Phase Ib Study of MK-3475 in Subjects With Advanced Melanoma
Phase: PHASE1
Conditions: Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02180061
12-Apr-2016
Document Date: 
Phase Ib Study of MK-3475 in Subjects with Advanced Melanoma

Product:  MK-3475 (SCH900475)
1
Protocol/Amendment No.: 041-01
MK-3475-041-01 Final Protocol
12-Apr-2016
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
Phase Ib Study of MK-3475 in Subjects with Advanced Melanoma
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 16
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
Primary Objective(s) & Hypothesis(es) .............................................................. 16
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 17
3.2
Exploratory Objectives......................................................................................... 17
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 17
Background ........................................................................................................... 17
4.1
Pharmaceutical and Therapeutic Background .................................................... 17
4.1.1
Ongoing Clinical Trials....................................................................................... 19
4.1.2
Rationale................................................................................................................ 19
4.2
Rationale for the Trial and Selected Subject Population .................................... 19
4.2.1
Rationale for Dose Selection/Regimen............................................................... 20
4.2.2
Rationale for Endpoints ...................................................................................... 20
4.2.3
4.2.3.1
Safety Endpoints .......................................................................................... 20
4.2.3.2
Efficacy Endpoints....................................................................................... 21
4.2.3.3
Pharmacokinetic/Immunogenicity Endpoints .............................................. 22
4.2.3.4
Planned Exploratory Biomarker Research................................................... 22
4.2.3.5
Future Biomedical Research........................................................................ 23
5.0
METHODOLOGY ................................................................................................... 23
Entry Criteria........................................................................................................ 23
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 23
5.1.1
Subject Inclusion Criteria.................................................................................... 23
5.1.2
Subject Exclusion Criteria .................................................................................. 26
5.1.3
Trial Treatment(s) ................................................................................................ 28
5.2
Dose Selection/Modification .............................................................................. 28
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 28
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 28
Timing of Dose Administration .......................................................................... 30
5.2.2
Trial Blinding/Masking....................................................................................... 30
5.2.3
Randomization or Treatment Allocation............................................................ 30
5.3
Stratification.......................................................................................................... 30
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 30
5.5
Allowed Concomitant Medications .................................................................... 31
5.5.1
Prohibited Concomitant Medications.................................................................. 31
5.5.2
Rescue Medications & Supportive Care............................................................. 32
5.6
Supportive Care Guidelines ................................................................................ 32
5.6.1
Diet/Activity/Other Considerations..................................................................... 35
5.7
Diet...................................................................................................................... 35
5.7.1
Contraception...................................................................................................... 36
5.7.2
Use in Pregnancy ................................................................................................ 36
5.7.3
Use in Nursing Women....................................................................................... 36
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 37
5.8
Temporary Discontinuation of Study Therapy after CR..................................... 38
5.8.1
Subject Replacement Strategy............................................................................. 38
5.9
Beginning and End of the Trial ........................................................................... 38
5.10
Clinical Criteria for Early Trial Termination ................................................... 38
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 39
Treatment Phase ................................................................................................... 39
6.1
Second Course Phase (Retreatment ONLY) ...................................................... 42
6.2
7.0
TRIAL PROCEDURES ........................................................................................... 44
Trial Procedures ................................................................................................... 44
7.1
Administrative Procedures.................................................................................. 44
7.1.1
7.1.1.1
Informed Consent......................................................................................... 44
7.1.1.1.1
General Informed Consent.................................................................... 44
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 45
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 45
7.1.1.3
Subject Identification Card .......................................................................... 45
 
 
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7.1.1.4
Medical History ........................................................................................... 45
7.1.1.5
Prior and Concomitant Medications Review ............................................... 45
7.1.1.5.1
Prior Medications.................................................................................. 45
7.1.1.5.2
Concomitant Medications..................................................................... 45
7.1.1.6
Disease Details and Treatments................................................................... 46
7.1.1.6.1
Disease Details...................................................................................... 46
7.1.1.6.2
Prior Treatment Details......................................................................... 46
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 46
7.1.1.7
Assignment of Screening Number............................................................... 46
7.1.1.8
Assignment of Randomization Number....................................................... 46
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other) ................................... 47
Clinical Procedures/Assessments........................................................................ 47
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 47
7.1.2.2
Physical Exam.............................................................................................. 47
7.1.2.3
Vital Signs, Height and Weight ................................................................... 48
7.1.2.4
12-lead ECG................................................................................................. 48
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 48
Laboratory Procedures/Assessments .................................................................. 48
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 49
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 50
7.1.3.2.1
Blood Collection for Serum Pharmacokinetics of MK-3475 ............... 50
7.1.3.2.2
Blood Collection for Serum Anti-MK-3475 Antibodies ...................... 50
7.1.3.2.3
Blood Collection for Correlative Studies.............................................. 50
7.1.3.3
Future Biomedical Research........................................................................ 51
7.1.3.4
Tumor Imaging and Assessment of Disease................................................ 51
7.1.3.5
Photography for Cutaneous Lesions ............................................................ 53
7.1.3.6
Pulmonary 
Radiographic 
Evaluation 
for 
MK-3475-Induced 
Pneumonitis ................................................................................................. 53
7.1.3.7
Tumor Tissue Collection.............................................................................. 53
Other Procedures................................................................................................. 54
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 54
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 54
 
 
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7.1.4.2
Blinding/Unblinding .................................................................................... 54
7.1.4.3
Calibration of Critical Equipment................................................................ 55
Visit Requirements.............................................................................................. 55
7.1.5
7.1.5.1
Screening...................................................................................................... 55
7.1.5.2
Treatment Period.......................................................................................... 56
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 56
7.1.5.3
Discontinuation............................................................................................ 57
7.1.5.4
Post-Treatment Visits................................................................................... 57
7.1.5.4.1
Safety Follow-Up Visit......................................................................... 57
7.1.5.4.2
Follow-up Visits ................................................................................... 58
7.1.5.4.3
Survival Follow-up ............................................................................... 58
Assessing and Recording Adverse Events .......................................................... 58
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 59
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 60
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 60
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 60
7.2.3.2
Events of Clinical Interest............................................................................ 61
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ............ 63
Evaluating Adverse Events ................................................................................. 63
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 66
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 66
7.3
Efficacy and Safety Evaluation Committee........................................................ 66
7.3.1
Independent Pulmonary Radiographic Adviser .................................................. 66
7.3.2
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 66
Statistical Analysis Plan Summary ..................................................................... 66
8.1
Efficacy Analyses ............................................................................................... 66
8.1.1
Safety Analyses................................................................................................... 67
8.1.2
Power and Sample Size....................................................................................... 67
8.1.3
Statistical Analysis Plan ....................................................................................... 68
8.2
Responsibility for Analyses/In-House Blinding ................................................. 68
8.2.1
Hypotheses/Estimation ....................................................................................... 68
8.2.2
 
 
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Analysis Endpoints ............................................................................................. 68
8.2.3
8.2.3.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints.............................. 68
8.2.3.2
Safety Endpoints .......................................................................................... 69
Analysis Populations........................................................................................... 69
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 69
8.2.4.2
Safety Analysis Populations ........................................................................ 69
Statistical Methods.............................................................................................. 69
8.2.5
8.2.5.1
Statistical Methods for Efficacy Analyses ................................................... 70
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 71
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 71
8.2.5.4
Statistical Methods for Immunogenicity/pharmacokinetics endpoints 
Analyses....................................................................................................... 71
Multiplicity ......................................................................................................... 71
8.2.6
Sample Size and Power Calculations.................................................................. 71
8.2.7
Subgroup Analyses and Effect of Baseline Factors ............................................ 72
8.2.8
Interim Analyses ................................................................................................. 72
8.2.9
Compliance (Medication Adherence) ................................................................. 72
8.2.10
Extent of Exposure.............................................................................................. 72
8.2.11
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 73
Investigational Product ........................................................................................ 73
9.1
Packaging and Labeling Information ................................................................. 73
9.2
Clinical Supplies Disclosure................................................................................. 73
9.3
Storage and Handling Requirements.................................................................. 73
9.4
Returns and Reconciliation.................................................................................. 74
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 74
Confidentiality....................................................................................................... 74
10.1
Confidentiality of Data ....................................................................................... 74
10.1.1
Confidentiality of Subject Records ..................................................................... 74
10.1.2
Confidentiality of Investigator Information........................................................ 74
10.1.3
Confidentiality of IRB/IEC Information............................................................. 75
10.1.4
Compliance with Financial Disclosure Requirements....................................... 75
10.2
 
 
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Compliance with Law, Audit and Debarment ................................................... 76
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 78
10.4
Quality Management System............................................................................... 78
10.5
Data Management................................................................................................. 78
10.6
Publications ........................................................................................................... 79
10.7
11.0
LIST OF REFERENCES......................................................................................... 80
12.0
APPENDICES........................................................................................................... 83
Merck Code of Conduct for Clinical Trials........................................................ 83
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 85
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 92
ECOG Performance Status................................................................................ 103
12.4
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
12.5
Evaluating Response in Solid Tumors .............................................................. 104
Immune Related Response Criteria .................................................................. 105
12.6
Clinical Study Conduct System ......................................................................... 107
12.7
13.0
SIGNATURES......................................................................................................... 108
Sponsor's Representative ................................................................................... 108
13.1
Investigator.......................................................................................................... 108
13.2
 
 
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LIST OF TABLES
Table 1  Adequate Organ Function Laboratory Values.......................................................... 25
Table 2  Trial Treatment ......................................................................................................... 28
Table 3 Dose Modification Guideline..................................................................................... 29
Table 4  Infusion Reaction Treatment Guidelines .................................................................. 35
Table 5  Laboratory Tests ....................................................................................................... 49
Table 6  Imaging and Treatment after 1st radiologic evidence of PD.................................... 52
Table 7  Evaluating Adverse Events....................................................................................... 64
Table 8  Primary Analysis Strategy for Efficacy Endpoints................................................... 67
Table 9  Analysis Strategy for Key Efficacy Variables.......................................................... 70
Table 10  Product Descriptions............................................................................................... 73
 
