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysi s 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs, and/or to ensure that subjects receive the 
correct dose of the correct drug at the correct time.  The details of this Future Biomedical 
Research sub-trial are presented in Section 12.2 - Collection and Management of Specimens 
for Future Biomedical Research.  Additional informational material for institutional review 
boards/ethics committees (IRBs/ERCs) and investigational site staff is provided in Section 
12.3.
5.0 METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with triple negative breast cancer (Cohort A), head/neck cancer 
(Cohort B and Cohort B2), urothelial tract cancer (Cohort C), or gastric cancer (Cohort D) of
at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial. The 
subject may also provide consent/assent for Future Biomedical Research. However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
2. Be 18 years of age on day of signing informed consent.
 
 
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3. Have histologically or cytologically-confirmed diagnosis of cancer that is recurrent, 
metastatic, or persistent and meet the following corresponding requirements for the 
cohort of the study they will enroll into.  There is no limit to the number of prior 
treatment regimens.  
a.
Cohort A:  Have diagnosis of triple negative breast cancer (Estrogen, 
Progesterone, and HER2 negative carcinoma of the breast)
b. Cohort B and B2:  Have a diagnosis of squamous cell carcinoma of the head 
and neck
Note:  A subset of subjects enrolled to Cohort B known to have HPV
positive head and neck squamous cell cancer will be assessed.
Note:  Cohort B2 will enroll both HPV positive and HPV negative 
subjects
c.
Cohort C:  Have a diagnosis of urothelial tract cancer of the renal pelvis, 
ureter, bladder, or urethra.  Both transitional cell and non-transitional cell 
histologies are allowed.
d. Cohort D: Have a diagnosis of adenocarcinoma of the stomach or gastro-
esophageal junction
4. Have provided tissue for biomarker analysis from an archival tissue sample or newly 
obtained core or excisional biopsy of a tumor lesion not previously irradiated.  
(Subjects with H/N cancer may provide tissue from a previously irradiated lesion.)    
5. Cohorts A, B, C and D only:  Have a PD-L1 positive tumor as determined by IHC at a 
central laboratory from either an archived formalin fixed paraffin embedded (FFPE) 
tumor sample or a newly obtained biopsy.
6. Have measurable disease based on RECIST 1.1. Tumor lesions situated in a 
previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
8. Demonstrate adequate organ function as defined in Table 1; all screening labs should 
be performed within 10 days of treatment initiation.  
 
 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal
Creatinine OR
Measured or calculateda creatinine clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN  OR
≤ 5 X ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated 
Partial 
Thromboplastin 
Time 
(aPTT)
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants
≤1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants
a
Creatinine clearance should be calculated per institutional standard.
9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  
10. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.
11. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks of the first dose of treatment.
 
 
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2. Has a diagnosis of immunosuppression or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.
3. Has had a prior anti-cancer monoclonal antibody 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.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.
-
Note:  Subjects with ≤ Grade 2 neuropathy 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.  
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.  
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.  
7. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Subjects with 
vitiligo, diabetes mellitus type I, or resolved childhood asthma/atopy would be an 
exception to this rule.  Subjects that require intermittent use of bronchodilators or
local steroid injections would not be excluded from the study.  Subjects with 
hypothyroidism stable on hormone replacement or Sjogren’s syndrome will not be 
excluded from the study.
8. Has evidence of interstitial lung disease.
9. Has an active infection requiring systemic therapy.
10. 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.  
 
 
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11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways).
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
16. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject.
5.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 2.
Table 2
Trial Treatment
Cohort
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
A, B, C, D
MK-3475
10 mg/kg
Q2W
IV infusion
Day 1 of each cycle
Experimental
B2
MK-3475
200 mg
Q3W
IV infusion
Day 1 of each cycle
Experimental
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned.
 
 
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Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background and Rationale.  
For Cohorts A, B, C, and D, the dose amount required to prepare the MK-3475 infusion 
solution will be based on the subject’s weight in kilograms (kg).  Details on the dose 
calculation, preparation and administration are provided in the Pharmacy Manual.
For Cohort B2, subjects will be given 200 mg Q3W.  
5.2.1.2
Dose Modification 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 
5.6 and the Events of Clinical Interest Guidance Document for supportive care guidelines, 
including use of corticosteroids.
 
 
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Table 3  Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate 
subjects
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) 
and 
of 
bowel 
perforation 
(ie, peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects
with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate 
insulin 
replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 
1-2 
mg/kg 
or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based 
on 
severity 
of 
AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial 
treatment should be discontinued after consultation with the Sponsor.  With investigator and 
Sponsor agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks 
may continue treatment in the trial only if asymptomatic and controlled.  For information on 
the management of adverse events, see Section 5.6.1.  
Timing of Dose Administration
5.2.2
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons.
All trial treatments will be administered on an outpatient basis.
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption 
should be documented in the patient's study record
MK-3475 will be administered as a 30 minute IV infusion every 2 or 3 weeks depending on 
the Cohort the subjects have been enrolled into.    Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Treatment after initial evidence of radiologic disease progression
Immunotherapeutic agents such as MK-3475 may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  
If radiologic imaging shows PD, tumor assessment should be repeated 4 weeks later in 
order to confirm PD with the option of continuing treatment per below while awaiting 
radiologic confirmation of progression.  If repeat imaging shows a reduction in the tumor 
burden compared to the initial scan demonstrating PD, treatment may be continued as per 
treatment calendar.  If repeat imaging confirms progressive disease, subjects will be 
discontinued from study therapy (exception noted in Section 7.1.2.5.1).  In determining 
whether or not the tumor burden has increased or decreased, Investigators should consider all 
target lesions as well as non-target lesions (please refer to the Site Imaging Manual).
 
 
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When feasible, subjects should not be discontinued until progression is confirmed; however, 
the decision to continue study treatment after the 1st evidence of disease progression is at the 
Investigator’s discretion based on the clinical status of the subject as described in Table 4
below.  Subjects may receive study treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Table 4
Imaging and Treatment After 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologic 
evidence of PD
Repeat imaging at 
>
4 weeks to 
confirm PD
May 
continue 
study treatment at 
the Investigator’s 
discretion 
while 
awaiting 
confirmatory scan 
Repeat imaging at 
>
4 weeks to 
confirm 
PD 
if 
possible
Discontinue 
treatment
Repeat
scan 
confirms PD
No 
additional 
imaging required
Discontinue 
treatment 
(exception noted 
in 
Section 
7.1.2.5.1)
No 
additional 
imaging required
N/A
Repeat
scan 
shows SD, PR or 
CR
Continue 
regularly 
scheduled
imaging 
assessments every 
8 weeks
Continue 
study 
treatment at the 
Investigator’s 
discretion
Continue 
regularly 
scheduled
imaging 
assessments every 
8 weeks
May restart study 
treatment
if 
condition 
has 
improved and/or
clinically 
stable 
per Investigator’s 
discretion
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
PD-L1 IHC biomarker testing is used to determine study eligibility for Cohorts A, B, C, and 
D and therefore the subject, investigator and SPONSOR will know the PD-L1 IHC result.   
Access to PD-L1 subject-level biomarker results for subjects enrolled in Cohort B2 will be 
 
 
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limited to an unblinded SPONSOR statistician, and unblinded SPONSOR statistical 
programmer who will be responsible for data review to ensure validity of results and 
summary reporting of clinical response by biomarker status, but who will have no other 
responsibilities associated with the study.
5.3
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated to trial treatment by non-random 
assignment. 
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  Listed below are some specific restrictions for concomitant therapy 
or vaccination during the course of the trial.  If there is a clinical indication for one of these 
or other medications or vaccinations specifically prohibited during the trial, discontinuation 
from trial therapy or vaccination may be required.  The investigator should discuss any 
questions regarding this with the local Clinical Monitor.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  However, the decision to continue the subject on trial therapy or vaccination 
schedule requires the mutual agreement of the investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
5.5.2
Subjects are prohibited from receiving the following therapies during the Screening and
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol
 
 
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
Investigational agents other than MK-3475

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor.  

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, , rabies, BCG, and 
typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., 
Flu-Mist) are live attenuated vaccines, and are not allowed.

Glucocorticoids for any purpose other than to modulate acute symptoms from an 
adverse event.  The use of physiologic doses for subjects requiring ongoing 
corticosteroids, may be approved after consultation with the Sponsor.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.6
Rescue Medications & Supportive Care
Supportive Care Guidelines
5.6.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below.  Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance. Refer to Section 5.2.1 for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
 
 
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
Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
 
 
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
Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.
 
 
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
Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
5.7
Diet/Activity/Other Considerations
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
5.7.2
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can either be two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after 
the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
 
 
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Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.   
If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and followed as described 
above and in Section 7.2.2.
Use in Nursing Women
5.7.4
It is unknown whether MK-3475 is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.
5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
 
 
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A subject must be discontinued from treatment (but may continue to be monitored in the 
post-treatment follow-up portion of the trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2.
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 
7.1.2.5.1.

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of treatment with MK-3475
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop MK-3475 after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.5.2.1.   

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, as described in Section 7.2.3.1).  
Subjects who discontinue 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.
 
