A Phase Ib Study of Pembrolizumab (MK-3475) in Chinese Subjects With Locally Advanced or Metastatic Melanoma (Keynote-151)
Phase: PHASE1
Conditions: Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase Ib Study of Pembrolizumab (MK-3475)
in Chinese Subjects with Locally Advanced or
Metastatic Melanoma (Keynote-151)
NCT02821000
18-March-2022

Product:  MK-3475 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
This protocol amendment is applicable only to China.
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, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase Ib Study of Pembrolizumab (MK-3475) in Chinese Subjects with Locally Advanced 
or Metastatic Melanoma (Keynote-151)
EudraCT NUMBER:  Not Applicable
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
TRIAL SUMMARY.................................................................................................. 12
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
Trial Diagram........................................................................................................ 14
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es).............................................................. 14
Secondary Objective(s) & Hypothesis(es)........................................................... 14
BACKGROUND & RATIONALE.......................................................................... 15
Background ........................................................................................................... 15
Pharmaceutical and Therapeutic Background .................................................... 15
Ongoing Clinical Trials....................................................................................... 17
Rationale................................................................................................................ 17
Rationale for the Trial and Selected Subject Population .................................... 17
Rationale for Dose Selection/Regimen............................................................... 18
Rationale for Endpoints ...................................................................................... 18
4.2.3.1
Safety Endpoints.......................................................................................... 18
4.2.3.2
Efficacy Endpoints....................................................................................... 19
4.2.3.3
Pharmacokinetic/Immunogenicity Endpoints.............................................. 20
Benefit/Risk ........................................................................................................... 20
METHODOLOGY ................................................................................................... 20
Entry Criteria........................................................................................................ 20
Diagnosis/Condition for Entry into the Trial...................................................... 20
Subject Inclusion Criteria.................................................................................... 20
Subject Exclusion Criteria .................................................................................. 22
Trial Treatment(s) ................................................................................................ 24
Dose Selection/Modification .............................................................................. 24
5.2.1.1
Dose Selection (Preparation) ....................................................................... 24
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 24
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Timing of Dose Administration.......................................................................... 29
Trial Blinding/Masking....................................................................................... 30
Randomization or Treatment Allocation............................................................ 30
Stratification.......................................................................................................... 30
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 30
Allowed Concomitant Medications .................................................................... 30
Prohibited Concomitant Medications.................................................................. 30
Rescue Medications & Supportive Care............................................................. 31
Supportive Care Guidelines for MK-3475.......................................................... 31
Diet/Activity/Other Considerations..................................................................... 32
Diet...................................................................................................................... 32
Contraception...................................................................................................... 32
Use in Pregnancy ................................................................................................ 34
Use in Nursing Women....................................................................................... 34
Subject Withdrawal/Discontinuation Criteria................................................... 34
Subject Replacement Strategy............................................................................. 35
Beginning and End of the Trial ........................................................................... 35
Clinical Criteria for Early Trial Termination ................................................... 36
TRIAL FLOW CHART ........................................................................................... 37
Treatment Phase ................................................................................................... 37
Second Course Phase (Retreatment ONLY) ...................................................... 40
TRIAL PROCEDURES ........................................................................................... 42
Trial Procedures ................................................................................................... 42
Administrative Procedures.................................................................................. 42
7.1.1.1
Informed Consent......................................................................................... 42
General Informed Consent.................................................................... 42
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 43
7.1.1.3
Subject Identification Card .......................................................................... 43
7.1.1.4
Medical History ........................................................................................... 43
7.1.1.5
Prior and Concomitant Medications Review............................................... 43
Prior Medications.................................................................................. 43
Concomitant Medications..................................................................... 43
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7.1.1.6
Disease Details and Treatments................................................................... 43
Disease Details...................................................................................... 43
Prior Treatment Details......................................................................... 44
Subsequent Antineoplastic Therapy Status........................................... 44
7.1.1.7
Assignment of Screening Number............................................................... 44
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 44
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 44
Clinical Procedures/Assessments........................................................................ 45
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 45
7.1.2.2
Physical Exam.............................................................................................. 45
7.1.2.3
Vital Signs, Height and Weight ................................................................... 45
7.1.2.4
12-lead Electrocardiogram (ECG)............................................................... 46
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 46
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 46
Initial Tumor Imaging........................................................................... 46
Tumor Imaging During Trial ................................................................ 46
End of Treatment and Follow-up Tumor Imaging................................ 47
Second Course (Retreatment) Tumor Imaging..................................... 47
Assessment of Disease.......................................................................... 48
Immune-related RECIST (irRECIST) .................................................. 48
7.1.2.7
Photography for Cutaneous Lesions............................................................ 51
7.1.2.8
Tumor Tissue Collection.............................................................................. 52
Laboratory Procedures/Assessments .................................................................. 52
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 52
7.1.3.2
Pharmacokinetic/ Immunogenicity Evaluations .......................................... 54
Blood Collection for Serum MK-3475 ................................................. 54
Blood Collection for Serum Anti-MK-3475 Antibodies ...................... 54