 
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LIST OF FIGURES
Figure 1  Trial Design Diagram.............................................................................................. 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
1.0
TRIAL SUMMARY
After marketing approval of MK-
3475, “clinical trial” will be 
replaced 
with 
“post-marketing 
clinical trial” and this study will 
be continued. 
Between the marketing approval 
of MK-3475 and 1) the delivery of 
marketed product of MK-3475 in 
each site, or 2) 6 months from 
marketing approval, whichever 
occurs first, the subjects can 
receive treatment of MK-3475 as 
post-marketing clinical trial drug. 
1) 
This 
amendment 
makes 
continuing patients use MK-3475 
on this protocol between the 
approval and the availability of 
marketed product of MK-3475
2) Due to the requirement of 
Japanese 
regulation, 
after 
marketing approval of MK-3475, 
“clinical trial” will be replaced 
with “post-marketing clinical trial 
".
3) Patients can use study drug 
MK-3475 until the availability of 
marketed product of MK-3475 or 
6 
months 
from 
marketing 
approval, whichever occurs first.
2.1
Trial Design
5.8
Subject 
Withdrawal/Discontinuation 
Criteria
“The delivery of marketed product 
of MK-3475 in each site” and ”6 
months from marketing approval”
is 
added 
to 
the 
criteria 
of 
discontinuation from the treatment 
of MK-3475.
9.1
Investigational Product
After the time of the marketing 
approval of MK-3475, “clinical 
trial drug” of MK-3475 will be 
replaced 
with 
“post-marketing 
clinical trial drug”. Until the 
delivery of marketed product of 
MK-3475 in each site, the subjects 
can receive treatment of MK-3475 
as post-marketing
clinical trial 
drug
 
 
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1.0
TRIAL SUMMARY
“1) the marketing approval of 
MK-3475, 2) the completion of 
safety follow-up or 3) the time 
when a possibility of entry to 
second course is lost, whichever 
occurs last” is added into the 
criteria of discontinuation of this 
study.
Study end is 1) the marketing 
approval of MK-3475, 2) the 
completion of safety follow-up or 
3) the time when a possibility of 
entry to second course is lost, 
whichever occurs last.
More data becomes to be not 
required.
2.1
Trial Design
5.8
Subject
Withdrawal/Discontinuation 
Criteria
1.0
TRIAL SUMMARY
The treatment of marketed product 
of MK-3475 is included to non-
study cancer treatment
If patients start marketed product 
of MK-3475, safety follow-up for 
30 days from the last dose of study 
drug MK-3475 should be required.
2.1
Trial Design
2.1
Trial Design
Good 
Post-marketing 
Study 
Practice (GPSP) is added and this 
study is to be conducted in 
conformance with GPSP
In Japan, by law, filling of re-
examination is required, based on 
information after approval.
Post-marketing clinical trial is 
specified in GPSP and post-
marketing clinical trial must obey 
GPSP.
10.3
Compliance with Law, Audit and 
Debarment
10.5
Quality Management System
13.2
Investigator
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2.1.2
Dose 
Modification 
(Escalation/Titration/Other)
Table 3 Dose Modification 
Guideline is updated.
Instruction 
for 
Dose 
Modification is modified
Clarification and consistency in 
alignment with program level 
MK-3475 ECI guidance
5.6.1
Supportive Care Guidelines
Table 
5 
Recommended 
Approach 
to 
Handling 
Pneumonitis
and 
Table 
6 
General Approach to Handling
irAEs are deleted.
Instruction for Supportive Care 
Guidelines is modified
7.2
Assessing 
and 
Recording 
Adverse Events
Revised wording to provide
further clarification on adverse
event collection.
Clarification and consistency in 
alignment with program level 
MK-3475
4.2.1
Rationale for the Trial and 
Selected Subject Population
timing (at the start of this 
study) is added when newly 
therapies such as ipilimumab
have not been approved yet in 
Japan
Therapies such as ipilimumab 
have been approved already in 
Japan now.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase Ib Study of MK-3475 in Subjects with Advanced Melanoma
Trial Phase
Ib
Clinical Indication
The treatment of subjects with locally advanced or metastatic melanoma
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
MK-3475 2 mg/kg every 3 weeks (Q3W)
Number of trial subjects
Approximately 35 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 10 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 up to 4 weeks, eligible subjects will
receive treatment on Day 1 of each 3-week dosing cycle.  Treatment with 
MK-3475 will continue until the subject meets the discontinuation 
criteria such as 24 months of therapy completion, documented disease 
progression (per modified RECIST 1.1), or unacceptable toxicity, etc. 
Subjects who meet criteria for temporary discontinuation of study 
therapy after complete response (CR) may consider stopping trial 
treatment. 
These subjects may be eligible for re-treatment after 
experiencing disease progression at the discretion of the investigator if 
they meet the criteria for re-treatment for up to one year; this will be 
designated the Second Course Phase. After the end of treatment, each 
subject will be followed for a minimum of 30 days for adverse event 
monitoring (serious adverse events will be collected for up to 90 days 
after the end of treatment).  Subjects who discontinue for reasons other 
than disease progression will have post-treatment follow-up for disease 
status until initiating a non-study cancer treatment (including the 
treatment of marketed product of MK-3475), disease progression, 
withdrawing consent, death, or the end of the study.  All subjects will be 
followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study.
After marketing approval of MK-3475 for melanoma, “clinical trial” will be replaced with 
“post-marketing clinical trial” and this study will be continued. Between the marketing 
approval of MK-3475 for melanoma and 1) the delivery of marketed product of MK-3475 in 
each site, or 2) 6 months from marketing approval for melanoma, whichever occurs first, the 
subjects can receive treatment of MK-3475 as post-marketing clinical trial drug.
The end of the study of each subject is 1) the marketing approval of MK-3475 for melanoma,
2) the completion of safety follow-up or 3) the time when a possibility of entry to second 
course is lost, whichever occurs last.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is an open-label, non-randomized, multi-center Phase Ib study of MK-3475 in subjects 
with advanced melanoma to be conducted in conformance with Good Clinical Practices
(GCP) and Good Post-marketing Study Practice (GPSP).  Approximately 35 subjects will be 
enrolled in this trial to examine the safety and efficacy of the 2 mg/kg dose of MK-3475 
administered every 3 weeks. The primary objectives of the trial are to determine the safety, 
tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) in subjects with advanced cutaneous melanoma.  The 
secondary objectives include the duration of response (DOR), progression-free survival 
(PFS) per RECIST 1.1, and the ORR, DOR, and PFS per immune-related response criteria 
(irRC), and overall survival (OS) in subjects with advanced cutaneous melanoma.  As the 
exploratory objectives, the efficacy (ORR, DOR, and PFS) per RECIST 1.1 and irRC and OS
in subjects with advanced mucosal melanoma, the pharmacokinetic (PK) properties of MK-
3475, the presence of anti-MK-3475 antibodies, pulmonary radiographic changes and its 
features, and the relationship between candidate biomarkers (including PD-L1 expression) 
and anti-tumor activity of MK-3475 will also be evaluated.  Subjects will be evaluated every 
6 weeks starting at 12 weeks through 48 weeks, and after 48 weeks, every 12 weeks with 
radiographic imaging to assess response to treatment.  Tumor response will be assessed using 
RECIST 1.1 and irRC by the central independent radiology review.  RECIST 1.1 will be used 
by the local site to determine eligibility and modified RECIST 1.1 will be used to make 
treatment decisions (refer to Section 4.2.3.2).  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 unless the subject meets the discontinuation criteria 
such as disease progression (evaluated by modified RECIST 1.1), unacceptable toxicity, or
completion of 24 months of treatment with MK-3475 (refer to Section 5.8 for further details). 
Subjects who attain an investigator-determined confirmed CR may consider stopping trial 
treatment after receiving at least 24 weeks of treatment (Treatment Phase).  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 (Second Course Phase) after they have experienced radiographic disease 
progression.  The decision to retreat will be at the discretion of the investigator only if no 
cancer treatment (including the treatment of marketed product of MK-3475) 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 in Treatment Phase and Second Course phase, 
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).  Subjects who discontinue 
treatment for reasons other than disease progression will have post-treatment follow-up for 
disease status until initiating a non-study cancer treatment, disease progression, withdrawing 
consent, death, or the end of the study, whichever occurs first.  Response and progression in 
the Second Course Phase will not count towards the ORR and PFS of the efficacy endpoint in 
 
 
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this trial. 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.  Clinical data may
temporarily be locked to assess the efficacy endpoint, ORR per RECIST 1.1 for advanced 
melanoma when once all of the enrolled subject has either progression disease or has had an 
imaging 24 weeks after treatment initiation, whichever occurs first.  
Participation in this trial will require submitting an archival tissue sample or newly obtained 
biopsy of a tumor lesion not previously irradiated for PD-L1 expression evaluation.  This 
specimen will be evaluated at a central laboratory for expression status of PD-L1 by 
immunohistochemistry (IHC).  Both PD-L1 positive and negative subjects will be enrolled in
this trial, and the clinical activity in both subsets will be evaluated as a pre-defined subgroup 
analysis.  
After marketing approval of MK-3475 for melanoma, “clinical trial” will be replaced with 
“post-marketing clinical trial” and this study will be continued. Between the marketing 
approval of MK-3475 for melanoma and 1) the delivery of marketed product of MK-3475 in 
each site, or 2) 6 months from marketing approval for melanoma, whichever occurs first, the 
subjects can receive treatment of MK-3475 as post-marketing clinical trial drug. 
The end of the study of each subject is 1) the marketing approval of MK-3475 for melanoma, 
2) the completion of safety follow-up or 3) the time when a possibility of entry to second 
course is lost, whichever occurs last.
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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Trial Diagram
2.2
The trial design is depicted in Figure 1 below. 
Figure 1  Trial Design Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1) Objective:  To determine the safety and tolerability of the 2 mg/kg Q3W dose of 
MK-3475 in subjects with advanced melanoma.
2) Objective: To evaluate anti-tumor activity of the 2 mg/kg Q3W dose of MK-3475 in 
subjects with advanced cutaneous melanoma based on RECIST 1.1 assessed by the 
central independent radiology review.  
Hypotheses:  Intravenous administration of single agent MK-3475 to subjects with 
advanced cutaneous melanoma will result in a clinically meaningful overall response 
rate (ORR) based on RECIST 1.1.
 
 
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Secondary Objective(s) & Hypothesis(es)
3.2
1) Objective:  To evaluate the duration of response (DOR) and progression-free survival 
(PFS) per RECIST 1.1 assessed by the central independent radiology review in 
subjects with advanced cutaneous melanoma receiving MK-3475.
2) Objective:  To evaluate the ORR, DOR, and PFS per irRC assessed by the central
independent radiology review in subjects with advanced cutaneous melanoma
receiving MK-3475.
3) Objective:  To evaluate the overall survival (OS) in subjects with advanced 
cutaneous melanoma receiving MK-3475.
Exploratory Objectives
3.3
1) Objective:  To evaluate the efficacy (ORR, DOR, and PFS) per RECIST 1.1 and 
irRC assessed by the central independent radiology review and OS in subjects with 
advanced mucosal melanoma receiving MK-3475.
2) Objective: 
To explore the PK profile of MK-3475 in the advanced melanoma
population.
3) Objective: To evaluate the presence of anti-MK-3475 antibodies.
4) Objective: To evaluate the pulmonary radiographic changes and its features for a
diagnosis of MK-3475-induced pneumonitis.
5) Objective: To investigate the correlation between candidate biomarkers (including 
PD-L1 expression) and anti-tumor activity of MK-3475 in subjects with advanced 
melanoma.
4.0 BACKGROUND & RATIONALE
Background
4.1
Pharmaceutical and Therapeutic Background
4.1.1
MK-3475 is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 (programmed 
cell death-1) and its ligands PD-L1 and PD-L2. This blockade enhances functional activity 
of the target lymphocytes to facilitate tumor regression and ultimately immune rejection.  
 