 
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Discontinuation of Study Therapy after CR
5.8.1
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with MK-3475 and had at least two 
treatments with MK-3475 beyond the date when the initial CR was declared.  Subjects who
then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with MK-3475 at the discretion of the investigator if no cancer treatment 
was administered since the last dose of MK-3475, the subject meets the safety parameters 
listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy 
at the same dose and schedule at the time of initial discontinuation.  Additional details are 
provided in Section 7.1.5.2.1.
5.9
Subject Replacement Strategy
Additional subjects may be enrolled in a given cohort to ensure that the required number of 
evaluable subjects in each cohort is achieved.  A subject that discontinues the trial for 
progressive disease or a drug-related AE will not be replaced and will be counted in the 
evaluable population of subjects for the respective cohort.  Further details are provided in 
Section 8.1.3.
5.10 Beginning and End of the Trial
The study begins when the first subject signs the informed consent (either pre-screening 
consent or main study consent).  The end of the study may be designated as the time point 
when all subjects have discontinued the study or are a minimum of 6 months post initial 
study medication administration or all subjects still on study have received their 24-week 
scan (i.e. completed their third 8-week efficacy assessment). If, by the end of the study, there 
remains at least 1 subject still on study treatment for at least 6 months, the subject(s) may 
enter additional treatment cycles.  At this point a database lock of the trial may occur to allow 
the analysis of the study data. Any remaining subjects may continue to receive study 
medication and be seen by the investigator per usual standard of care for this subject
population. In addition, the investigator will be expected to monitor for and report any 
serious adverse events, events of clinical interest, and pregnancies, as detailed in Section 
7.2.3 (Serious Adverse Experiences). The subject is considered on study until such time that 
he/she meets any of the discontinuation criteria and written notification is given to the 
Sponsor. Upon study completion, subjects are discontinued and enrolled in a pembrolizumab 
extension trial.
5.11 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
 
 
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3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
 
 
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6.0 TRIAL FLOW CHART
6.1
Study Flow Chart for Cohorts A, B, C and D (10 mg/kg Q2W dosing)
Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Pre-
screening 
(Visit 1)b
Main 
Study 
Screening 
(Visit 2)c
1
2 
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Follow 
Up 
Visitsd
Survival 
Follow-
Upe
Scheduling Window (Days)f:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post discon
Every 8 
weeks 
post 
discon
Approx. 
every 12 
weeks 
Administrative Procedures
Pre-screening Consent
Xg
Informed Consent
Xh
Informed Consent for Future Biomedical 
Research
Xi
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
Xj
X
X
X
X
X
X
X
X
X
Xj
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Statuse
X
Clinical Procedures/Assessments
Review Adverse Eventsk
X
X
X
X
X
X
X
X
X
X
Xl
Xl
Full Physical Examination
X
Xm
Directed Physical Examination
X
X
X
X
Xff
Xff
Xff
X
Vital Signs and Weightn
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Xgg
Xgg
Xgg
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test – Urine or Serum . -HCGo
X
PT/INR and aPTTp
Xq
CBC with Differentialr
Xq
X
X
X
X
X
X
X
X
Xs
Comprehensive Chemistry Panelr
Xq
X
X
X
X
X
X
X
X
Xs
Urinalysisr
Xq
Xm
Xs
T3, FT4 and TSHr
Xq
Xm
Xs
 
 
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Trial Period:
Screening Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Pre-
screening 
(Visit 1)b
Main 
Study 
Screening 
(Visit 2)c
1
2 
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Follow 
Up 
Visitsd
Survival 
Follow-
Upe
Scheduling Window (Days)f:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post discon
Every 8 
weeks 
post 
discon
Approx. 
every 12 
weeks 
Laboratory Procedures/Assessments: analysis performed by central laboratory
Anti-MK-3475 Antibodiest
Xt
Xt
Xt
Xt
Pharmacokineticst
Xt,u
Xt
Xt
Xt
Blood for Future Biomedical Researchv
X
Efficacy Measurements
Tumor Imagingw,x
X
X
Xy
Xd
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival Tissue Collectionz
Xaa
Cohort B (H/N) and Cohort D (gastric 
cancer) Tumor Tissue Collectionz
Xaa,bb
Xbb
Xcc
Cohort A (TNBC) and Cohort C (urothelial tract 
cancer) Tumor Tissue Collectionz
Xaa,dd
Xdd
Xcc
Correlative Studies Blood Collection
Xee
Xee
Xee
 
 
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a.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 2 
weeks.  Imaging should always be performed every 8 weeks (56 days ± 7 days) regardless of any treatment delays.
b.
At the pre-screening visit, subjects will sign the pre-screening consent and submit an archival sample for PD-L1 characterization.
c.
Subjects who submit an archival tumor sample at the prescreening visit and are found to be PD-L1 positive will continue to the screening portion of the study.  Subjects who 
do not have an archival sample will go directly to the screening phase of the study.  
d.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imagingx every 8 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever 
occurs first. If imaging assessment beyond the protocol-required imaging time frame is necessary, the reason for the extended imaging schedule should be documented in the 
subject’s chart and recorded in the Oncologic Response-Solid Tumor (ORST) eCRF for each imaging assessment completed within the extended time frame. The maximum 
imaging time frame allowed is no greater than twice the imaging time frame noted (ie, for every 8 weeks’ imaging, the maximum imaging schedule allowance is every 16
weeks).  Every effort should be made to target the protocol-required imaging schedule as closely as possible; however, in the interest of the subject’s continued participation 
in the follow-up phase of the study, the extended imaging time frame may be considered at the discretion of the investigator.
e.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the 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 who have a death 
event previously recorded).
f.
In general, the window for each visit is ± 3 days unless otherwise noted. 
g.
Pre-screening informed consent must be obtained prior to sending an archival sample to the lab for characterization.  Subjects that do not have archival tissue available to 
send must sign the main study consent prior to undergoing a newly obtained biopsy.
h.
Written consent must be obtained prior to performing any protocol specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.  
i.
Signing the informed consent for future biomedical research (FBR) samples is optional.  Detailed instructions for the collection and management of specimens for FBR are 
provided in the Procedures Manual and Section 12.2. 
j.
Prior medications – Record all medications taken within 28 days of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
k.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
l.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only SAEs 
and ECIs that are related to trial treatment.
m. To be repeated every 4 cycles after cycle 5.
n.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 2 only.  
o.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
p. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
q.
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory tests.  
r.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  
s.
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
 
 
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t.
Pre-dose trough and post-dose peak PK samples will be collected at Cycles 1 and 2.  Pre-dose trough samples only will be collected every 4 cycles starting with Cycle 5 and 
through Cycle 37, 30 days after discontinuation of study drug, and 3 months and 6 months after discontinuation of study drug (or until the subject starts new anti-neoplastic 
therapy).  All trough samples should be drawn within 24 hours before infusion of MK-3475.  All peak samples should be drawn within 30 minutes after the end of the 
infusion. Anti-MK-3475 antibodies should be drawn with all pre-dose trough PK samples, the 30 day discontinuation draw and 3 months and 6 months after discontinuation 
of study drug (or until the subject starts new anti-neoplastic therapy).  Procedures for sample collection are described in the Procedures Manual.  
u.
An additional single PK sample should be drawn between 24 to 96 hours after Cycle 1 dosing.
v.
Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained.
Detailed instructions for the collection and 
management of specimens for FBR are provided in the Procedures Manual and Section 12.2.
w. The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment.  Scans performed as part of routine clinical management are acceptable 
for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  On-study imaging will be performed 
every 8 weeks (± 7 days) after the first dose of trial treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of MK-3475 cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local reading 
(investigator assessment with site radiology reading) will be used to determine eligibility and for subject management; Sponsor will collect radiological assessments for 
retrospective analysis by an independent central radiology review vendor.  The processes for image collection and transmission to the independent central radiology review
vendor are in the Site Imaging Manual.
x.
Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later in 
order to confirm progressive disease as described in Section 4.2.3.1. Please refer to the Procedure Manual for additional details on modifications to RECIST.
y.
In subjects who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the time of treatment discontinuation (i.e. 
date of 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.
z.
Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual.  If the subject signs the Future Biomedical Research (FBR) 
consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for FBR.
aa. Baseline tumor tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy (FNA not adequate) of a tumor lesion not previously 
irradiated must be provided and received by the independent central radiology review vendor before enrollment for characterization of PD-L1 status.  These samples are not 
required to be obtained within 28 days of enrollment.  Subjects with H/N cancer may provide tissue from a previously irradiated lesion.  
bb. Newly obtained tumor biopsy is required for subjects enrolled into Cohort B (H/N cancer) and Cohort D (gastric cancer) of the study.  Tumor biopsies that are inaccessible 
or contraindicated due to subject safety concerns are exempt from this requirement. The pre-dose newly obtained biopsy is not required for PD-L1 characterization and may 
be performed just prior to the first dose of study treatment after all eligibility criteria has been met.  
cc. Tumor biopsy for clinically stable subjects at treatment discontinuation is highly encouraged.
dd. Tumor biopsy is highly encouraged for all subjects.  If activity within the Cohort is observed (at least 2 responders within the Cohort) the tumor biopsy will become 
mandatory. Tumor biopsies that are inaccessible or contraindicated due to subject safety concerns are exempt from this requirement.  The pre-dose newly obtained biopsy is 
not required for PD-L1 characterization and may be performed just prior to the first dose of study treatment after all eligibility criteria has been met
ee. Blood for correlative studies should be collected prior to Cycle 1, at Cycle 5 and again at treatment discontinuation.  
ff. Following Cycle 8, the directed physical exam is only required at Cycle 11, 15, 19, and every 4 cycles thereafter.  
gg. Following Cycle 8, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam (Cycle 9, 11, 13, 15, 17, 
19 and every 2 cycles thereafter.
 
 
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6.2
Study Flow Chart for Cohort B2 (200 mg Q3W dosing)
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 
6 cycles
Treatment Cycle/Title:
Main Study 
Screening 
(Visit 2)
1
2 
3
4
5
6
Discon
Post-
Treatment 
Safety 
Follow-up
Follow Up 
Visitsb
Survival 
Follow-
Upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
discon
Every 8 
weeks post 
discon
Approx. 
every 12 
weeks 
Informed Consent
Xe
Informed Consent for Future Biomedical Research
Xf
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
Xg
X
X
X
X
X
X
X
Xg
Trial Treatment Administration
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Statusc
X
Review Adverse Eventsh
X
X
X
X
X
X
X
X
Xi
Xi
Full Physical Examination
X
Xj
Directed Physical Examination
X
X
X
Xk
Xk
X
Vital Signs and Weightl
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Xm
Xm
X
Pregnancy Test – Urine or Serum -HCGn
X
PT/INR and aPTTo
Xp
CBC with Differentialq
Xp
X
X
X
X
X
X
Xr
Comprehensive Chemistry Panelq
Xp
X
X
X
X
X
X
Xr
Urinalysisq
Xp
Xj
Xr
T3, FT4 and TSHq
Xp
Xj
Xr
Blood for Future Biomedical Researchs
X
Tumor Imagingt,u
X
X
Xv
Xb
Archival Tissue Collectionw
Xx
Newly Obtained Biopsy  Collectionw
Xy
Xy
Xz
Correlative Studies Blood Collection
Xaa
Xaa
Xaa
 