Other Procedures................................................................................................. 54
7.1.4.1
Withdrawal/Discontinuation........................................................................ 54
7.1.4.2
Blinding/Unblinding .................................................................................... 54
7.1.4.3
Calibration of Critical Equipment................................................................ 55
Visit Requirements.............................................................................................. 55
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7.1.5.1
Screening...................................................................................................... 55
7.1.5.2
Treatment Period.......................................................................................... 56
Second Course Phase (Retreatment Period) ......................................... 56
7.1.5.3
Discontinuation............................................................................................ 57
7.1.5.4
Post-Treatment Visits................................................................................... 57
Safety Follow-Up Visit......................................................................... 57
Follow-up Visits ................................................................................... 57
Survival Follow-up ............................................................................... 58
7.1.5.5
Survival Status ............................................................................................. 58
Assessing and Recording Adverse Events .......................................................... 58
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 59
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 59
Immediate Reporting of Adverse Events to the Sponsor.................................... 60
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............ 62
Evaluating Adverse Events................................................................................. 62
Sponsor Responsibility for Reporting Adverse Events ...................................... 65
STATISTICAL ANALYSIS PLAN ........................................................................ 65
Statistical Analysis Plan Summary ..................................................................... 65
Responsibility for Analyses/In-house Blinding .................................................. 65
Hypotheses/Estimation......................................................................................... 66
Analysis Endpoints ............................................................................................... 66
Efficacy Endpoints.............................................................................................. 66
Safety Endpoints ................................................................................................. 66
Analysis Populations............................................................................................. 66
Efficacy Analysis Populations ............................................................................ 66
Safety Analysis Populations ............................................................................... 67
Statistical Methods................................................................................................ 67
Statistical Methods for Efficacy Analyses.......................................................... 67
Statistical Methods for Safety Analyses ............................................................. 69
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 69
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Statistical 
Methods 
for 
Immunogenicity/pharmacokinetics 
endpoints 
Analyses.............................................................................................................. 69
Interim Analyses ................................................................................................... 69
Multiplicity ............................................................................................................ 69
Sample Size and Power Calculations .................................................................. 69
Subgroup Analyses and Effect of Baseline Factors ........................................... 70
Compliance (Medication Adherence).................................................................. 70
Extent of Exposure................................................................................................ 70
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 70
Investigational Product ........................................................................................ 70
Packaging and Labeling Information ................................................................. 71
Clinical Supplies Disclosure................................................................................. 71
Storage and Handling Requirements.................................................................. 71
Discard/Destruction/Returns and Reconciliation .............................................. 71
Standard Policies................................................................................................... 71
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 72
Confidentiality....................................................................................................... 72
Confidentiality of Data ....................................................................................... 72
Confidentiality of Subject Records..................................................................... 72
Confidentiality of Investigator Information........................................................ 72
Confidentiality of IRB/IEC Information............................................................. 73
Compliance with Financial Disclosure Requirements....................................... 73
Compliance with Law, Audit and Debarment ................................................... 73
Compliance with Trial Registration and Results Posting Requirements........ 75
Quality Management System............................................................................... 75
Data Management................................................................................................. 76
Publications ........................................................................................................... 76
LIST OF REFERENCES......................................................................................... 78
APPENDICES........................................................................................................... 80
Merck Code of Conduct for Clinical Trials........................................................ 80
ECOG Performance Status.................................................................................. 82
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............... 83
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors ................................................................ 84
Clinical Study Conduct System ........................................................................... 85
List of Abbreviations ............................................................................................ 86
SIGNATURES........................................................................................................... 89
Sponsor's Representative ..................................................................................... 89
Investigator............................................................................................................ 89
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 21
Table 2
Trial Treatment/Vaccination................................................................................... 24
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab ........................................................ 25
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 28
Table 5
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease (PD)........................................................................................................... 49
Table 6
Laboratory Tests ..................................................................................................... 53
Table 7
Evaluating Adverse Events..................................................................................... 63
Table 8
Censoring Rules for DOR....................................................................................... 68
Table 9
Analysis Strategy for Efficacy Variables................................................................ 68
Table 10 Two-sided 95% CI of ORR with 100 Evaluable Subjects...................................... 70
Table 11 Product Descriptions............................................................................................... 71
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LIST OF FIGURES
Figure 1 Trial Design Diagram ............................................................................................. 14
Figure 2 Imaging and Treatment for Clinically Stable Subjects after First 
Radiologic Evidence of PD Assessed by the Site .................................................. 50
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
151-06
18-Mar-2022
Added standard extension study language.