 
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The PD-1 pathway represents a major immune control switch which may be engaged by
tumor cells to overcome active T-cell immune surveillance. The normal function of PD-1,
expressed on the cell surface of activated T-cell under healthy conditions, is to down-
modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1
is an Ig superfamily member which has been shown to negatively regulate antigen receptor
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [1, 2]. Although healthy
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express
abundant levels of this T-cell inhibitor. High expression of PD-L1 on tumor cells (and to a
lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in
various cancer types including renal cell carcinoma (RCC), pancreatic carcinoma,
hepatocellular carcinoma, ovarian carcinoma and NSCLC [3-6]. Furthermore, PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma [7].  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor evasion and is thus an 
attractive target for therapeutic intervention.  
Melanoma is a malignant tumor of melanocytes, which are the cells that create the pigment
melanin and are derived from the neural crest. Although melanoma accounts for less than 
5% of skin cancer cases; it is the most lethal form and accounts for over 75% of skin cancer 
deaths [8]. Internationally, approximately 160,000 new cases of melanoma are diagnosed per 
year, with over 70% of these diagnosed in Australia, Europe, or North America [9-10].  In 
Japan, approximately 1,300 new cases of melanoma were diagnosed and more than 600 
people died of melanoma in 2012 [Globocan 2012, IARC].  The incidence of melanoma is 
increasing worldwide, with a growing fraction of subjects with advanced disease for which 
prognosis remains poor.  The median survival for subjects with metastatic melanoma has 
been under 1 year. The 5-year survival rate of patients with visceral involvement is under
10% and the goal of treatment for this incurable condition is palliative with marginal survival
benefit [11].  
Recent data with anti-PD-1 antibodies, including nivolumab (BMS-936558, ONO-4538) and 
MK-3475, have validated PD-1 as an attractive target for clinical intervention and have 
provided proof of concept for anti-PD-1 mAbs in melanoma [12-14]. Nivolumab has an 
observed objective response rate of 28% in melanoma subjects who had not previously 
received ipilimumab (IPI) [13]; MK-3475 has shown a promising response rate of 41% in 
melanoma subjects. Specifically, a response rate of more than 40% was observed with
MK-3475 in melanoma subjects who have not received prior IPI treatment [15].  This 
response rate is much higher than the 11-15% response rate observed in IPI registration trials.  
Importantly, responses have been of long duration and both MK-3475 and nivolumab are 
generally well tolerated.  Median overall survival of nivolumab was 16.8 months, and 1- and 
2-year survival rates were 62% and 43%, respectively [15-16].  The median overall survival
rate in melanoma of MK-3475 PN001 was not reached for the entire study population nor for 
any of the individual dose schedules at the time of the analysis. For all patients and dose 
schedules the fraction of patients alive at one year was more than approximately 80% [see 
Investigators Brochure (IB)].  Drug related AEs were reported for 340 of 411 (83%) in 
PN001 (all melanoma patients: Parts B1+B2+D).  The most common drug-related AEs in 
melanoma subjects, reported in at least 10% of patients, were: fatigue (36.0%), pruritus 
(23.8%), rash (19.7%), nausea (12.2%), diarrhea (16.3%), arthralgia (15.6%), and vitiligo 
 
 
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(10.7%) (unpublished internal data: as of 18-Oct-2013). Safety data from PN001 indicate 
that most AEs were typically grade 1-2 in severity and reversible and that MK-3475 has an 
acceptable safety profile for the treatment of advanced melanoma patients.
Therefore, clinical development of MK-3475 would have a great significance in patients with 
advanced melanoma including the IPI-naïve population in Japan.  
Ongoing Clinical Trials
4.1.2
MK-3475 is being studied for various oncology indications including melanoma, non-small 
cell lung cancer, head and neck cancer, triple negative breast cancer, gastric cancer, bladder 
cancer, hematologic malignancies and other solid tumors. The overseas clinical development 
program in melanoma is ongoing and includes PN001, an open-label Phase I study evaluating 
the safety and efficacy of MK-3475; and two ongoing, randomized studies with active 
comparators (PN002/PN006).  For trial details please refer to the IB.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
As described in 4.1.1 Pharmaceutical and Therapeutic Background, MK-3475 has shown to 
be very well-tolerated and lead to objective response rates in melanoma subjects > 40% [15], 
and hence melanoma is considered to be one of the promising indications of potential tumors.  
Also, non-clinical and clinical data obtained so far supports clinical development of MK-
3475 in Japan.  
Treatment options for metastatic melanoma have been limited to chemotherapeutic agents 
such as dacarbazine and high-dose interleukin-2 immunotherapy. Outside Japan, there has 
been steady progress in the development of targeted therapy and immunotherapy for
metastatic melanoma. BRAF inhibitors (vemurafenib and dabrafenib), anti-CTLA4 mAb
(IPI), and MEK inhibitor (trametinib) were approved for treatment of metastatic melanoma in 
the past few years; however at the start of this study, these newly therapies have not been 
approved yet in Japan.
Available treatment options for Japanese patients are currently 
limited to cytotoxic chemotherapies, which have very limited activity even in the first-line
setting.  Thus, the outcome of patients with metastatic melanoma still remains dismal and the
development of new effective therapy is still needed.  
This is a multi-center, open-label, Phase Ib trial of MK-3475 in subjects with advanced 
melanoma. Subjects with 0-2 prior lines of therapy will be enrolled in this trial.  All subjects 
will be required to submit a tumor tissue sample for PD-L1 expression evaluation as a pre-
defined subgroup analysis.  
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents.
 
 
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Rationale for Dose Selection/Regimen
4.2.2
The dosing regimen of MK-3475 in this study was determined based on the results from the
overseas ongoing phase I study (PN001, refer to IB).  PK data analysis of MK-3475 
administered Q3W showed slow systemic clearance, limited volume of distribution, and a 
long half-life (13-21 days).
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 Q3W dosing schedule.  Also, preliminary 
preclinical data in syngeneic mouse tumor models suggests that sustained inhibition of PD-1 
is important for maintaining anti-tumor activity (unpublished internal data). Thus, MK-3475 
will be given until disease progression, unacceptable toxicity, or completion of 24 months of 
treatment with MK-3475 in the trial. The only exception is those patients who experience a 
confirmed CR; these patients may discontinue treatment with MK-3475 at the discretion of 
the investigator (see Section 5.8.1 for details).
A recent interim analysis from PN001 reported that, when evaluated in a randomized setting
(in Cohorts B2 and D), the efficacy of MK-3475 given Q3W is comparable between 2 mg/kg 
and 10 mg/kg doses, indicating no improvement in efficacy with a 5-fold higher dose of 
MK-3475 beyond the 2 mg/kg dose (as determined by ORR, PFS, and OS endpoints). 
Similarly, the safety and AE profile of MK-3475 also appear similar between the 2 mg/kg 
Q3W and 10 mg/kg Q3W doses. Finally, PK analysis indicates a flat exposure-efficacy
relationship beyond the 2 mg/kg dose. Taken together, these analyses indicate that the 
2 mg/kg dose is associated with optimal efficacy and safety when MK-3475 is administered 
on a Q3W schedule for the patients with advanced melanoma (unpublished internal data; an 
ongoing study will compare efficacy and safety of 10 mg/kg Q2W vs 10 mg/kg Q3W in a 
randomized manner).  
Rationale for Endpoints
4.2.3
4.2.3.1
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of 
MK-3475 in subjects with advanced melanoma.
In addition to general laboratory tests, 
immune laboratory test will be evaluated considering the mode of action of MK-3475.  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).  
 
 
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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.  Since pneumonitis has been previously 
reported in clinical studies of anti-PD-1 antibodies including MK-3475, pulmonary 
radiographic changes and its features will be evaluated by investigators and an independent 
radiologist from a potential risk of pneumonitis.  
4.2.3.2
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate ORR per RECIST 1.1 in subjects 
with advanced cutaneous melanoma. The secondary objectives are to evaluate DOR and PFS 
per RECIST 1.1, ORR, DOR, and PFS per irRC, and OS in subjects with advanced cutaneous
melanoma.  In this study, the efficay in subjects with advanced mucosal melanoma will also 
be evaluated as an exploratory objective. Having considered the rarity, unique biology, and 
poor prognosis of mucosal melanoma, the proportion of subjects with mucosal melanoma in 
this study is limited up to 20% of the total subjects.  Response rates per RECIST 1.1 [17] and
irRC [18] will be evaluated by the central independent radiology review. RECIST 1.1 will 
be used by the local site to determine eligibility and modified RECIST 1.1 will be used to
make treatment decisions. 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen
with treatment of MK-3475.
Immunotherapeutic agents such as MK-3475 may produce
antitumor effects by potentiating endogenous cancer-specific immune responses. 
The
response patterns seen with such an approach may extend beyond the typical time course of
responses seen with cytotoxic agents, and can manifest a clinical response after an initial
increase in tumor burden or even the appearance of new lesions. Standard RECIST may not
provide an accurate response assessment of immunotherapeutic agents such as MK-3475.  
Therefore, modified RECIST 1.1 will be used with the adaptations (refer to Section 7.1.3.4), 
in which a confirmation assessment of disease progression must be obtained at least 4 weeks 
after the initial disease assessment indicating progressive disease.  
The irRC are a published set of guidelines proposed for immunotherapies in solid tumors.  
Inclusion of this method is based on the observation that some patients with melanoma may 
have a transient increase in measured tumor size or small new lesions on CT scans (due to 
infiltration of inflammatory cells) in the first few months after start of immunotherapy, with 
subsequent reduction in tumor size (due to immune-mediated tumor cell kill). Immune-based 
response criteria differ predominantly from RECIST 1.1 by measurement of lesions using 
two dimensions rather than one, as well as inclusion of new lesions into the overall tumor 
burden calculation, rather than having new lesions automatically define progression (refer to 
Section 7.1.3.4).  
 