 
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a.
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 
weeks;  Imaging should always be performed every 8 weeks (56 days ± 7 days) regardless of any treatment delays.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imagingu every 8 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever 
occurs first. If imaging assessment beyond the protocol-required imaging time frame is necessary, the reason for the extended imaging schedule should be documented in the 
subject’s chart and recorded in the ORST eCRF for each imaging assessment completed within the extended time frame. The maximum imaging time frame allowed is no 
greater than twice the imaging time frame noted (ie, for every 8 weeks’ imaging, the maximum imaging schedule allowance is every 16 weeks).  Every effort should be made 
to target the protocol-required imaging schedule as closely as possible; however, in the interest of the subject’s continued participation in the follow-up phase of the study, 
the extended imaging time frame may be considered at the discretion of the investigator.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the 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 participants that have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
Written consent must be obtained prior to performing any protocol specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.  
f.
Signing the informed consent for future biomedical research (FBR) samples is optional.  Detailed instructions for the collection and management of specimens for FBR are 
provided in the Procedures Manual and Section 12.2. 
g.
Prior medications – Record all medications taken within 28 days of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
h.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only SAEs 
and ECIs that are related to trial treatment.
j.
To be repeated every 3 cycles after cycle 4.
k.
Following Cycle 6, the directed physical exam is only required as clinically appropriate as long as a physical exam is performed every 6 weeks.
l.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at the screening visit (visit 2) only.
m. Following Cycle 6, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam.  
n.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
o.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
p.
Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory tests.  
q.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  
r.
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
s.
Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained.
Detailed instructions for the collection and 
management of specimens for FBR are provided in the Procedures Manual and Section 12.2.
 
 
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t.
The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment.  Scans performed as part of routine clinical management are acceptable 
for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  On-study imaging will be performed 
every 8 weeks (± 7 days) after the first dose of trial treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of MK-3475 cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local reading 
(investigator assessment with site radiology reading) will be used to determine eligibility and for subject management; Sponsor will collect radiological assessments for 
retrospective analysis by an independent central radiology review vendor.  The processes for image collection and transmission to the independent central radiology review
vendor are in the Site Imaging Manual.
u.
Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later in 
order to confirm progressive disease as described in Section 4.2.3.1. Please refer to the Procedure Manual for additional details on modifications to RECIST.
v.
In subjects who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the time of treatment discontinuation (i.e. 
date of 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.
w. Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual.  If the subject signs the Future Biomedical Research (FBR) 
consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for FBR.
x.
Baseline tumor tissue for biomarker analysis from an archival tissue sample  of a tumor lesion must be provided and submitted to the independent central radiology review
vendor before enrollment  These samples are not required to be obtained within 28 days of enrollment.  .  Exceptions to the archival tissue requirement may be granted after 
discussion with the Sponsor if a newly obtained biopsy is performed at baseline.   
y.
Newly obtained tumor biopsies are mandatory for subjects prior to Cycle 1 initiation of MK-3475 and again at Cycle 3.  Exemptions to the tumor biopsy require Sponsor 
approval and appropriate justification..  
z.
Tumor biopsy for clinically stable subjects at treatment discontinuation is highly encouraged.
aa. Blood for correlative studies should be collected prior to Cycle 1, at Cycle 3 and again at treatment discontinuation.  
 
 
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6.3
Second Course Phase (Retreatment ONLY) for Cohorts A, B, C and D
Trial Period:
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Second Course Phase
Discon
Post-Treatment 
Safety Follow-
up
Follow Up 
Visitsb
Survival 
Follow-Upc
1
2
3
4
5
6
7
8
Scheduling Window (Days)d:
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
discon
Every 8 
weeks post 
discon
Approx. 
every 12 
weeks
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administrationg
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X
X
X
X
X
X
Xi
Xi
Full Physical Examination
X
Xj
Directed Physical Examination
X
X
X
Xu
Xu
Xu
X
Vital Signs and Weightk
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Xv
Xv
Xv
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCGl
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
X
X
Xs
Comprehensive Chemistry Panelo
Xn
X
X
X
X
X
X
X
X
Xs
T3, FT4 and TSHo
Xn
Xj
Xs
Laboratory Procedures/Assessments: analysis performed by central laboratory
Anti-MK-3475 Antibodies
Xt
Xt
Xt
Xt
Xt
Pharmacokinetics
Xt
Xt
Xt
Xt
Xt
Efficacy Measurements
Tumor Imagingp,q
X
X
Xr
Xb
 
 
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a. In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 2 
weeks  Imaging should always be performed every 8 weeks (56 days ± 7 days) regardless of any treatment delays.
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imagingp until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs first.  If imaging 
assessment beyond the protocol-required imaging time frame is necessary, the reason for the extended imaging schedule should be documented in the subject’s chart and 
recorded in the ORST eCRF for each imaging assessment completed within the extended time frame. The maximum imaging time frame allowed is no greater than twice the 
imaging time frame noted (ie, for every 8 weeks’ imaging, the maximum imaging schedule allowance is every 16 weeks).  Every effort should be made to target the protocol-
required imaging schedule as closely as possible; however, in the interest of the subject’s continued participation in the follow-up phase of the study, the extended imaging 
time frame may be considered at the discretion of the investigator.
c. After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status.  Updated survival status may be requested by the Sponsor at any time during the course of the 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 participants that have a death 
event previously recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted.
e. Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on MK-3475 for reasons other than disease progression or 
intolerability may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1.  
f. Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
g. Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
h. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
i. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days
after the last dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only SAEs 
and ECIs that are related to trial treatment.
j. To be repeated every 4 cycles after cycle 5.
k. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  
l. For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of retreatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
m. Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
n. Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of MK-3475.  See Section 7.1.3 for details 
regarding laboratory tests.
o. After the first dose, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.
p. A scan must be performed within 28 days prior to restarting treatment with MK-3475.  Imaging should continue to be performed every 8 weeks (56 ± 7 days) from the first 
dose of trial treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or 
extension of MK-3475 cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local reading (investigator assessment with site 
radiology reading) will be used to determine eligibility and for subject management.  The Sponsor will collect radiological assessments for retrospective analysis by an
independent central radiology review vendor.  The processes for image collection and transmission to the independent central radiology review vendor are in the Site 
Imaging Manual.
q. Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later in 
order to confirm progressive disease as described in Section 4.2.3.1. Please refer to the Procedure Manual for additional details on modifications to RECIST.
 
 
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r. In subjects who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the time of treatment discontinuation (i.e. 
date of 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.
s.
Unresolved labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal range.
t.
Pre-dose trough PK samples will be collected at Cycles 1 and 2.  Pre-dose trough samples will be collected every 4 cycles starting with Cycle 5 and through Cycle 37, 30 
days after discontinuation of study drug, and 3 months and 6 months after discontinuation of study drug (or until the subject starts new anti-neoplastic therapy).  All trough 
samples should be drawn within 24 hours before infusion of MK-3475.  Anti-MK-3475 antibodies should be drawn with all pre-dose trough PK samples, the 30 day 
discontinuation draw and 3 months and 6 months after discontinuation of study drug (or until the subject starts new anti-neoplastic therapy).  Procedures for sample 
collection are described in the Procedures Manual.  
u.
Following Cycle 8, the directed physical exam is only required at Cycle 11, 15, 19, and every 4 cycles thereafter.
v
Following Cycle 8, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam (Cycle 9, 11, 13, 15, 17, 
19 and every 2 cycles thereafter.
 
 
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6.4
Second Course Phase (Retreatment ONLY) for Cohort B2
Trial Period:
Treatment Cyclesa
End of 
Treatment
Post-Treatment
To be repeated beyond 
6 cycles
Treatment Cycle/Title:
Second Course Phase
Discon
Post-Treatment 
Safety Follow-up
Follow Up 
Visitsb
Survival 
Follow-Upc
1
2
3
4
5
6
Scheduling Window (Days)d:
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
discon
Every 8 
weeks post 
discon
Approx. every 
12 weeks
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
Trial Treatment Administrationg
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Statusc
X
Clinical Procedures/Assessments
Review Adverse Eventsh
X
X
X
X
X
X
X
Xi
Xi
Full Physical Examination
X
Xj
Directed Physical Examination
X
X
Xt
Xt
X
Vital Signs and Weightk
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
Xu
Xu
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCGl
X
PT/INR and aPTTm
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
Xs
Comprehensive Chemistry Panelo
Xn
X
X
X
X
X
X
Xs
T3, FT4 and TSHo
Xn
Xj
Xs
Efficacy Measurements
Tumor Imagingp,q
X
X
Xr
Xb
 
 
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a. In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 weeks  
Imaging should always be performed every 8 weeks (56 days ± 7 days) regardless of any treatment delays.
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic imagingp until 
(1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs first.  If imaging assessment beyond the protocol-
required imaging time frame is necessary, the reason for the extended imaging schedule should be documented in the subject’s chart and recorded in the ORST eCRF for each imaging 
assessment completed within the extended time frame. The maximum imaging time frame allowed is no greater than twice the imaging time frame noted (ie, for every 8 weeks’
imaging, the maximum imaging schedule allowance is every 16 weeks).  Every effort should be made to target the protocol-required imaging schedule as closely as possible; however, 
in the interest of the subject’s continued participation in the follow-up phase of the study, the extended imaging time frame may be considered at the discretion of the investigator.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for survival 
status.  Updated survival status may be requested by the Sponsor at any time during the course of the 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 participants that have a death event previously 
recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted.
e. Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on MK-3475 for reasons other than disease progression or intolerability may 
restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1.  
f. Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
g. Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
h. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days after the last 
dose of trial treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only SAEs and ECIs that are related 
to trial treatment.
j.
To be repeated every 3 cycles after cycle 4.
k. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  
l.
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of retreatment.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by local 
guidelines.
m. Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
n. Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of MK-3475.  See Section 7.1.3 for details regarding 
laboratory tests.
o. After the first dose, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.
p. A scan must be performed within 28 days prior to restarting treatment with MK-3475.  Imaging should continue to be performed every 8 weeks (56 ± 7 days) from the first dose of trial 
treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or extension of MK-3475 cycle 
frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility and for subject management.  The Sponsor will collect radiological assessments for retrospective analysis by an independent central radiology review vendor.  The processes 
for image collection and transmission to the independent central radiology review vendor are in the Site Imaging Manual.
q. Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later in order to 
confirm progressive disease as described in Section 4.2.3.1. Please refer to the Procedure Manual for additional details on modifications to RECIST.
r. In subjects who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the time of treatment discontinuation (i.e. date of 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.
s. Unresolved labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal range.
t. Following Cycle 6, the directed physical exam is only required clinically appropriate as long as a physical exam is performed every 6 weeks..
u. Following Cycle 6, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam.
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in the study will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
 
 
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7.1.1.6
Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  HPV status will be collected for those subjects enrolled in Cohort B and B2.
7.1.1.6.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.6.3 Subsequent Anti-neoplastic Therapy Status
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-neoplastic 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-neoplastic therapy has been initiated
the subject will move into survival follow-up.  
7.1.1.7
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.
7.1.1.8
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, to trial treatment and will 
receive a unique number.  This unique number is termed a randomization number throughout 
the protocol for operational purposes.  The randomization number identifies the subject for 
all procedures occurring after treatment allocation.  Once a randomization number is 
assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
MK-3475 doses due to toxicity
require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff.  
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.  
 