 
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4.2.3.3
Pharmacokinetic/Immunogenicity Endpoints
Serum samples will be obtained to measure pharmacokinetics of MK-3475. In addition, an 
exploratory investigation on the formation of anti-MK-3475 antibody and its effect on the 
pharmacokinetics of MK-3475 will also be evaluated for interpretation of immunogenicity 
results considering MK-3475 is a humanized monoclonal anti-PD-1 antibody. Subsequently, 
the concentration-time data to be obtained from MK-3475 serum assay will be diverted to a 
population PK analysis (or non-compartment analysis). 
The sampling time points for 
MK-3475 pharmacokinetics and anti-MK-3475 antibody have been determined taking the 
long half-life (two to three weeks) of MK-3475 into account. The timepoints for PK blood 
sampling are described in Section 6 – Trial Flow Chart.
4.2.3.4
Planned Exploratory Biomarker Research
Biomarker research to identify factors important for MK-3475 monotherapy may also be 
pursued. For example, tumor and blood samples from this study may undergo proteomic, 
genomic and transcriptional analyses (both DNA and RNA analyses). PD-L1 expression by 
IHC will be evaluated retrospectively and the clinical activity in PD-L1 positive and negative 
subjects will be evaluated. 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:
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material will be completed to
assess expression of approximately 600 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 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 Analyses
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 
nonresponse.  
In addition, DNA isolated from blood or tumor tissue will be analyzed in order to identify 
genetic alterations and to evaluate specific genetic alterations that may correlate with clinical
response to MK-3475. These and other additional biomarker or genomic research to identify
factors important for MK-3475 therapy (for example, HLA genotype) may also be pursued.
 
 
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4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on blood and tumor tissue specimens 
routinely and specifically collected during this clinical trial. This research may include 
genetic analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics 
(serum, plasma) and/or the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with advanced melanoma of at least 20 years 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 for the trial. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
2. Be ≥ 20 years of age on day of signing informed consent.
 
 
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3. Have histologically confirmed diagnosis of locally advanced (unresectable Stage III)
or metastatic (Stage IV) melanoma not amenable to local therapy.

Subject may not have a diagnosis of uveal or ocular melanoma.

Subject who have mucosal melanoma are eligible.
NOTE: the proportion of subjects with mucosal melanoma will not exceed 20% 
of the total subjects (limited up to 7 subjects).

Subject who have received 0-2 prior lines of therapy (excluding adjuvant or 
neoadjuvant therapy) for melanoma.

LDH ≤local ULN
4. Have at least one measurable lesion as defined by RECIST 1.1 on imaging studies 
(CT or MRI). 
Note: Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
Note: Cutaneous lesions and other superficial lesions are not considered measurable 
lesions for the purposes of this protocol, but may be considered as non-target lesions.  
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Have an anticipated life expectancy of at least 3 months.
7. 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 (without supportive care)
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L (without transfusions)
Renal
Serum creatinine OR
Measured or calculated creatinine clearance (CrCl) a
(GFR can also be used in place of creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥50 mL/min for subjects with creatinine levels 
> 1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤1.5 X ULN (or < 3x ULN in subjects with 
Gilbert’s syndrome) OR
direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN OR
≤5 X ULN for subjects with liver metastases
Endocrine
Thyroid stimulating hormone (TSH)
Within normal range
Coagulation
Prothrombin Time (PT) / International Normalized 
Ratio (INR), activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless the subject is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
a Creatinine clearance should be calculated per institutional standard.  If no local guideline is available, 
Creatinine Clearance should be calculated using the Cockcroft-Gault Method:
CrCl = [(140-age) * weight (kg) * (0.85 for females only)] / (72 * serum creatinine)
8. Have provided tissue for PD-L1 expression evaluation from an archival tissue sample 
or newly obtained core or excisional biopsy of a tumor lesion not previously 
irradiated.  
Note: Subjects will be eligible to participate regardless of the level of PD-L1 
expression.
9. Have documented BRAF mutation status or be willing to provide a tumor tissue for 
BRAF genotyping.  
Note: BRAF V600 mutation analysis should be performed at screening in subjects
without documented BRAF status.
10. (Female subject of childbearing potential) 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 borderline a serum pregnancy test will be required.
 
 
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11. (Female subjects of childbearing potential)  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 (Refer to Section
5.7.2).  The commonly used criteria for subjects of child bearing potential are those 
who have not been surgically sterilized or have not been free from menses for >1 
year.
12. (Male subjects)  Agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has 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) agents (including
ipilimumab or any other antibody/drug specifically targeting T-cell co-stimulation or
checkpoint pathways).
2. Is currently participating or has participated in a study with an investigational 
compound or device within 30 days, or 5X half-life of the investigational compound, 
whichever is longer, of initial dosing on this study. 
3. Has had chemotherapy, targeted small molecule therapy, radiotherapy, or biological 
cancer therapy (including monoclonal antibodies) within 4 weeks prior to the first 
dose of trial treatment, or who has not recovered (≤Grade 1 or baseline) from adverse 
events due to a previously administered agent.  
Note: Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this 
criterion and may qualify for the study.
Note: If subject received major surgery or radiation therapy of > 30 Gy, they must 
have recovered from the toxicity and/or complications from the intervention prior to 
starting therapy.
4. Has a known history of another (including unknown primary) malignancy within 5 
years prior to first study drug administration.  
Note: Exceptions include adequately treated Stage 1 or Stage 2 basal/squamous cell 
carcinoma of the skin, superficial bladder cancer, or cancer in situ which has 
undergone potentially curative therapy, or no evidence of that disease recurrence for 5 
years since initiation of that therapy.  
5. Is expected to require any other form of systemic or localized antineoplastic therapy
while in study.
 
 
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6. Has known active central nervous system (CNS) mets and/or carcinomatous 
meningitis.  
Note: Subjects with previously treated brain metastases and clinically stable CNS 
mets are allowed to participate (clinically stabile is defined as a period (at least 4
weeks prior to the first dose of trial treatment) in which (1) there is no evidence of 
new or enlarging CNS mets by MRI, (2) the subject is off steroids for at least two 
weeks, and (3) any neurologic symptoms have returned to baseline).
7. Has an active autoimmune disease requiring systemic treatment within the past 3 
months prior to first study drug administration, a documented history of clinically 
severe autoimmune disease, or a syndrome that requires systemic steroids or 
immunosuppressive agents. 
Note: 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 Sjorgen’s 
syndrome will not be excluded from the study.
8. Is receiving systemic steroid therapy or any other form of immunosuppressive 
therapy within 1 week prior to the first dose of trial treatment.
9. Has an active infection requiring intravenous systemic therapy.
10. Has received a live vaccine within 4 weeks prior to the first dose of trial treatment
(refer to Section 5.5.2 for further details).
11. Has a known hypersensitivity to the components of the study drug or another
monoclonal antibody.
12. Has history or evidence of active pneumonitis.
13. Is known to be Human Immunodeficiency Virus (HIV)-positive (HIV 1/2 antibodies).
14. Has known history of active Hepatitis B (HBsAg reactive) or C (HCV RNA 
[qualitative] is detected).
15. Has a history or current evidence of any condition, therapy, or lab abnormality that 
might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate.
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
 
 
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17. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit (Visit 1) through 120 
days after the last dose of trial treatment.
18. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial
unless, prospective IRB approval (by chair or designee) is given allowing exception 
to this criterion for a specific subject.
Trial Treatment(s)
5.2
The treatment to be used in this trial is outlined below in Table 2.
Table 2 Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment
Use
MK-3475
2 mg/kg
Q3W
IV infusion
Day 1 of each cycle
Experimental
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.2.1.2.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background and Rationale.  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 Procedures Manual.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 
5.6 for supportive care guidelines, including use of corticosteroids.
 
 
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Table 3 Dose Modification Guideline
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Treatment Discontinuation
Diarrhea/Colitis
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12
weeks
4
Permanently discontinue
Permanently discontinue
AST, 
ALT, 
or 
Increased Bilirubin
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks
3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycemia
T1DM or 
3-4
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia 
associated 
with 
evidence of beta cell failure
Resume pembrolizumab when patients are clinically 
and metabolically stable
Hypophysitis
2-4
Toxicity 
resolves 
to 
Grade 
0-1. 
Therapy with pembrolizumab can be 
continued while endocrine replacement
therapy is instituted
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks
Hyperthyroidism 
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted
Infusion Reaction
2b
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite 
adequate premedication 
3-4
Permanently discontinue
Permanently discontinue
Pneumonitis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks
3-4
Permanently discontinue
Permanently discontinue
Renal Failure or 
Nephritis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks
3-4
Permanently discontinue
Permanently discontinue
All Other Drug-
Related Toxicityc
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last 
dose or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 
weeks
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs, or any life-threatening event.
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week then patients should be discontinued.
b 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; Refer to Table 4 – Infusion Treatment Guidelines for further management details.
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 
12 weeks of the last dose.
 
 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
Timing of Dose Administration
5.2.2
MK-3475 should be administered on Day 1 of each cycle as a 30-minute IV infusion (25-40
min) every 3 weeks (Q3W) after all procedures/assessments have been completed as detailed 
on the Trial Flow Chart (Section 6.0), except for the post-infusion PK sample time points 
listed in the Trial Flow Chart.  Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible. MK-3475 may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle due to administrative reasons only.
All trial treatments will be administered on an outpatient basis.  The specific time of trial 
treatment infusion (e.g., time of the week for first administration; time of the day for each 
administration) should take into consideration PK sampling time points and study visit 
procedures. 
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
 
 
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Allowed 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 prior/concomitant medications received within 4 weeks 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

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 4 weeks 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.

Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  
o
Note: The use of physiologic doses of 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.  
Local surgery or radiation therapy (if indicated for palliative measure only after discussion 
with the SPONSOR) may be permitted beyond Week 24 tumor assessment.
 
 
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The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
5.6
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 does 
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. 
Administer additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis.
 
 
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o
For Grade 2 diarrhea/colitis,  administer oral corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis, 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. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
 
 
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o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 

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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
 
 
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Table 4 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion interruption 
not 
indicated; 
intervention 
not 
indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic medications indicated for 
< =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate 
premedication 
should 
be 
permanently discontinued from further trial 
treatment administration.
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief 
interruption 
of 
infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
 
 
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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 be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after
the last dose of study therapy.
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with 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.
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.
 
 
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Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
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.

The marketing approval of MK-3475 for melanoma, the completion of all safety 
follow-up or the time when a possibility of entry to second course is lost (e.g. the time 
of decision by investigator or subject for no enter to second course, the start of a new 
anti-cancer therapy, the delivery of marketed product of MK-3475 in each site, 6 
months from marketing approval), whichever occurs last
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:

Radiographic disease progression
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 
7.1.3.4

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

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 1 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.

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements
 
 
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
The subject is lost to follow-up

Administrative reasons

The delivery of marketed product of MK-3475 in each site

6 months from marketing approval for melanoma
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Protocol 
Flow Chart) and Section 7.1.5 (Visit Requirements).
Temporary Discontinuation of Study Therapy after CR
5.8.1
Discontinuation of treatment may be considered for subjects who have attained an
investigator-determined confirmed CR per modified RECIST 1.1 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 per modified RECIST 1.1 may be eligible for up to 1 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.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Treatment Phase
6.1
Treatment Cycle (Week) / Title:
Screening
Treatment Cycles (2 mg/kg Q3W) 1)
End of
Treatment
Post-Treatment
(-4)
1
(0)
2
(3)
3
(6)
4
(9)
5
(12)
6
(15)
7
(18)
8 (21)
and beyond
Discon
Safety
Follow-up
Follow Up
Visits 2)
Survival
Follow-Up 3)
Scheduling Window (Days):
-28
±3
±3
±3
±3
±3
±3
±3
At time of
Discon
30 days (±3) 
post discon
Every 12 weeks (±7)
post discon
Administrative Procedures
Informed Consent 4)
X
Informed Consent for Future Biomedical 
Research (Optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior/Concomitant Medication Review 5)
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events 6)
X-------------------------------------------------------------------------------------------------------------------------X
Full Physical Examination 7)
X
X
X
Directed Physical Examination 7)
X
X
X
X
X
X
X
Vital Signs, Height and Weight 8)
X
X
X
X
X
X
X
X
X
X
12-Lead ECG 9)
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test (Urine or Serum β-HCG) 10)
X
Coagulation Parameters 11), 12)
X
Hematology and Chemistry 12)
X
X
X
X
X
X
X
X
X
X 13)
Urinalysis 12)
X
X
X
X 13)
FT3, FT4 and TSH 12)
X
X
X
X
X 13)
KL-6, β-D glucan 14)
X
Laboratory Procedures/Assessments: analysis performed by central laboratory
Pharmacokinetics 15)
X
X
X
X
X
Anti-MK-3475 Antibodies 15)
X
X
X
X
X
Correlative Studies Blood Collection 16)
X 17)
X
Blood for Future Biomedical Research (optional)
X 18)
Efficacy Measurements
 
 
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Treatment Cycle (Week) / Title:
Screening
Treatment Cycles (2 mg/kg Q3W) 1)
End of
Treatment
Post-Treatment
(-4)
1
(0)
2
(3)
3
(6)
4
(9)
5
(12)
6
(15)
7
(18)
8 (21)
and beyond
Discon
Safety
Follow-up
Follow Up
Visits 2)
Survival
Follow-Up 3)
Scheduling Window (Days):
-28
±3
±3
±3
±3
±3
±3
±3
At time of
Discon
30 days (±3) 
post discon
Every 12 weeks (±7)
post discon
Tumor Imaging 19)
X
X
X
X
Digital Photography (if applicable) 20)
X
X
X
X
Tumor Tissue Collection 21)
X
BRAF Testing 22)
X
1) In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle, and the window for each visit is ± 3 days unless 
otherwise specified.  Treatment cycles are 3 weeks (Q3W); however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines 
provided in Section 5.2.1.2.  If the interval is increased, all procedures except imaging should be performed based on the new dosing schedule.  
2) 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 12 weeks (± 1 week) 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. 
3) After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone every 12 weeks to assess for survival status.
4) 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 4 weeks prior to the first dose of trial treatment).  Screening
number will be assigned when the study informed consent is signed.  
5) Prior medications – Record all medications taken within 4 weeks of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for SAE/ECI s as defined in Section 7.2.
6) Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs occurring within 90 days after the last dose of trial treatment or 30 days of the 
end of treatment if the subject initiates new anticancer therapy, whichever is earlier. Report all ECIs occurring up until 90 days after the last dose of trial treatment or the start 
of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial treatment.  Adverse experiences and laboratory safety 
measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness.
7) Perform physical examinations at predose on the day of the study treatment visit. A full physical examination will be performed at screening and every 3 cycles after Cycle 5.
8) Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  If a patient's baseline weight does not fluctuate by more than 10%, this weight can be 
used to calculate dose.  Height will be measured at screening only.
9) ECG should be performed within 30 minutes of the end of infusion after dosing for Cycle 1 and Cycle 8, and 30 day post-discontinuation.
10) 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.
11) 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.  
12) Laboratory tests for screening are to be performed locally within 10 days prior to the first dose of trial treatment.  After Cycle 1, lab samples can be collected up to 72 hours 
prior to the scheduled time point.  Following Cycle 6, urinalysis should be performed every 6 cycles and FT3, FT4 and TSH should be performed every 2 cycles. See Section 
7.1.3 for details regarding laboratory tests.
13) 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.
14) KL-6 and β–D glucan will be measured for pulmonary evaluation at screening (within 10 days prior to the first dose of study treatment) and thereafter if a subject develops 
suspected pneumonitis, an additional test may be performed at the descretion of the investigator.
 
 
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15) Trough (pre-dose) and peak (post-dose) PK samples will be collected at Cycles 1 and 8.  A trough sample only will be collected at Day 1 of Cycles 2, 4, 9, 13 and 17
(following Cycle 17, every 4 cycles), 30 days after discontinuation of study drug, and 12 weeks and 24 weeks 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 and between 
72 to 168 hours (Day 4 to 8 of Cycles 1 and 8) 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 12 weeks and 24 weeks after discontinuation of study drug (or until the subject starts new anti-neoplastic therapy).  Procedures for sample collection 
are described in the Procedures Manual. 
16) Blood for transcriptional analyses should be collected prior to Cycle 1, postdose at Day 4 to 8 of Cycle 1 (between 72 to 168 hours after the end of the infusion of Cycle 1 with 
PK sample), and again at treatment discontinuation.  Blood for genetic analyses should be collected prior to Cycle 1.
17) The sample for genetic analysis should be collected unless there is a documented law or regulation or IRB/IEC ruling prohibiting a required collection for genetic analysis.
18) 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.
19) The initial tumor imaging will be performed within 4 weeks 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 4 weeks prior to the first dose of trial treatment.  On-study imaging should be performed every 
6 weeks initially (± 1 week) starting at 12 weeks through 48 weeks, and after 48 weeks, imaging assessments should be performed every 12 weeks (i.e. Screening visit, Cycles 
5, 7, 9, 11, 13, 15, 17 and then every 4 cycles [12 weeks]) 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; Sponsor will collect radiological assessments for retrospective analysis by a central vendor.  The 
processes for image collection and transmission to the central vendor are in the Investigator Imaging Operations Manual (IIOM).  After the first documentation of progression 
(if the subject is clinically stable) or response per modified RECIST 1.1 used in this protocol, repeat imaging for confirmation is required. Confirmatory imaging may be 
performed as early as 4 weeks later; alternately, the scan performed at the next scheduled timepoint may be used as confirmation.  CTs should include the chest, abdomen, and 
pelvis. A chest CT performed for tumor imaging will be used for pulmonary radiographic evaluation.
20) Qualitative digital photography should be performed at baseline and at time of scheduled tumor assessments for cutaneous lesions. Cutaneous lesions are not considered
measurable for the purposes of this protocol, but may be considered to be non-target lesions for tumor assessments by investigators. Copies of digital photographs should also 
be submitted to the central imaging vendor.
21) Tumor tissue for biomarker analysis from an archival tissue sample or newly obtained biopsy (core or excisional: FNA/EBUS not adequate) of a tumor lesion not previously 
irradiated must be provided to the central vendor for characterization of PD-L1 status.  These samples are not required to be obtained within 4 weeks of enrollment.  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 study will be retained for FBR.
22) BRAF V600 mutation analysis should be performed locally by the sites or at the central lab during screening in subjects without documented BRAF status.
 
 
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Second Course Phase (Retreatment ONLY)
6.2
Treatment Cycle (Week) / Title:
Treatment Cycles (2 mg/kg Q3W) 1)
End of
Treatment
Post-Treatment
1
(0)
2
(3)
3
(6)
4
(9)
5
(12)
6
(15)
7
(18)
8 (21)
and beyond
Discon
Safety
Follow-up
Follow Up
Visits 2)
Survival
Follow-Up 3)
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
At time of
Discon
30 days (±3) 
post discon
Every 12 weeks (±7)
post discon
Administrative Procedures
Eligibility Criteria (See Section 7.1.5.2.1)
X
Concomitant Medication Review 4)
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events 5)
X------------------------------------------------------------------------------------------------------------ X
Full Physical Examination 6)
X
X
X
Directed Physical Examination 6)
X
X
X
X
X
X
Vital Signs and Weight 7)
X
X
X
X
X
X
X
X
X
12-Lead ECG 8)
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test (Urine or Serum β-HCG) 9)
X
Coagulation Parameters 10), 11)
X
Hematology and Chemistry 11)
X
X
X
X
X
X
X
X
X
X 12)
Urinalysis 11)
X
X
X
X 12)
FT3, FT4 and TSH 11)
X
X
X
X
X
X 12)
KL-6, β-D glucan 13)
Laboratory Procedures/Assessments: analysis performed by central laboratory
Pharmacokinetics 14)
X
X
X
X
X
Anti-MK-3475 Antibodies 14)
X
X
X
X
X
Efficacy Measurements
Tumor Imaging 15)
X
X
X
X
Digital Photography (if applicable) 16)
X
X
X
X
 