 
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The instructions for preparing and administering MK-3475 will be provided in the Pharmacy
Manual.  
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment. 
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 in the administrative binder regarding the identification, 
evaluation and management of AEs of a potential immunological etiology.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed as specified in the Trial Flow Chart 
(Section 6.0) for the appropriate cohort.  After the first dose of trial treatment new clinically 
significant abnormal findings should be recorded as AEs.
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  Directed physical exams should be performed as specified in 
the Trial Flow Chart (Section 6.0) for the appropriate cohort. For Cohorts A, B, C and D 
after Cycle 8 directed physical exams should occur at Cycle 11 and every 4 cycles thereafter.  
For Cohort B2 after Cycle 6 a physical exam (either full or directed) is required to be 
performed at least every 6 weeks but should be performed more frequently if clinically 
indicated.  New clinically significant abnormal findings should be recorded as AEs. 
 
 
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7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.  After Cycle 8 (Cohorts A, B, C or D) or 
Cycle 6 (Cohort B2) assessment of ECOG status will be performed in conjunction with the 
directed or full physical exam.
7.1.2.5
Tumor Imaging and Assessment of Disease
Processes for image collection and transmission to the independent central radiology review
vendor can be found in the Site Imaging Manual.
7.1.2.5.1 Assessment of Disease
RECIST 1.1 will be applied by the site as the primary measure for assessment of tumor 
response and as a basis for all protocol guidelines related to disease status (e.g.,
discontinuation of study therapy).  
RECIST 1.1 will be adapted as follows to account for the unique tumor response seen in this 
class of therapeutics.  
If imaging shows PD, tumor assessment should be repeated 4 weeks later in order to 
confirm PD with the option of continuing treatment for clinically stable subjects as discussed 
below in Table 6.  Clinically stable is defined by the following criteria:  

Absence of signs and symptoms indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
 
 
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Table 6
Imaging and Treatment after 1st radiologic evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat imaging 
at 4 weeks to 
confirm PD
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan
Repeat imaging 
at 4 weeks to 
confirm PD if 
possible
Discontinue 
treatment
Repeat scan 
confirms PD
No additional 
imaging 
required
Discontinue 
treatment 
(exception noted 
below)
No additional 
imaging 
required
N/A
Repeat scan 
shows SD, PR 
or CR
Continue 
regularly 
scheduled
imaging 
assessments 
every 8 weeks
Continue study 
treatment at the 
Investigator’s 
discretion
Continue 
regularly 
scheduled
imaging 
assessments 
every 8 weeks
May restart 
study treatment 
if condition has 
improved and/or
clinically stable 
per 
Investigator’s 
discretion
In determining whether or not the tumor burden has increased or decreased, Investigators 
should consider all target lesions as well as non-target lesions (please refer to the Site 
Imaging Manual).  Subjects that are deemed clinically unstable are not required to have 
repeat imaging for confirmation. If radiologic progression is confirmed, then the subject will 
be discontinued from trial treatment.  If radiologic progression is not confirmed, then the 
subject should resume/continue trial treatment and have their next scan according to the 
every 8 week (56 ± 7 days) schedule.  
NOTE:  If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment upon consultation with the Sponsor.  Clinically stable 
subjects should also have at the confirmatory scan no further increase in the target lesions, no 
unequivocal increase in non-target lesions, and no additional new lesions develop (non-
worsening PD) to continue study treatment.
Imaging during the follow-up period is to be repeated every 8 weeks (56 ± 7 days) for 
subjects who discontinue trial treatment for reasons other than disease progression until the 
subject experiences confirmed disease progression or starts a new anti-neoplastic therapy.  
 
 
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If imaging assessment beyond the protocol-required imaging time frame is necessary for the 
subject’s continued participation in the follow-up phase of the study, an extended imaging 
schedule may be considered at the discretion of the investigator. Please refer to the applicable 
Trial Flow Chart in Section 6.0.
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1 
will be used to determine subject eligibility and for subject management.  The Sponsor will 
also receive radiologic images for a retrospective analysis of subject eligibility and treatment 
response to be performed by an independent central radiology review vendor, including 
RECIST 1.1 and evaluation of volumetric tumor response.
7.1.2.5.2 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.  The site study team must review pre-trial images to confirm the subject has 
measurable disease per RECIST 1.1.  The baseline imaging scan should be submitted to the 
independent central radiology review vendor for a retrospective analysis of this eligibility 
criterion. 
Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to the first 
dose of trial treatment.  The same imaging technique should be used in a subject throughout 
the study. 
7.1.2.5.3 Tumor Imaging During Trial
Tumor imaging may be performed by CT or magnetic resonance imaging (MRI), but the 
same imaging technique should be used in a subject throughout the trial.  Imaging should be 
performed every 8 weeks (56 days ± 7 days) from the first dose of trial treatment or more 
frequently if clinically indicated.  Imaging should not be delayed for delays in cycle starts or 
extension of MK-3475 cycle intervals.  
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (8 weeks later), whichever is clinically indicated.  
Imaging should continue to be performed until documented disease progression, the start of 
new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever 
occurs first.  Disease progression should be confirmed at least 4 weeks after the first scan 
indicating progressive disease in clinically stable subjects.  Subjects who have unconfirmed 
disease progression may continue on treatment until progression is confirmed provided they 
have met the conditions detailed in Section 7.1.2.5.1.
 
 
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7.1.2.6
Tumor Tissue Collection and Correlative Studies Blood Sampling
Enrollment in this study is limited to those subjects with tumors who have submitted archival 
FFPE tumor sample or newly obtained core or excisional biopsy (FNA not adequate) to a 
central lab for PD-L1 characterization.. These samples are not required to be obtained within 
28 days of enrollment, however, a biopsy for screening purposes cannot be performed until 
the main consent is signed.
Enrollment in Cohorts A, B, C and D of this study is limited to those subjects with tumors 
characterized as PD-L1 positive by IHC at a central laboratory.  
Subjects in Cohort B2 should submit both archival FFPE tumor samples and newly obtained 
biopsy samples (as described below) to the central laboratory.  PD-L1 expression by IHC 
will be evaluated retrospectively.  The tumor biopsy specimen must be sufficient for 
assessment of PD-L1 expression by the central lab or an additional sample will be required. 
Exceptions to this requirement must be discussed with the Sponsor prior to enrollment in the 
study. 
Biopsy sites should be selected so that subsequent biopsies can be performed at the same 
location.  Exceptions from the mandatory tumor biopsy requirement that allow subjects to 
continue receiving trial treatment must occur in consultation with the Sponsor.  
Blood for correlative biomarker studies should be collected at baseline, on treatment and 
upon treatment discontinuation.  The treatment sample should be collected at Cycle 5 
(subjects enrolled in Cohorts A, B, C and D) or Cycle 3 (subjects enrolled in Cohort B2) as 
appropriate.
Serial tumor biopsy requirements for each cohort are detailed below:
Cohort A – TNBC
Every effort should be made to obtain an optional biopsy prior to Cycle 1 initiation of MK-
3475, at Cycle 5, and upon disease progression.  If clinical activity of MK-3475 is observed 
(2 responders in Cohort A), the pre-dose Cycle 1 biopsy and the biopsy at Cycle 5 will 
become mandatory for all remaining subjects enrolled into the cohort.  A tumor biopsy at 
treatment discontinuation is highly encouraged for all subjects.  Tumor biopsies that are 
inaccessible or contraindicated due to subject safety concerns are exempt from this 
requirement.  
Cohort B – H/N Cancer
Tumor biopsies are mandatory for subjects prior to Cycle 1 initiation of MK-3475 and again 
at Cycle 5.  A tumor biopsy at treatment discontinuation is highly encouraged.  Tumor 
biopsies that are inaccessible or contraindicated due to subject safety concerns are exempt 
from this requirement.
 
 
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Cohort B2 – H/N Cancer
Newly obtained tumor biopsies are mandatory for subjects prior to Cycle 1 initiation of MK-
3475 and again at Cycle 3.  Exemptions to the mandatory tumor biopsy require Sponsor 
approval and appropriate justification.   A tumor biopsy at the time of treatment 
discontinuation is highly encouraged.
Cohort C – Urothelial Tract Cancer
Every effort should be made to obtain an optional biopsy prior to Cycle 1 initiation of MK-
3475, at Cycle 5, and upon disease progression.  If clinical activity of MK-3475 is observed 
(2 responders in Cohort C), the pre-dose Cycle 1 biopsy and the biopsy at Cycle 5 will 
become mandatory for all remaining subjects enrolled into the cohort.  A tumor biopsy at 
treatment discontinuation is highly encouraged for all subjects.  Tumor biopsies that are 
inaccessible or contraindicated due to subject safety concerns are exempt from this 
requirement.  
Cohort D – Gastric Cancer
Tumor biopsies are mandatory for subjects prior to Cycle 1 initiation of MK-3475 and again 
at Cycle 5.  A tumor biopsy at treatment discontinuation is highly encouraged.  Tumor 
biopsies that are inaccessible or contraindicated due to subject safety concerns are exempt 
from this requirement.
Detailed instructions for tissue collection, process and shipment are provided in the 
Procedures Manual.  
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7.
 