 
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1) In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle, and the window for each visit is ± 3 days unless 
otherwise specified.  Treatment cycles are 3 weeks (Q3W); however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines 
provided in Section 5.2.1.2.  If the interval is increased, all procedures except imaging should be performed based on the new dosing schedule.  
2) 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 12 weeks (± 1 week) 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. 
3) After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone every 12 weeks to assess for survival status.
4) Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for SAE/ECI s as defined in 
Section 7.2.
5) Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs occurring within 90 days after the last dose of trial treatment or 30 days of the 
end of treatment if the subject initiates new anticancer therapy, whichever is earlier. Report all ECIs occurring up until 90 days after the last dose of trial treatment or the start 
of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial treatment.  Adverse experiences and laboratory safety 
measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness.  
6) Perform physical examinations at predose on the day of the study treatment visit. A full physical examination will be performed at predose of the first dose of trial retreatment
and every 3 cycles after Cycle 5.
7) Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  If a patient's baseline weight does not fluctuate by more than 10%, this weight can be 
used to calculate dose.
8) ECG should be performed within 30 minutes of the end of infusion after dosing for Cycle 1 and Cycle 8, and 30 day post-discontinuation.
9) 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.
10) Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.  
11) Laboratory tests for determining eligibility for Second Course Phase are to be performed locally within 10 days prior to the first dose of trial retreatment.  After Cycle 1, lab 
samples can be collected up to 72 hours prior to the scheduled time point.  Following Cycle 6, urinalysis should be performed every 6 cycles and FT3, FT4 and TSH should be 
performed every 2 cycles. See Section 7.1.3 for details regarding laboratory tests.
12) 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.
13) KL-6 and β–D glucan will be measured if a subject develops suspected pneumonitis; an additional test may be performed at the descretion of the investigator.
14) A trough (pre-dose) PK sample will be collected at Day 1 of Cycles 1, 2, 4, 8, 9, 13 and 17 (following Cycle 17, every 4 cycles), 30 days after discontinuation of study drug, 
and 12 weeks and 24 weeks 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 12 weeks and 24 weeks
after discontinuation of study drug (or until the subject starts new anti-neoplastic therapy).  Procedures for sample collection are described in the Procedures Manual. 
15) The Second Course Cycle 1 scan will be performed within 4 weeks prior to restarting with trial treatment in the Second Course Phase after relapse from CR, PR or SD.  
Imaging should be performed every 6 weeks initially (± 1 week) starting at 12 weeks through 48 weeks, and after 48 weeks, imaging assessments should be performed every 
12 weeks (i.e. Cycles 1, 5, 7, 9, 11, 13, 15, 17 and then every 4 cycles [12 weeks]) 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; Sponsor will collect radiological assessments for retrospective analysis 
by a central vendor.  The processes for image collection and transmission to the central vendor are in the Investigator Imaging Operations Manual (IIOM).  After the 
documentation of progression (if the retreated subject is clinically stable) or response per modified RECIST 1.1 used in this protocol, repeat imaging for confirmation is 
required. Confirmatory imaging may be performed as early as 4 weeks later; alternately, the scan performed at the next scheduled timepoint may be used as confirmation. CTs 
should include the chest, abdomen, and pelvis. A chest CT performed for tumor imaging will be used for pulmonary radiographic evaluation.
16) Qualitative digital photography should be performed at baseline and at time of scheduled tumor assessments for cutaneous lesions. Cutaneous lesions are not considered
measurable for the purposes of this protocol, but may be considered to be non-target lesions for tumor assessments by investigators. Copies of digital photographs should also 
be submitted to the central imaging vendor.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator to ensure that the 
subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator. 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.  Record any prior cancer other than the current 
cancer evaluated in this study even if diagnosed greater than 10 years prior to the first dose of 
MK-3475. History of melanoma 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 will review prior medication use, including any protocol-specified washout 
requirement, and record prior medication taken by the subject within 4 weeks before starting 
the trial.  In addition, record all treatments for a prior cancer other than melanoma even if 
taken greater than 4 weeks prior to starting the trial therapy.  Prior treatments for melanoma
will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator will record medication, if any, taken by the subject during the trial from start 
of study treatment through the 30-day safety follow-up visit.  After the safety follow-up visit 
record all medications related to reportable SAEs and ECIs 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 will obtain prior and current melanoma disease details.  BRAF status must
be collected.  If the site is unable to provide the documentation, then the Sponsor will offer
this molecular testing of the tumor to be performed locally by the sites or at the central lab 
during screening. NRAS and c-KIT status will also be collected if available. Detailed 
instructions for tissue collection, processing and shipment are provided in the Procedure 
Manual.
7.1.1.6.2 Prior Treatment Details
The investigator will review all prior cancer treatments for melanoma including systemic 
treatments, radiation and surgeries.
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator 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 allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.8
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a
randomization number. The randomization number identifies the subject for all procedures
occurring after 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.
 
 
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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.  The instructions for preparing and 
administering MK-3475 will be provided in the Procedures Manual.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring
The investigator 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 Appendix 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 the separate guidance document in the Investigator Trial File 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
The investigator will perform a full 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 cycles that do 
not require a full physical exam per the Trial Flow Chart, the investigator will perform a 
directed physical exam as clinically indicated prior to trial treatment administration.  After 
the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
 
 
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7.1.2.3
Vital Signs, Height and Weight
The investigator 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.  
Patients must be resting in a sitting position for approximately 10 minutes prior to obtaining 
vital signs. If a patient's baseline weight does not fluctuate by more than 10%, this weight 
can be used to calculate dose.  Height will be measured at screening only.
If blood pressure is >150/100 mmHg in a patient without a history of hypertension, or 
increased >20 mmHg (diastolic) from baseline measurement in a patient with a previous 
history of hypertension, the assessment should be repeated in 10 minutes for confirmation. 
7.1.2.4
12-lead ECG
A standard 12-lead ECG will be performed within 30 minutes of the end of infusion after 
dosing using local standard procedures as specified in the Trial Flow Chart (Section 6.0) by
the investigator. Clinically significant abnormal findings at screening should be recorded as 
medical history. After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator will assess ECOG status (see Section 12.4) as specified in the Trial Flow 
Chart.
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, including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per subject can be found in Procedure Manual.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
Table 5  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 
Free triiodothyronine (FT3)
Red Blood Cell 
Count
Lactate dehydrogenase (LDH)
Microscopic exam, if 
abnormal 
results 
are 
noted
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Creatinine
Urine pregnancy test*
Thyroid 
stimulating
hormone (TSH)
Absolute 
Lymphocyte 
Count
Uric Acid
HIV antibody**
Calcium
HBsAg**
Chloride
HCV RNA**
Glucose
KL-6
Phosphorus
β-D glucan
Potassium
IgG**
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.  
** For screening visit only.
Laboratory tests (hematology, serum chemistry, urinalysis, coagulation parameters, thyroid 
function, KL-6, and β-D glucan) 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 and found to be acceptable prior to each dose of trial treatment.
PT/INR and aPTT will be collected as coagulation parameters.
TSH, FT3, and FT4 will be measured for thyroid function test.
 
 
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Testing for HIV 1/2 antibodies, HBsAg, and HCV RNA (qualitative) will be performed at
screening. If results of these tests obtained within 3 months before screening are available,
they can be used even before consent is obtained.
For women of reproductive potential, a urine/serum pregnancy test will be performed within
72 hours of the first dose. If urine pregnancy results cannot be confirmed as negative, a
serum pregnancy test will be required.
KL-6 is a lung-specific marker for pneumonitis [19]. β-D glucan is a marker for fungus
infectious disease [20], and is used for the differential diagnosis for pneumonitis. KL-6 and
β-D glucan will be measured before starting the tratment courses, and thereafter if a subject 
develops suspected pneumonitis, an additional test will be performed as needed by 
investigator’s judgment.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Blood Collection for Serum Pharmacokinetics of MK-3475
The timepoints for PK blood sampling are described in Section 6 – Trial Flow Chart.  Sample 
collection, storage and shipment instructions for the samples will be provided in the 
Procedures Manual.
Every effort should be made to collect blood samples for PK after the discontinuation visit 
for up to 24 weeks from the last dose of MK-3475 or until start of a new anti-cancer therapy, 
whichever occurs first. 
7.1.3.2.2 Blood Collection for Serum Anti-MK-3475 Antibodies
The timepoints for Anti-MK-3475 Antibodies blood sampling are described in Section 6 –
Trial Flow Chart.  Sample collection, storage and shipment instructions for the samples will 
be provided in the Procedures Manual.
Every effort should be made to collect blood samples for anti-MK-3475 antibodies after the 
discontinuation visit for up to 24 weeks from the last dose of MK-3475 or until start of a new 
anti-cancer therapy, whichever occurs first. 
7.1.3.2.3 Blood Collection for Correlative Studies
Blood for correlative biomarker studies and genetic analysis should be collected as specified 
in the Trial Flow Chart.  Sample collection, storage and shipment instructions for the samples 
will be provided in the Procedures Manual.  The genetic sample should be collected unless 
there is a documented law or regulation or IRB/IEC ruling prohibiting a required collection 
for genetic analysis.
 
 
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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
7.1.3.4
Tumor Imaging and Assessment of Disease
The tumor imaging (CT or MRI) for screening should be performed within 4 weeks 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 central imaging 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 4 weeks prior to the 
first dose of trial treatment.
The same imaging technique should be used in a subject 
throughout the study.  
Tumor imaging should be performed every 6 calendar weeks (± 1 week) starting at 12 weeks 
through 48 weeks, and after 48 weeks, imaging assessments should be performed every 12 
calendar weeks (± 1 week) (i.e. Screening visit, Cycles 5, 7, 9, 11, 13, 15, 17 and then every 
4 cycles [12 weeks]) or more frequently if clinically indicated.
Tumor imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts or extension 
of MK-3475 cycle frequencies. Tumor response will be assessed using irRC (See Section 
12.6) and the RECIST 1.1 criteria (See Section 12.5) by the central independent radiology 
review.
After the first documentation of progression per RECIST 1.1, it is at the discretion of the 
investigator to keep a clinically stable subject on trial treatment or to stop trial treatment until 
at least 4 weeks later confirms progression or scheduled next confirmatory scan (6 or 12 
weeks later from the first documentation of progression). When feasible, subjects should not 
be discontinued until progression is confirmed per modified RECIST 1.1 criteria, in which a 
confirmation assessment of disease progression must be obtained at least 4 weeks after the 
initial disease assessment indicating progressive disease 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 
No additional 
imaging required
N/A
Repeat scan 
shows SD, 
PR or CR
Continue regularly 
scheduled imaging 
assessments every 
6 weeks (every 12 
weeks after 48 
weeks)
Continue study 
treatment at the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments every 
6 weeks (every 12 
weeks after 48 
weeks)
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
Investigator’s 
discretion
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation.  If progression is confirmed, then the subject will be discontinued from trial 
treatment.
If progression is not confirmed, then the subject should resume/continue trial 
treatment and have their next scan according to the every 6 week schedule (every 12 weeks 
schedule after 48 weeks).  
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans 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 12 weeks (± 1 week) 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.  
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1 
will be used to determine subject eligibility.  The Sponsor will also receive radiologic images 
for a retrospective analysis of subject eligibility and treatment response to be performed by a 
central vendor, including RECIST 1.1 and irRC.
 