 
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Table 7
Laboratory Tests
Hematology‡
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum 
β-human 
chorionic 
gonadotropin (β-hCG)†
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT
WBC 
(total 
and 
differential)
Aspartate aminotransferase (AST)
Specific gravity 
Total triiodothyronine (T3)¶
Red 
Blood 
Cell 
Count
Lactate dehydrogenase (LDH)
Microscopic 
exam, 
if 
abnormal results are notedǁ
Free thyroxine (T4)
Absolute Neutrophil 
Count
Carbon 
Dioxide§
(CO2
or 
bicarbonate)
Urine pregnancy test*
Thyroid stimulating hormone 
(TSH)
Absolute 
Lymphocyte Count
Creatinine††
Anti-MK-3475 Antibodies
Uric Acid
PK
Calcium
Blood for FBR
Chloride
Blood for correlative studies
Glucose
Phosphorus
Potassium  
Sodium
Magnesium
Total Bilirubin
Direct Bilirubin, if total bilirubin is 
elevated above the upper limit of 
normal
Total protein
Blood Urea Nitrogen
†
Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.
‡
Either differential or absolute value is acceptable
§
If considered standard of care in your region
ǁ
Institutional standards are acceptable
¶
Free T3 may be performed in place of Total T3 per local standards
†† GFR (measured or calculated) or CrCl can be used in place of creatinine
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.
 
 
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7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures Manual.
The time points for PK blood sampling are described in Section 6 – Trial Flow Chart.
Please note that PK blood sampling will occur in Cohorts A, B, C, and D only.  Subjects in 
Cohort B2 (H/N expansion) will not undergo PK blood sampling.
7.1.3.2.2 Blood Collection for Anti-MK-3475 Antibodies
Sample collection, storage and shipment instructions for blood samples will be provided in 
the Procedures Manual.
Please note that blood collection for anti-MK-3475 antibodies will occur in Cohorts A, B, C, 
and D only.  Subjects in Cohort B2 (H/N expansion) will not undergo blood collection for 
anti-MK-3475 antibodies.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover archival tumor tissue or leftover newly obtained biopsy samples taken 
throughout the study
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
Subjects who a) attain a CR or b) complete 24 months of 
treatment with MK-3475 may discontinue treatment with the option of restarting treatment if 
they meet the criteria specified in Section 7.1.5.2.1.  After discontinuing treatment following 
assessment of CR, these subjects should return to the site for a Safety Follow-up Visit 
(described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4).
 
 
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7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
7.1.5.1.1 Pre-screening Period
The Pre-screening period may be utilized by subjects in Cohorts A, B, C and D to determine 
biomarker eligibility based on PD-L1 status using an archival tumor biopsy sample.  After 
providing a pre-screening consent, subjects will be assigned a screening number. 
Characterization of PD-L1 status will be performed at a pre-screening visit for subjects with 
an available archival tumor biopsy sample.  
Subjects that do not have an archival tumor biopsy sample available must provide written 
consent for the main study before the tumor biopsy or any other protocol-specified 
procedures can occur.  These subjects will not enter the pre-screening period as eligibility 
based on PD-L1 expression will be determined in the main study screening period.
As PD-L1 tumor expression is not an inclusion criterion for subjects in Cohort B2, the Pre-
screening period is not relevant for this cohort and all subjects in this cohort will begin the 
study in the Screening Period.
 
 
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7.1.5.1.2 Screening Period
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1.  Visit requirements are 
outlined in Section 6.0 – Trial Flow Chart.  
Written consent for the main study must be obtained prior to performing any protocol 
specific procedure.  Results of a test performed prior to the subject signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.  Screening procedures are to be completed within 28 days prior to the 
first dose of trial treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the 
local study site laboratory)

Biopsy for PD-L1 characterization is not required to be obtained within 28 days prior 
to the first dose of trial treatment
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.2
Treatment Period
7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects who stop MK-3475 with SD or better may be eligible for up to one year of 
additional MK-3475 therapy if they progress after stopping MK-3745.  This retreatment is 
termed the Second Course Phase of this study and is only available if the study remains open 
and the subject meets the following conditions:

Either 
o
Stopped initial treatment with MK-3475 after attaining an investigator-
determined confirmed CR according to RECIST 1.1

Was treated for at least 24 weeks with MK-3475 before discontinuing 
therapy

Received at least two treatments with MK-3475 beyond the date when 
the initial CR was declared
 
 
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OR
o
Subject had SD, PR or CR and stopped MK-3475 treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with MK-3475

Did not receive any anti-cancer treatment since the last dose of MK-3475

Have a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrate adequate organ function as detailed in Section 5.1.2

Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year. 

Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.  

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 MK-3475.  Treatment will be administered for up to one additional year.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
7.1.5.3
Post-Treatment Visits
7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-neoplastic treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  
 
 
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SAEs that occur within 90 days of the end of treatment or 30 days after the end of treatment 
if the subject initiates new anticancer therapy should also be followed and recorded.  
Subjects who are eligible for retreatment with MK-3475 (as described in Section 7.1.5.2.1) 
may have up to two safety follow-up visits, one after the Treatment Period and one after the 
Second Course Phase.
7.1.5.4
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8 weeks (56 ± 7 days) by 
radiologic imaging to monitor disease status. If imaging assessment beyond the protocol-
required imaging time frame is necessary for the subject’s continued participation in the 
follow-up phase of the study, an extended imaging schedule may be considered at the 
discretion of the investigator. Please refer to the applicable Trial Flow Chart in Section 6.0.
Every effort should be made to collect information regarding disease status until the start of 
new anti-neoplastic therapy, disease progression, death, end of the study or if the subject 
begins retreatment with MK-3475 as detailed in Section 7.1.5.2.1.  Information regarding 
post-study anti-neoplastic treatment will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with MK-3475 according to the criteria in 
Section 7.1.5.2.1 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment.  
7.1.5.4.1 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-neoplastic 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone approximately every 12 weeks (+/- 4 weeks) to assess for survival status until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
7.1.5.5
Survival Status
To ensure current and complete survival data are available at the time of database locks, 
updated survival data may be requested during the course of the trial by the Sponsor.  For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee 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 
who have a previously recorded death event in the collection tool).
 
 
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7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
From the time of randomization/treatment allocation through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
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.
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose. No specific information is available on 
the treatment of overdose of MK-3475. In the event of overdose, MK-3475 should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder.
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.  
Pregnancies and lactations that occur from the time of randomization/treatment allocation 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. 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).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 8 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study (reference Section 7.2.3.3 
for additional details), that occurs to any subject must be reported within 24 hours to the 
Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
For the time period beginning at randomization/treatment allocation through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
 
 
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All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at randomization/treatment allocation through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any 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.
 
 
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3. Additional adverse events:
A separate guidance document has been provided entitled Event of Clinical Interest Guidance 
Document” (previously entitled “Event of Clinical Interest and Immune-Related Adverse 
Event Guidance Document”).  This document can be found in the administrative binder and 
provides guidance regarding identification, evaluation and management of ECIs and irAEs.  
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.
Events of clinical interest that occur to any subject from the date of first dose through 90 
days following cessation of treatment, or 30 days after the end of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, whether or not related to the Sponsor's 
product, must be reported within 24 hours to the Sponsor either by electronic media or paper.  
Sponsor Contact information can be found in the administrative binder.
7.2.3.3
Protocol-Specific Exceptions to Serious 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
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
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Table 8
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
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 U.S. CLINICAL 
MONITOR 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
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice. 
8.0 STATISTICAL ANALYSIS PLAN
8.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
The primary purpose of this study is to:

investigate the safety, tolerability, and anti-tumor activity of MK-3475 10 mg/kg 
Q2W administered intravenously to subjects with PD-L1 positive triple negative 
advanced breast cancer (Cohort A), subjects with PD-L1 positive advanced head and 
neck cancer (Cohort B), subjects with PD-L1 positive advanced urothelial tract 
cancer (Cohort C), and subjects with PD-L1 positive advanced gastric cancer (Cohort 
D).

investigate the safety, tolerability, and anti-tumor activity of MK-3475 200 mg Q3W 
administered intravenously to subjects with advanced head and neck cancer 
irrespective of PD-L1 expression (Cohorts B2).
Efficacy Analyses
8.1.1
The full analysis set (FAS) population (defined as all subjects with a baseline scan with 
measurable disease; by independent central radiology review for each cohort, and who either 
have a post baseline scan or discontinue the trial due to progressive disease or a drug-related 
AE) will serve as the primary population for the analyses of efficacy data in this trial. 
Supportive analyses of efficacy will be conducted in the all subjects as treated (ASaT) 
population and the FAS population by Investigator review.  For each cohort, overall response 
rate will be used as the primary endpoint for efficacy assessment.  A 95% confidence interval 
along with a one-sided p-value for testing the null hypothesis based on the binomial 
distribution will be provided for the response rate in each cohort.  The respective cohort is 
considered to have reached the efficacy objective if the corresponding p-value for testing the 
respective null hypothesis is less than 2.5%.  An outline of the efficacy analysis strategy is 
presented in Table 9 below.
 
 
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Table 9
Primary Analysis Strategy for Efficacy Endpoints
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary:
Overall RECIST 1.1 
response rate based on 
independent central 
radiology review (Cohort A, 
Cohort B HPV negative 
subjects, Cohort C, and 
Cohort D evaluated 
separately)
Exact test of binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Overall RECIST 1.1  
response rate based on 
independent central 
radiology review for subjects
in Cohort B2 
Exact test of binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Secondary:
Overall RECIST1.1 
response rate based on
independent central 
radiology review, Cohort B 
HPV positive subjects, 
Exact test of binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Overall RECIST 1.1
response rate based on 
independent central 
radiology review, Cohort D 
AP subjects.
Exact test of binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Overall RECIST 1.1 
response rate based on based 
on independent central 
radiology review, for 
subjects previously treated 
with cetuximab and platinum 
in Cohorts B and B2 
Exact test of binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Overall RECIST 1.1 
response rate based on 
investigator assessment for 
cohorts A,B, C and D
Exact methods for binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Overall RECIST 1.1 
response rate based on 
investigator assessment for 
Cohort B2
Exact methods for binomial 
parameter
FAS
Subjects with 
missing data are 
considered non-
responders
Progression-free survival
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
Overall survival
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
Response duration
Summary statistics using 
Kaplan-Meier method
All responders
Non-responders are 
excluded in analysis
‡ For Cohort D, the analyses for the Asia Pacific (AP) population will be performed as appropriate.
 
 
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Safety Analyses
8.1.2
The All-Subjects-as-Treated population will be employed for safety analyses.  
Power and Sample Size 
8.1.3
The calculation of power and sample size for each cohort does not account for interim 
analysis.  Cohort A (triple negative breast cancer subjects): With approximately 26 evaluable 
PD-L1 positive subjects with triple negative breast cancer, the study has approximately 80% 
power to detect a 25% difference in ORR under the null hypothesis of ORR=20% with a type 
I error rate of 2.5% if the true ORR is 45%.  Success for this hypothesis requires at least 
10/26 responses.  The actual number of subjects enrolled may be larger than 26 to ensure that 
at least 26 subjects are evaluable for analysis.
Cohort B (head and neck cancer subjects): HPV negative head and neck cancer subjects will 
be evaluated separately from HPV positive head and neck cancer subjects.  With a maximum 
of 22 evaluable PD-L1 positive subjects with HPV negative head and neck cancer, the study 
has approximately 80% power to detect a 25% difference in ORR under the null hypothesis 
of ORR=10% with a type I error rate of 2.5% if the true ORR is 35%.  Success for this 
hypothesis requires at least 6/22 responses.  The actual number of subjects enrolled may be 
larger than 22 to ensure that at least 22 subjects are evaluable for analysis.
With a maximum of 12 evaluable PD-L1 positive subjects with HPV positive head and neck 
cancer, the study has approximately 73% power to detect a 35% difference in ORR under the 
null ORR=20% with a type I error rate of 5% if the true ORR is 55%.  Success for this 
hypothesis requires at least 6 responses.  The actual number of subjects enrolled may be 
larger than 12 to ensure that at least 12 subjects are evaluable for analysis.  However, if 6 
responses are observed prior to 12 subjects with HPV positive head and neck cancer 
enrolling in the trial, enrollment may be stopped in this group as the hypothesis success 
criterion will have been reached.
Cohort C (urothelial tract cancer subjects): With a maximum of 22 evaluable PD-L1 positive 
subjects with urothelial tract cancer, the study has approximately 80% power to detect a 25% 
difference in ORR under the null hypothesis of ORR=10% with a type I error rate of 2.5% if 
the true ORR is 35%.  Success for this hypothesis requires at least 6/22 responses.  The 
actual number of subjects enrolled may be larger than 22 to ensure that at least 22 subjects 
are evaluable for analysis.
Cohort D (gastric cancer subjects): With a maximum of 32 evaluable PD-L1 positive subjects 
with gastric cancer, stratified to include 16 Asia Pacific (AP) and 16 non-AP, the study has 
approximately 90% power to detect a 25% difference in ORR under the null hypothesis of 
ORR=15% with a type I error rate of 2.5% if the true ORR is 40%.  Success for this 
hypothesis requires at least 10/32 responses. 
A total of 16 AP subjects will provide 
approximately 80% power with a type I error rate of 0.1 to detect a 25% difference in ORR 
under the null hypothesis of ORR=15% if the true ORR is 40%. At least 4/16 responses will 
be needed to claim the success of this hypothesis for AP population. The actual number of 
subjects enrolled may be larger than 32 to ensure that at least 32 subjects are evaluable for 
analysis.
 
 
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Cohort B2 (head and neck cancer subjects, expansion cohort): With 100 evaluable subjects in 
Cohort B2, the study provides >99% power to detect a 15% difference in ORR under the null 
hypothesis of ORR=5% with a type I error rate of 2.5% if the true ORR is 20%. Success for 
this hypothesis requires at least 11/100 responses.  The actual number of subjects enrolled 
may be larger than 100 to ensure at least 100 subjects are evaluable for analysis.
Cohorts B and B2 previously treated with cetuximab and platinum: With 60 evaluable head 
and neck cancer subjects previously treated with cetuximab and platinum, the study has 93% 
power to detect a 15% difference in ORR under the null hypothesis of ORR=5% with a type I 
error rate of 2.5% if the true ORR is 20%. Success for this hypothesis requires at least 8/60
responses.
Interim Analysis
8.1.4
No efficacy interim analyses are planned for Cohort B2 or Cohort D in this trial.  However, 
an interim analysis for Cohort A, B or C may be performed if the rate of enrollment is much 
slower than anticipated during the course of the trial.  An interim analysis for each cohort
would only be performed in this study when ≥10 subjects in the respective cohort have had 
post-baseline scans through Week 16.  Results will be reviewed by the study team.  Table 10
summarizes the strategy and timing of the potential interim analysis for each cohort. 
For Cohort A, if an interim analysis is conducted and 2 or fewer subjects out of the first 10 
subjects with post-baseline imaging scans (Week 16) have a confirmed or unconfirmed 
response, then enrollment may be paused until response data for the subsequent imaging scan 
(Week 24) are reviewed for subjects already enrolled in the trial.  Enrollment may be 
resumed if the binomial probability of the observed response rate is 80% under the 
assumption of a 20% true response rate  (e.g., ≥4/16 confirmed or unconfirmed response).
For Cohorts B (HPV negative subjects only) and C, if an interim analysis is conducted and 1 
or fewer subjects out of the first 10 subjects with post-baseline imaging scans (Week 16) 
have a confirmed or unconfirmed response, then enrollment may be paused until response 
data for the subsequent imaging scan (Week 24) are reviewed for subjects already enrolled in 
the trial.  Enrollment may be resumed if the binomial probability of the observed response 
rate is 80% under the assumption of a 10% true response rate (e.g., ≥2/16 confirmed or 
unconfirmed response). No interim analysis will be performed for the subjects with HPV 
positive head and neck cancer in Cohort B.
Although safety monitoring will occur continuously in the study, an assessment of Grade 4/5 
drug-related immunologic AEs will be performed after 10 subjects have been enrolled within 
each cohort for 1 cycle of therapy.  Enrollment will be paused if 4 or more subjects out of the 
first 10 subjects within a cohort experience a Grade 4/5 drug-related immunologic adverse 
event.  Enrollment may be resumed within a cohort only after a full safety evaluation is 
performed in consultation between the study investigators and the Sponsor.
 
 
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Table 10
Summary of Interim Analysis Strategy
Interim Analysis 
Number
Key Endpoints 
for Interim 
Analysis
Timing (Sample 
Size) for Analysis
Purpose of Analysis
Interim Analysis Cohort A
ORR
≥10 subjects with
post-baseline scans 
(Week 16)
Pause enrollment until 
further evidence of 
efficacy
Pause enrollment for 
safety based on Grade 4+ 
drug-related immunologic 
AEs out of first 10 
subjects
Interim Analysis Cohort B
(HPV negative subjects 
only)
ORR
≥10 subjects with 
post-baseline scans 
(Week 16)
Pause enrollment until 
further evidence of 
efficacy
Pause enrollment for 
safety based on Grade 4+ 
drug-related immunologic 
AEs out of first 10 
subjects
Interim Analysis Cohort C
ORR
≥10 subjects with 
post-baseline scans 
(Week 16)
Pause enrollment until 
further evidence of 
efficacy
Pause enrollment for 
safety based on Grade 4+ 
drug-related immunologic 
AEs out of first 10 
subjects
8.2
Statistical Analysis Plan
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.  Access to the PD-L1 subject-level biomarker results for 
subjects in Cohort B2 for the purpose of summary reporting of PD-L1 level until the time 
that a clinical study report (CSR) is generated will be limited to an unblinded SPONSOR 
statistician and unblinded SPONSOR statistical programmer who will be responsible for data 
review to ensure validity of results and summary reporting of clinical response by biomarker 
status, but who will have no other responsibilities associated with the study.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.  Allocation will be implemented in an interactive voice response 
system (IVRS).
 
 
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Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
8.2.3.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Efficacy and safety endpoints that will be evaluated for are listed below, followed by the 
descriptions of the derivations of selected endpoints.
The primary efficacy endpoint is response rate, defined as the proportion of subjects in the 
analysis population who have complete response (CR) or partial response (PR) using 
RECIST 1.1 criteria at any time during the study.  Response for the primary analysis for 
cohorts A, B, C, D and B2 will be determined by a central independent radiology review.
Secondary analyses will be based on the responses as assessed by the investigator.
Key secondary efficacy endpoints include:

RECIST 1.1 response rate among HPV positive subjects.

Response rate based on site assessments using RECIST 1.1.
Other secondary efficacy endpoints include: (1) duration of response, defined as time from 
first RECIST 1.1 response to disease progression in subjects who achieve a PR or better; (2) 
progression-free survival (PFS), defined as the time from allocation to the first documented 
disease progression according to RECIST 1.1 or death due to any cause, whichever occurs 
first; and (3) overall survival (OS).  
8.2.3.2
Safety Endpoints
A description of safety measures is provided in Section 4.2.3.2.  
The primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who have 
received MK-3475, including serious adverse events (SAEs) and events of clinical interest 
(ECIs).  Immune-related ECIs, as described in Section 7.2.3.2 will be collected.  Other safety 
endpoints include laboratory safety assessments, ECOG performance status, vital signs and 
physical examinations.
 