 
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7.1.3.5
Photography for Cutaneous Lesions
Digital photographs documenting measureable cutaneous lesions should be obtained if the 
cutaneous lesion is included as part of the non-target lesions for disease assessment
according to RECIST 1.1.
Copies of the photograph should be forwarded to the central 
vendor for potential retrospective analysis. 
The timing for capturing cutaneous lesion 
photographs should follow the same schedule as the imaging scans. The requirement for the 
digital photographs and the process for transmitting photographs to the central vendor is 
located in the Procedures Manual.
7.1.3.6
Pulmonary Radiographic Evaluation for MK-3475-Induced Pneumonitis
Pulmonary radiographic imaging is used in a diagnosis of MK-3475-induced pneumonitis. A
chest CT performed for tumor imaging may be used for pulmonary radiographic evaluation.  
For a subject with suspected pneumonitis based on respiratory symptoms, other clinical
findings or laboratory findings, a chest CT should be performed immediately. If a finding on
pneumonitis is observed, the subject should be followed every month with chest imaging to
monitor the pneumonitis.
Pulmonary radiographic evaluation will be performed according to the table in Section 6.0.  
The investigator will judge whether the variation after the study drug administration is an 
adverse experience or not and record it in the Case Report Form.
Additionally, an independent radiologist will review chest CTs of all subjects for pulmonary
radiographic evaluation. For this purpose, the chest CT imaging will be submitted to the
SPONSOR.
7.1.3.7
Tumor Tissue Collection
Participation in this trial will require submitting tumor sample for PD-L1 expression
evaluation.  This specimen will be evaluated at a central laboratory for expression status of 
PD-L1 by IHC.  Tumor tissue for biomarker analysis from an archival tissue sample or newly 
obtained core or excisional biopsy of a tumor lesion not previously irradiated must be 
provided at screening.  Subjects without archival sample may obtain a new biopsy at the 
discretion of the investigator.  Needle or excisional biopsies, or resected tissue is required. A 
fine needle aspirate (including EBUS-TBNA), or cytologic specimen will not be acceptable.  
Both PD-L1 positive and negative subjects will be enrolled in this trial, and the clinical 
activity in both subsets will be evaluated as a pre-defined subgroup analysis.  
Site must be able to provide documentation of the subject’s tumor BRAF mutation status.
BRAF V600 testing can be performed locally by the sites or at the central lab during 
screening, if not already known when the subject signs informed consent.
 
 
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These samples are not required to be obtained within 4 weeks of enrollment.  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 study will be retained for FBR.
Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the 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.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
 
 
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7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained with the study 
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:
None
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
Up to 4 weeks 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 study must be obtained prior to performing any protocol specific 
procedure.  After providing consent, subjects will be assigned a screening number. 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 4 weeks prior to the first dose of trial 
treatment except for the following:

Laboratory tests (hematology, serum chemistry, urinalysis, coagulation parameters,
thyroid function test, KL-6, and β-D glucan) 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).

If results of HIV 1/2 antibodies, HBsAg, and HCV RNA (qualitative) test obtained
within 3 months before screening are available, they can be used even before consent 
is obtained.

Archival tumor biopsy for PD-L1 characterization is not required to be obtained 
within 4 weeks prior to the first dose of trial treatment.
 
 
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Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures. Subject will be received study
treatment until the subject meets 5.8 Discontinuation criteria.
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 1 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 modified 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
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.  
 
 
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
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 not 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 1 additional year.  Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart.
7.1.5.3
Discontinuation
When a subject discontinues trial treatment in treatment period and/or retreatment period,
procedures for discontinuation will be conducted.
7.1.5.4
Post-Treatment Visits
7.1.5.4.1 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 baseline until the beginning of a new anti-neoplastic therapy, whichever 
occurs first.  SAEs that occur within 90 days of the end of treatment or 30 days of the end of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, 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.
 
 
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7.1.5.4.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (± 1 week) by 
radiologic imaging to monitor disease status and collect serum samples for pharmacokinetics 
and anti-MK-3475 antibodies as specified in the Trial Flow Chart (Section 6.0).  Every effort 
should be made to collect information regarding disease status and serum samples until the 
start of new anti-neoplastic therapy, disease progression, withdrawal of consent, death, or the 
end of the study, whichever occurs first.  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.   
7.1.5.4.3 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 every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
 
 
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Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 500% over the prescribed dose (> 10 mg/kg). 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 by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a
subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
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.
 
 
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Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 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).
 
 
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Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
3. Additional Adverse Events:
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune –
Related Adverse Event Guidance Document”). This document can be found in the 
administrative binder and provides guidance regarding identification, evaluation and 
management of ECIs and irAEs.
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
to the SPONSOR within 24 hours of the event, regardless of attribution to study 
treatment, consistent with standard SAE reporting guidelines and either by electronic 
media or paper.Sponsor Contact information can be found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose. Lab results should 
beevaluated and subjects should be asked for signs and symptoms suggestive of an 
immune - related event. Subjects who develop an ECI thought to be immune -related 
should have additional testing to rule out other etiologic causes. If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes. If no other cause is found, then it is assumed 
to be immune-related.
 
 
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7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study
Evaluating Adverse Events
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 7  Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product 
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
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.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Efficacy and Safety Evaluation Committee
7.3.1
The Efficacy and Safety Evaluation Committee (ESEC) will be established for the purpose of
evaluating the safety information of this study from the specialist and objective viewpoints to
ensure the safety of subjects.
The details of the ESEC are prescribed by separate instructions.
Independent Pulmonary Radiographic Adviser
7.3.2
An independent pulmonary radiographic adviser will review pulmonary radiographic
changes and its features using chest CT imaging.  The details of the independent pulmonary 
radiographic adviser are prescribed by separate instructions.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
The primary purpose of this study is to investigate the safety, tolerability, and anti-tumor 
activity of MK-3475 administered intravenously to subjects with advanced melanoma.
Efficacy Analyses
8.1.1
The full analysis set (FAS) population (defined as all subjects with a baseline scan with 
measurable disease 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.  Overall response rate based on RECIST 1.1 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 (ORR=10%) based on the binomial 
distribution will be provided for the response rate.  The study 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 8 below.
 
 
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Table 8 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 
central radiology review 
Exact test of binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Secondary:
Overall RECIST 1.1
response rate based on site 
assessment
Exact methods for binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Progression-free survival
(RECIST 1.1)
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
Response duration
(RECIST 1.1)
Summary statistics using 
Kaplan-Meier method
All responders
Non-responders are 
excluded in analysis
Overall survival
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
Overall irRC response rate 
based on central radiology 
review 
Exact methods for binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Progression-free survival
(irRC)
Summary statistics using 
Kaplan-Meier method
FAS
Censored at last 
assessment
Response duration (irRC)
Summary statistics using 
Kaplan-Meier method
All responders
Non-responders are 
excluded in analysis
Safety Analyses
8.1.2
The All-Patients-as-Treated population will be employed for safety analyses.
Power and Sample Size 
8.1.3
In this study, approximately total 35 subjects with advanced melanoma will be enrolled, 
among them at least 28 from cutaneous melanoma and at most 7 from mucosal melanoma. 
The at least 28 cutaneous melanoma subjects are the main analysis population. At most 7
subjects with mucosal melanoma are population for exploratory analysis.  
With approximately 28 evaluable subjects with advanced cutaneous melanoma, the study has 
approximately 90% 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 7/28 responses.  The actual number of subjects enrolled may be 
larger than 28 to ensure that at least 28 subjects are evaluable for main analysis.
 
 
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Statistical Analysis Plan
8.2
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment. 
Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.2.3
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 will be 
determined by the central independent radiology review.
Key secondary efficacy endpoints include:

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; (3) overall survival (OS) ; (4) Response rate based on irRC ; (5) duration of response
based on irRC and (6) progression-free survival (PFS) based on irRC.
Immunogenicity/pharmacokinetics endpoints are exploratory endpoints in this study.
Immunogenicity endpoint include anti-MK-3475 antibody and pharmacokinetics endpoints
include pharmacokinetic parameters of MK-3475.
 
 
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8.2.3.2
Safety Endpoints
A description of safety measures is provided in Section 4.2.3.1.  
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, 12-
lead ECG and physical examinations.
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all allocated subjects with 
subjects excluded for the following reasons:

Failure to receive at least one dose of study treatment,

Lack of baseline data for those analyses that require baseline 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 Patients as Treated (APaT) population will be used for the analysis of safety data in
this study.  The APaT population consists of all allocated subjects who received at least one 
dose of study treatment. 
At least one laboratory, 12-lead ECG 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. 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
For the primary efficacy endpoint centrally reviewed RECIST 1.1 response rate, the point 
estimate, 95% confidence interval, and p-value for testing the RECIST 1.1 response rate is 
greater than the historical control 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.
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 9 summarizes the key efficacy analyses.
Table 9 Analysis Strategy for Key Efficacy Variables
Endpoint/Variable‡
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Hypothesis #1
Overall RECIST 1.1 response 
by central radiology assessment
P
Exact test of 
binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Secondary Hypothesis #1
Overall RECIST 1.1 response rate 
based on site assessment
P
Exact methods for 
binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Progression-free survival
(RECIST 1.1)
P
Summary statistics 
using Kaplan-
Meier method
FAS
Censored at last 
assessment
Response duration
(RECIST 1.1)
P
Summary statistics 
using Kaplan-
Meier method
All 
responders
Non-responders are 
excluded in analysis
Overall survival
P
Summary statistics 
using Kaplan-Meier 
method
FAS
Censored at last 
assessment
Overall irRC  response rate based 
on central radiology review 
P
Exact methods for 
binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
Progression-free survival
(irRC)
P
Summary statistics 
using Kaplan-
Meier method
FAS
Censored at last 
assessment
Response duration
(irRC)
P
Summary statistics 
using Kaplan-
Meier method
All 
responders
Non-responders are 
excluded in analysis
 †
P=Primary approach; S=Secondary approach.
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.
 