 
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Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all randomized subjects in 
each Cohort who:

Receive at least one dose of study treatment,

Have a baseline scan with measurable disease per RECIST 1.1 by independent central 
radiology review, and 

Have a post baseline scan OR discontinue the trial due to progressive disease/drug 
related AE
For secondary by Investigator assessment, measurable disease for inclusion in the FAS 
population will be defined using Investigator assessment of the baseline scan.  
A supportive analysis using the All Subjects as Treated (ASaT) population, defined as all 
randomized subjects, who received at least one dose of study treatment, will be performed for 
the primary efficacy endpoint(s).  
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data.  Details on the approach to handling missing data are provided in 
Section 8.2.5 Statistical Methods.
8.2.4.2
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all allocated subjects who received at least one 
dose of study treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
Statistical Methods
8.2.5
Statistical testing and inference for safety analyses are described in 8.2.5.2. Efficacy results 
that will be considered to be statistically significant after consideration of the strategy for 
controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values 
may be computed for other efficacy analyses as a measure of strength of association between 
the endpoint and the treatment effect rather than formal tests of hypotheses.  Unless 
otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
 
 
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8.2.5.1
Statistical Methods for Efficacy Analyses
Efficacy will be evaluated separately in each cohort.  For the primary efficacy endpoint 
independent centrally reviewed RECIST 1.1 response rate, the point estimate, exact 95% 
Clopper-Pearson confidence interval, and p-value for testing the RECIST 1.1 response rate is 
greater than the historical control for each cohort will be provided using exact binomial 
distribution.  Subjects in the primary analysis population (FAS) without response data will 
be counted as non-responder.
Secondary efficacy evaluations of RECIST 1.1 response based on Investigator assessment 
will also be conducted using the same methodology as for the primary efficacy analysis.  
Efficacy for the secondary analysis of RECIST 1.1 response by independent central 
radiology review among subjects with HPV positive head and neck cancer will be evaluated 
in the same manner as in the primary analysis.  
For PFS endpoint, Kaplan-Meier (KM) curves and median estimates from the KM curves
will be provided as appropriate. Subjects without efficacy evaluation data or without survival 
data will be censored at Day 1. Table 11 summarizes the key efficacy analyses.
Table 11
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data Approach
Overall RECIST 1.1 response rate based on 
independent central radiology review 
(Cohort A, Cohort B HPV negative 
subjects, Cohort C, and Cohort D
evaluated separately)
Exact test of 
binomial 
parameter
FAS (Primary)
ASaT  (Supportive)
Subjects with missing 
data are considered 
non-responders
Overall RECIST 1.1  response rate based 
on  independent central radiology review 
for subjects in Cohort B2 
Exact test of 
binomial 
parameter
FAS (Primary)
ASaT (Supportive)
Subjects with missing 
data are considered 
non-responders
Overall RECIST1.1  response rate based on 
independent central radiology review, 
Cohort B HPV positive subjects, 
Exact test of 
binomial 
parameter
FAS (Primary)
ASaT (Supportive)
Subjects with missing 
data are considered 
non-responders
Overall RECIST 1.1 response rate based on 
independent central radiology review, 
Cohort D AP subjects.
Exact test of 
binomial 
parameter
FAS (Primary)
ASaT (Supportive)
Subjects with missing 
data are considered 
non-responders
Overall RECIST 1.1 response rate based 
on based on independent central 
radiology review, for subjects previously 
treated with cetuximab and platinum in 
Cohorts B and B2 
Exact test of 
binomial 
parameter
FAS (Primary)
ASaT (Supportive)
Subjects with missing 
data are considered 
non-responders
Overall RECIST 1.1 response rate based on 
investigator assessment for cohorts A,B, C 
and D
Exact methods for 
binomial 
parameter
FAS (Primary)
ASaT (Supportive)
Subjects with missing 
data are considered 
non-responders
Overall RECIST 1.1 response rate based on 
investigator assessment for Cohort B2
Exact methods for 
binomial 
parameter
FAS (Primary)
ASaT (Supportive)
Subjects with missing 
data are considered 
non-responders
 
 
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Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data Approach
Progression-free survival
Summary 
statistics using 
Kaplan-Meier
method
FAS(Primary)
ASaT (Supportive)
Censored at last 
assessment
Overall survival
Summary 
statistics using 
Kaplan-Meier 
method
FAS(Primary)
ASaT (Supportive)
Censored at last 
assessment
Response duration
Summary 
statistics using 
Kaplan-Meier 
method
All responders
Non-responders are 
excluded in analysis
The strategy to address multiplicity issues with regard to multiple efficacy endpoints is 
described in Section 8.2.6, Multiplicity and Section 8.2.9, Interim Analyses.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. 
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate. The 80% confidence interval for the incidence rate of 
Grade 2 or higher adverse events with an immune etiology and the incidence rate of Grade 
4/5 AEs will be provided as appropriate.  
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.3.1
Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs for each cohort.  
No statistical hypothesis tests will be performed on these characteristics.  The number and 
percentage of subjects screened, randomized, the primary reasons for screening failure, and 
the primary reason for discontinuation will be displayed.  Demographic variables (e.g., age, 
gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
Multiplicity
8.2.6
The false positive rate for testing the primary efficacy endpoint in each cohort (Cohort A, 
Cohort B, Cohort C, Cohort D, and Cohort B2) is controlled at 0.025 (1-sided) for each 
cohort.  
If the primary hypothesis in Cohort B2 is successful, then alpha=0.025 (1-sided) will be 
passed to the secondary evaluation of subjects in Cohort B and Cohort B2 with prior 
exposure to cetuximab and platinum therapy in a step down approach.
 
 
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Sample Size and Power Calculations
8.2.7
The calculation of power and sample size for each cohort does not account for interim 
analysis.  Cohort A (triple negative breast cancer subjects): With approximately 26 evaluable 
PD-L1 positive subjects with triple negative breast cancer, the study has approximately 80% 
power to detect a 25% difference in ORR under the null hypothesis of ORR=20% with a type 
I error rate of 2.5% if the true ORR is 45%.  The null hypothesis rate of 20% is based on the 
historic response rate in large phase III trials for standard single agent chemotherapy in 2 nd
line breast cancer utilizing WHO-based bi-dimensional responses [34, 35, 36].  Success for 
this hypothesis requires at least 10/26 responses.  The actual number of subjects enrolled may 
be larger than 26 to ensure that at least 26 subjects are evaluable for analysis.  
Cohort B (head and neck cancer subjects): HPV negative head and neck cancer subjects will 
be evaluated separately from HPV positive head and neck cancer subjects.  With a maximum 
of 22 evaluable PD-L1 positive subjects with HPV negative head and neck cancer, the study 
has approximately 80% power to detect a 25% difference in ORR under the null hypothesis 
of ORR=10% with a type I error rate of 2.5% if the true ORR is 35%.  Success for this 
hypothesis requires at least 6/22 responses.  The actual number of subjects enrolled may be 
larger than 22 to ensure that at least 22 subjects are evaluable for analysis.
With a maximum of 12 evaluable PD-L1 positive subjects with HPV positive head and neck 
cancer, the study has approximately 73% power to detect a 35% difference in ORR under the 
null ORR=20% with a type I error rate of 5% if the true ORR is 55%.  The null hypothesis 
rate of 20% is based on historic response of chemotherapy in head and neck cancer trials [37, 
38].  Success for this hypothesis requires at least 6 responses.  The actual number of subjects 
enrolled may be larger than 12 to ensure that at least 12 subjects are evaluable for analysis.  
However, if 6 responses are observed prior to 12 subjects with HPV positive head and neck 
cancer enrolling in the trial, enrollment may be stopped in this group as the hypothesis 
success criterion will have been reached.
Cohort C (urothelial tract cancer subjects): With a maximum of 22 evaluable PD-L1 positive 
subjects with urothelial tract cancer, the study has approximately 80% power to detect a 25% 
difference in ORR under the null hypothesis of ORR=10% with a type I error rate of 2.5% if 
the true ORR is 35%.  The null hypothesis rate of 10% is based on the historic response rate 
of single agent pemetrexed (RR 6%) or vinflunine (RR 9%) chemotherapy for bladder cancer
[39, 40].  Success for this hypothesis requires at least 6/22 responses.  The actual number of 
subjects enrolled may be larger than 22 to ensure that at least 22 subjects are evaluable for 
analysis.
Cohort D (gastric cancer subjects): With a maximum of 32 evaluable PD-L1 positive subjects 
with gastric cancer, stratified to include 16 Asia Pacific (AP) and 16 non-AP, the study has 
approximately 90% power to detect a 25% difference in ORR under the null hypothesis of 
ORR=15% with a type I error rate of 2.5% if the true ORR is 40%. Success for this 
hypothesis requires at least 10/32 responses.  A total of 16 AP subjects will provide 
approximately 80% power with type I error rate of 0.1 to detect a 25% difference in ORR 
under the null hypothesis of ORR=15% if the true ORR is 40%. At least 4/16 responses will 
 
 
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be needed to claim the success of this hypothesis for the AP population. The null hypothesis 
rate of 15% is based on the response rate in large (n > 100), trials for standard of care 
chemotherapy irinotecan/mFOLFIRI (RR 12%), and irinotecan/docetaxel (RR 13%) for 2nd
line metastatic gastric cancer [28, 29].  The actual number of subjects enrolled may be larger 
than 32 to ensure that at least 32 subjects are evaluable for analysis.
Cohort B2 (head and neck cancer subjects, expansion cohort): With 100 evaluable subjects in 
Cohort B2, the study provides >99% power to detect a 15% difference in ORR under the null 
hypothesis of ORR=5% with a type I error rate of 2.5% if the true ORR is 20%.  Success for 
this hypothesis requires at least 11/100 responses.  The null hypothesis rate of 5% is based on 
historic response of chemotherapy in head and neck cancer trials [37].  The actual number of 
subjects enrolled may be larger than 100 to ensure at least 100 subjects are evaluable for 
analysis.
Cohorts B and B2 previously treated with cetuximab and platinum: With 60 evaluable head 
and neck cancer subjects previously treated with cetuximab and platinum, the study has 93% 
power to detect a 15% difference in ORR under the null hypothesis of ORR=5% with a type I 
error rate of 2.5% if the true ORR is 20%.  Success for this hypothesis requires at least 8/60 
responses.  The null hypothesis rate of 5% is based on historic response of chemotherapy in 
head and neck cancer trials [37].
Subgroup Analyses and Effect of Baseline Factors
8.2.8
Efficacy will be summarized for the key endpoints for the following subgroups:

HPV-positive vs. HPV negative head/neck cancer 

Subjects with head/neck cancer enrolled in Cohort B and Cohort B2 with prior 
cetuximab and platinum exposure.
Interim Analyses
8.2.9
8.2.9.1
Efficacy Interim Analyses
No efficacy interim analyses are planned in this trial.  
However, an interim analysis for Cohort A, B, or C may be performed if the rate of 
enrollment is much slower than anticipated during the course of the trial.  An interim analysis 
for each cohort would only be performed in this study when ≥10 subjects in the respective 
cohort have had scans through Week 16.  Results will be reviewed by the study team.
For Cohort A, if an interim analysis is conducted and 2 or fewer subjects out of the first 10 
subjects with post-baseline imaging scans (Week 16) have a confirmed or unconfirmed 
response, then enrollment may be paused until response data for the subsequent imaging scan 
(Week 24) are reviewed for subjects already enrolled in the trial.  Enrollment may be 
resumed if the binomial probability of the observed response rate is 80% under the 
assumption of a 20% true response rate (e.g., ≥4/16 confirmed or unconfirmed response).  
 