 
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8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements. 
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
Baseline characteristics will be assessed by the use of tables and/or graphs. No statistical 
hypothesis tests will be performed on these characteristics.  The number and percentage of 
subjects screened, randomized, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed.  Demographic variables (e.g., age, gender), 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized either by descriptive statistics or categorical tables.
8.2.5.4
Statistical Methods for Immunogenicity/pharmacokinetics endpoints Analyses
Summary statistics (mean, standard deviation and range) will be provided
for 
pharmacokinetics measures of MK-3475 and appropriate plots will be generated on 
pharmacokinetic profiles.
Summary statistics will also be provided for anti-MK-3475 antibody.
Multiplicity
8.2.6
The false positive rate for testing the primary efficacy endpoint is controlled at 0.025 (1-
sided).  No additional multiplicity adjustment is required.
Sample Size and Power Calculations
8.2.7
In this study, approximately total 35 subjects with advanced melanoma will be enrolled, 
among them at least 28 from cutaneous melanoma and at most 7 from mucosal melanoma. 
The 28 cutaneous melanoma subjects are the main analysis population. 7 subjects with 
mucosal melanoma are population for exploratory analysis.  
With approximately 28 evaluable subjects with cutaneous melanoma, the study has 
approximately 90% 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 in large phase III trials for standard single agent 
chemotherapy in melanoma [21-30].  Success for this hypothesis requires at least 7/28
responses.  The actual number of subjects enrolled may be larger than 28 to ensure that at 
least 28 subjects are evaluable for primary analysis.
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.2.8
Same efficacy and safety analysis will be conducted on PD-L1 positive subjects and PD-L1 
negative subjects, respectively.
Efficacy and safety analysis will also be conducted on BRAF, NRAS, and c-KIT mutation
status.
Although the main target population in this study is subjects with advanced cutaneous 
melanoma, same efficacy and safety analysis will be conducted on subjects with advanced 
mucosal melanoma exploratory.
Interim Analyses
8.2.9
No efficacy interim analyses are planned in this trial.
The analysis conducted at the time when all patients are enrolled and have either 
discontinued or have at least 24 weeks of follow-up since first dose is the main analysis time, 
if more  than 7 /28 responses observed at that time, the trial will declare positive and team 
will prepare for filing. After the main analysis, the study still follows patients for a longer 
period of time for duration of response and OS.  
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 Should be 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.
For each subject, percent compliance will then be calculated using the following formula:
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

x 100.
Summary statistics will be provided on percent compliance for the FAS population.
Extent of Exposure
8.2.11
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure 
for APaT population.
 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10.
After the time of the marketing approval of MK-3475, “clinical trial drug” of MK-3475 will 
be replaced with “post-marketing clinical trial drug”.  The subjects can receive treatment of 
MK-3475 as post-marketing clinical trial drug.
Table 10  Product Descriptions
Product Name & Potency
Dosage Form
MK-3475 100 mg/ 4mL
Solution for Injection
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label vials every 3 weeks (Q3W). Each kit will contain 1 vial.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
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Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal 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;
 
 
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3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further
agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
 
 
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Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice);
Good Post-marketing Study Practice, and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards, Good Post-marketing Study Practice, 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 
 
 
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since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a 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.
 
 
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Compliance with Trial Registration and Results Posting Requirements
10.4
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.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, Good Post-marketing Study Practice, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
 
 
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Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
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 
 
 
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Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1.
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
2.
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-
domaincontaining tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 
2001;98:13866-71.
3.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
is expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Cancer Res 2007;13:1757-61.
4.
Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-
L1 significantly associates with tumor aggressiveness and postoperative recurrence in 
human hepatocellular carcinoma. Clin Cancer Res 2009;15:971-9
5.
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. 
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are 
prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 2007;104:3360-5
6.
Mu CY, Huang JA, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung 
cancer may contribute to poor prognosis and tumor cells immune escape through 
suppressing tumor infiltrating dendritic cells maturation. Med Oncol. 2011;28:682-8.
7.
Liotta F, Gacci M, Frosali F,  uerci 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.
 
 
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8.
Shoo BA, Kashani-Sabet M. Melanoma arising in African-, Asian-, Latino- and Native-
American populations. Semin Cutan Med Surg. 2009;28:96-102.
9.
Ferlay J, Shin H-R, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide 
burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-917.
10. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA 
Cancer J Clin. 2011;61:69-90.
11. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 
2011;364:2517-26.
12. Sznol M, Powderly JD, Smith DC, Brahmer JR, Drake CG, McDermott DF, et al. Safety 
and antitumor activity of biweekly MDX-1106 (anti-PD-1, BMS-936558/ONO-4538) in 
patients with advanced refractory malignancies. Proc Am Soc Clin Oncol. 2010;28: 
abstr. 2506.
13. Topalian S, Sznol M, McDermott D, Kluger H, Carvajal R, Sharfman W. Safety, 
Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer. N Engl J Med. 
2012; (366):2443-2454.
14. Omid Hamid. “Preliminary Clinical Efficacy and Safety of MK-3475 (Anti-PD-1 
Monoclonal Antibody) in Patients with Advanced Melanoma.” Society of Melanoma 
Research. Los Angeles. 11 November 2012. Conference Presentation.
15. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and Tumor 
Responses with Lambrolizumab (Anti–PD-1) in Melanoma. New Eng J Med. 2013; 
369:134-144.
16. Topalian S, et al. Survival, Durable Tumor Remission, and Long-Term Safety in 
Patients With Advanced Melanoma Receiving Nivolumab.  J Clin Oncol. 2014;32
17. 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;45:228-47.
18. 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: 7412-20.
19. Kohno N, Awaya Y, Oyama T, Yamakido M, Akiyama M, Inoue Y, et al. KL-6, a 
mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial 
lung disease. Am Rev Respir Dis. 1993; 148:637-42.
20. Obayashi T, Yoshida M, Tamura H, et al. Determination of plasma (1/3)-β-D-glucan: a 
new diagnostic aid to deep mycosis. J Med Vet Mycol. 1992; 30: 275-80.
 
 
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21. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al.Improved 
survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 
2012;367:107-14.
22. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. 
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 
randomised controlled trial. Lancet 2012;380:358-65.
23. Patel PM, Suciu S, Mortier L, Kruit WH, Robert C, Schadendorf D, et al. Extended 
schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: Final 
results of a randomised phase III study (EORTC 18032). Eur J Cancer. 2011;47:1476-83.
24. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;64:2517-
26.
25. Chapman PB, Hauschild A, Robert C, Larkin JMG, Haanen JBAG, Ribas A, et al. 
Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, 
multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine 
(DTIC) in previously untreated patients with BRAF V600E-mutated melanoma. J Clin 
Oncol. 30(Suppl 15): (abstract 8502).
26. National Institute for Health and Clinical Excellence. Vemurafenib for treating locally 
advanced or metastatic BRAF V600 mutation-positive malignant melanoma. 2012.
27. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 
antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: 
The oblimersen melanoma study group. J Clin Oncol. 2006;24:4738-45.
28. Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, et al. Fotemustine 
compared with dacarbazine in patients with disseminated malignant melanoma: A phase 
III study. J Clin Oncol. 2004;22:1118-25.
29. Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen S, Seiter S, et al. Randomized 
phase III study of temozolomide versus dacarbazine in the treatment of patients with 
advanced metastatic malignant melanoma. J Clin Oncol. 2000;18:158-66.
30. Chapman PB, Einhorn LH, Meyers ML, saxman S, Destro AN, Panageas KS, et al. 
Phase III multicenter randomized trial of the dartmouth regimen versus dacarbazine in 
patients with metastatic melanoma. J Clin Oncol. 1999;17:2745-51.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and tumor specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The DNA and tumor
specimen(s) will be stored to provide a resource for future trials conducted by Merck 
focused on the study of biomarkers responsible for how a drug/vaccine enters and is 
removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may 
interact with, or other aspects of disease.  The specimen(s) may be used for future assay 
development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
 
 
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b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
 
 
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If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
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.
 
 
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The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
 
 
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In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
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.
 
 
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If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
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.
 
 
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12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Status
12.4
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
12.5
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.
*REFERENCE:
Eisenhauer E.A, Therasse P, Bogaerts J, Schwartz L.H, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009;45:228-47.
 
 
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Immune Related Response Criteria
12.6
For all patients who experience disease progression on study, the date noted for of disease
progression is the time of the scan where it is originally detected, and not the following date
of the confirmatory scan.
Definitions of measurable and non-measurable disease
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane
perpendicular diameters. Both its longest diameter and its longest perpendicular must be
greater than or equal to 10 mm or 2 times the axial slice thickness, whichever is greater.   
Lymph nodes must have a short-axis line-length of ≥ 15 mm. Malignant lymph nodes must
be measurable in 2 perpendicular diameters. 
Both its longest diameter and its longest
perpendicular must be greater than or equal to 15 mm or 2 times the axial slice thickness. 
The quantitative endpoint will be defined as the product of the longest diameter with its 
longest perpendicular.
Non-measurable disease: Non-measurable lesions are those that are not suitable for
quantitative assessment over time. These include:
1. Neoplastic masses that are too small to measure, because their longest uninterrupted
diameter or longest perpendicular are less than 10 mm or two times the axial slice
thickness.
2. Neoplastic masses whose boundaries cannot be distinguished. This includes masses which 
cannot be demarcated from surrounding tissue because of inadequate contrast, masses 
with overly complex morphology, or those with highly heterogeneous tissue composition.
3. Other types of lesions that are confidently felt to represent neoplastic tissue, but difficult 
to quantify in a reproducible manner. These include bone metastases, leptomeningeal 
metastases, malignant ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitis cutis/pulmonis, cystic lesions, ill defined abdominal masses, etc.
For irRC, only target lesions selected at baseline and measurable new lesions are taken 
into account.
At the baseline tumor assessment, the sum of the products of the two largest perpendicular 
diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and 
five cutaneous index lesions) is calculated.  
At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable 
lesions (≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral 
lesions) are added together to provide the total time-point tumor burden.
 
 
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Overall response using irRC:
Complete Response (irCR): Complete disappearance of all tumor lesions (whether
measureable or not, and no new lesions). CR must be confirmed by repeated, consecutive 
assessments made no less than 4 weeks from the date first documented.
Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive assessment 
at least 4 weeks after first documentation.
Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD.
Progressive Disease (irPD): At least 25% increase in SPD relative to nadir (minimum
recorded tumor burden) Confirmation by a repeat, consecutive assessment no less than 4 
weeks from the data first documented.
Please note other key differences between irRC and the original WHO criteria:
New measurable lesions will be incorporated into the SPD
New non measurable lesions do not define progression but preclude irCR
Non-index lesions contribute to defining irCR (complete disappearance required).
*REFERENCE
IrRC for the current protocol is adopted from the following reference:
Wolchok, JD, Hoos, A, O’Day S, et al., Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res. 
2009;15:7412-20.
 
 
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Clinical Study Conduct System
12.7
Clinical study conduct system in Japan is provided in Attachment by Japanese language.
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice and Good Post-marketing Study Practice.  I also 
agree to report all information or data in accordance with the protocol and, in particular, I 
agree to report any serious adverse events as defined in Section 7.0 – Assessing and 
Recording Adverse Events.  I also agree to handle all clinical supplies provided by the 
Sponsor and collect and handle all clinical specimens in accordance with the protocol.  I 
understand that information that identifies me will be used and disclosed as described in the 
protocol, and that such information may be transferred to countries that do not have laws 
protecting such information.  Since the information in this protocol and the referenced 
Investigator’s Brochure is confidential, I understand that its disclosure to any third parties, 
other than those involved in approval, supervision, or conduct of the trial is prohibited.  I will 
ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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