 
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The operating characteristics of the interim analysis rule are provided in Table 12.  The 
power in Cohort A (assuming true ORR of 45%) decreases to ~77% if the interim analysis is 
conducted.
Table 12
Operating Characteristics of Interim Analysis Rule for Triple Negative Breast 
Cancer – Pause Enrollment if ≤2/10 Subjects Respond
True ORR
Probability of Pausing 
Enrollment
Probability of Study Success
10%
0.93
<0.01
15%
0.82
<0.01
20%
0.68
0.02
25%
0.53
0.08
30%
0.38
0.21
35%
0.26
0.39
40%
0.17
0.60
45%
0.10
0.77
50%
0.06
0.88
For Cohorts B (HPV negative) and C, if an interim analysis is conducted and 1 or fewer 
subjects out of the first 10 subjects with post-baseline imaging scans (Week 16) have a 
confirmed or unconfirmed response, then enrollment may be paused until response data for 
the subsequent imaging scan (Week 24) are reviewed for subjects already enrolled in the 
trial.  Enrollment may be resumed if the binomial probability of the observed response rate is 
80% under the assumption of a 10% true response rate (e.g., ≥2/16 confirmed or 
unconfirmed response).   The operating characteristics of the interim analysis rule are 
provided in Table 13.  The power in Cohort B (HPV negative) and Cohort C (assuming true 
ORR of 35%) does not substantially decrease from 80% as a result of conducting the interim 
analysis.
Table 13
Operating Characteristics of Interim Analysis Rule for Head/Neck Cancer 
(HPV negative) and Urothelial Cancer– Pause Enrollment if ≤1/10 subjects 
respond
True ORR
Probability of Pausing 
Enrollment
Probability of Study Success
5%
0.91
<0.01
10%
0.74
0.02
15%
0.54
0.09
20%
0.38
0.25
25%
0.25
0.45
30%
0.15
0.65
35%
0.09
0.80
40%
0.05
0.90
45%
0.02
0.95
 
 
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8.2.9.2
Safety Interim Analyses
Although safety monitoring will occur continuously in the study, an assessment of Grade 4/5 
drug-related immunologic AEs will be performed after 10 subjects have been enrolled within 
each cohort for 1 cycle of therapy.  Enrollment will be paused if 4 or more subjects out of the 
first 10 subjects within a cohort experience a Grade 4/5 drug-related immunologic adverse 
event.  Enrollment may be resumed within a cohort only after a full safety evaluation is 
performed in consultation between the study investigators and the Sponsor.  
The estimate of and the upper bound of the 95% confidence interval for the underlying 
percentage of subjects with a Grade 4/5 drug-related immunologic adverse event given 
various hypothetical observed number of subjects are provided in Table 14. These 
calculations are based on the exact binomial method proposed by Clopper and Pearson [41].
Table 14
Estimate of Incidence of Grade 4/5 events and 95% Upper Confidence Bound 
Based on Hypothetical Number of Subjects with Event Out of 10 Subjects 
Evaluated
Hypothetical Number of 
Subjects
With Grade 4/5 Event
Estimate of 
Incidence
95% Upper Confidence 
Bound†
0
0%
30.9%
1
10%
44.5%
2
20%
55.6%
3
30%
65.2%
4
40%
73.8%
5
50%
81.3%
†
Based on the two-tailed exact confidence interval of a binomial proportion [41].
Compliance (Medication Adherence)
8.2.10
A day within the study will be considered an On-Therapy day if the subject receives the 
study medication infusion. The number of days on therapy is the total number of days from 
the first day of study medication to the date of the last dose of study medication.  Compliance
with trial treatment administration will be measured by the number of administered infusions 
divided by the number of infusions that were supposed to be administered as determined by 
the number of days on therapy.
Summary statistics for the number of Days on Therapy will be provided by treatment group 
for the FAS population.
Extent of Exposure
8.2.11
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure for 
ASaT population.
 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
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 15.
Table 15
Product Descriptions
Product Name & Potency
Dosage Form
MK-3475 50 mg
Lyophilized Powder for Injection
MK-3475 100 mg/ 4mL
Solution for Injection
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Vials will be provided in an open label fashion for subject dosing.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
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.
 
 
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9.6
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign drug to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal 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.
 
 
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Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for
regulatory agency review upon request by those agencies.
10.2 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.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
 
 
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The sponsor 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 discarding 
trial and/or subject files.  
 
 
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ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
10.4 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.    
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.
 
 
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10.5 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.
10.6 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 by the Sponsor.
10.7 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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11.0 LIST OF REFERENCES
1.
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.
2.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.  
3.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
4.
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.  
5.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
6.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.  
7.
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.
8.
Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.  
9.
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7.
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.  
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.  
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.  
 
 
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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.  
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.  
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.  
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.  
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.  
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.  
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.  
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-
24.  
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.  
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.  
 
 
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25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.  
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.  
28. Kang J, Lee S, Lim D, Park K, Oh S, Kwon H, et al.  Salvage chemotherapy for 
pretreated gastric cancer: a randomized Phase III trial comparing chemotherapy plus best 
supportive care with best supportive care alone.  J Clin Oncol 2012; 30(13): 1513-18. .  
29. Sym SJ, Ryu MH, Lee JL, Change HM, Kim TW, Lee SS, et al.  Salvage chemotherapy 
with biweekly irinotecan, plus 5-fluorouracil and leucovorin in patients with advanced 
gastric cancer previously treated with fluoropyrimidine, platinum, and taxane.  Am J 
Clin Oncol. 2008; 31(2):151-6.
30. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med 
2012:doi: 10.1056/NEJMoa1200690.  
31. Lyford-Pike S, Peng S, Young GD, et al.  Evidence for a role of the PD-1:PD-L1 
pathway in immune resistance of HPV-associated head and neck squamous cell 
carcinoma.  Cancer Res 2013;73(2): Published online January 3.
32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al.  New 
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). 
Eur J Cancer 2009;45(2):228-47.
33. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al.  Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria.  
Clin Cancer Res 2009;15(23):7412-20.
34. Blum JL, Jones SE, Buzdar AU, LoRusso PM, et al. Multicenter Phase II Study of 
Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer. J Clin Oncol 17: 485-
493, 1999
35. Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus 
vinorelbine monotherapy in patients with metastatic breast cancer previously treated 
with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer 
Research Group (GEICAM) trial. Lancet Oncol. 2007;8(3):219.
 
 
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36. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, et al.  Phase III Trial of 
Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-
Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193).   J Clin 
Oncol. 2003;21(4):588.
37. Stewart JSW, Ezra E.W. Cohen EEW, Licitra L, Van Herpen CML, et al.  Phase III 
Study of Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous 
Cell Carcinoma of the Head and Neck.  J Clin Oncol. 2009;27(11):1864.
38. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, et al.  Open-Label, 
Uncontrolled, Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of 
Cetuximab As a Single Agent in Patients With Recurrent and/or Metastatic Squamous 
Cell Carcinoma of the Head and Neck Who Failed to Respond to Platinum-Based 
Therapy.   J Clin Oncol. 2007;25(16):2171.
39. Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, et al.  Phase III Trial of 
Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone 
After a Platinum-Containing Regimen in Patients With Advanced Transitional Cell 
Carcinoma of the Urothelial Tract.  J Clin Oncol. 2009;27(27):4454
40. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, et al.  Phase II Study of 
Pemetrexed for Second-Line Treatment of Transitional Cell Cancer of the Urothelium.  J 
Clin Oncol. 2006;24(21):3451
41. Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 1934;26:404-413.
42. Garon E. Preliminary clinical safety and activity of MK-3475 monotherapy for the 
treatment of previously treated patients with non-small cell lung cancer.  Presented at:  
IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. 
MO18.02.
43. Robert, C., et. al, Updated Clinical efficacy and safety of MK-3475 (Anti-PD-1 
monoclonal antibody) in advanced melanoma.  Society for Melanoma Research 2013 
Congress; November 17-20, 2013; Philadelphia, PA, USA.  Pigment Cell & Melanoma 
Research: John Wiley & Sons Ltd; Volume 26, Issue 6, pages 932–1019, November 
2013.
 
 
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12.0 APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct

Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 

Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.

Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection

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. 

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.

Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  

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

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.

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.

Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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12.2 Collection and Management of Specimens for Future Biomedical Research
1. Definitions
1. 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
2. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug response.2
3. Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.2
4. DNA:  Deoxyribonucleic acid.
5. RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and tumor tissue specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug.  The DNA  and tumor tissue
specimen(s) will be stored to provide a resource for future trials conducted by Merck 
focused on the study of biomarkers responsible for how a drug enters and is removed by 
the body, how a drug works, other pathways a drug may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs, enhance our understanding of human disease and ultimately improve 
public health through development of novel treatments targeted to populations with the 
greatest need.  All specimens will be used by Merck or designees and research will be 
monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research

Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.

Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
 
 
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signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.

eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.

Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an objective 
to the main trial, this analysis is detailed in the main body of this protocol (Section 8.0 –
Statistical Analysis Plan).  These specimens will be processed, analyzed, and the 
remainder of the specimen will be destroyed.  The results of these analyses will be 
reported along with the other trial results.  A separate specimen will be obtained from 
properly-consented subjects in this protocol for storage in the biorepository for Future 
Biomedical Research.
 
 
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4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
 
 
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5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
 
 
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Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
 
 
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10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. [Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Therefore, there will not be an additional risk for the subject.]
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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12.3 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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12.4 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 MM, Creech RH, Tormey DC, Horton J, Davis TE,  
McFadden ET, Carbone PP. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol 1982;5:649-55. Eastern Cooperative Oncology Group, Robert Comis MD, 
Group Chair.
 
 
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12.5 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)
 
 
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12.6 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
13.2 Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information. Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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