151-05
17-Nov-2017
Changes made to the guidelines for dose modification and toxicity management for 
irAEs table, to add additional information of guidelines for dose modification and 
toxicity management of infusion reactions related to pembrolizumab, and to clarify 
survival follow-up in order to align with the program standard language.
151-04
11-Aug-2017
Changes made to add the sample size, replace primary hypothesis testing with 
estimation, and add subgroup analysis of liver metastasis.
151-03
20-Mar-2017
Changes made to the responsible person to determine eligibility per RECIST 1.1
for the consistency with common practices in China oncology clinical trials.
151-02
03-Feb-2017
Changes made to accurately describe the treatment in terms of cycles instead of 
duration. 
Changes made to the inclusion and exclusion criteria, trial flow chart, dose 
modification and discontinuation criteria to make the protocol clearer and 
consistent with the standard required text in MSD’s pembrolizumab studies, 
Changes made to remove the analysis of 95% confidence interval for AE incidence 
rate as this was a single arm study.
151-01
04-Apr-2016
Changes made to remove the Future Biomedical Research (FBR) and Planned 
Genetic Analysis (PGA) related language based upon request from Human Genetic 
Resource Administration of China (HGRAC) office, and to add the urea to lab test 
as there was no routine test of blood urea nitrogen in some sites in China.
151-00
18-Dec-2015
Original protocol
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial 
Summary/Duration 
of
Participation
Added: Once the subject has 
achieved the study objective or
the study has ended, the subject
is discontinued from the study 
and may be enrolled in an 
extension study to continue 
protocol-defined
assessments 
and treatment.
To include extension study
2.2
Trial Diagram
Added: Study Completion and 
Pembrolizumab
Extension 
Study
5.10
Beginning and End of the Trial
Updated template language and 
added: Upon study completion, 
participants are discontinued 
and may be enrolled in a 
pembrolizumab 
extension 
study, if available.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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TRIAL SUMMARY
Abbreviated Title
Phase Ib Study of MK-3475 in Chinese Subjects with Advanced 
Melanoma
Trial Phase
Ib
Clinical Indication
The treatment of subjects with locally advanced or metastatic 
melanoma with disease progression following  previous first line  
chemotherapy therapy
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 100 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 12-2 
4 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject 
signs the informed consent form (ICF) through the final protocol-
specified contact.  
After a screening phase of 28 days, each subject will be assigned to 
receive trial treatment until disease progression is confirmed by the 
site per immune related Response Evaluation Criteria in Solid 
Tumors (irRECIST), unacceptable adverse event(s), intercurrent 
illness 
that 
prevents 
further 
administration 
of 
treatment, 
investigator’s decision to withdraw the subject, noncompliance with 
trial treatment or procedures requirements or administrative reasons 
requiring cessation of treatment, or until the subject has received 
35 administrations of pembrolizumab (approximately 2 years).  
Subjects who stop trial treatment after receiving 35 administrations 
of pembrolizumab for reasons other than disease progression or 
intolerability, or subjects who attain a complete response and have 
been treated for at least 24 weeks, and stop trial treatment may be 
eligible for up to 17 additional administrations of pembrolizumab 
(approximately one year) upon experiencing disease progression.  
After the end of treatment, each subject will be followed for the 
occurrence of adverse events as described under section 7.1.5.4.1 of 
the protocol.  
Subjects who discontinue for reasons other than disease progression 
will have post-treatment follow-up for disease status until disease 
progression is confirmed by the site per irRECIST, initiating a 
non-study cancer treatment, withdrawing consent, or becoming lost 
to follow-up. All subjects will be followed approximately every 
12 weeks by telephone for overall survival until death, withdrawal 
of consent, or the end of the study.
Once the subject has achieved the study objective or the study has 
ended, the subject is discontinued from the study and may be 
enrolled in an extension study to continue protocol-defined 
assessments and treatment.
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A list of abbreviations used in this document can be found in Section 12.8.
TRIAL DESIGN
Trial Design
This is an open-label, non-randomized, multi-center, Phase Ib study of MK-3475 in Chinese 
subjects with advanced melanoma to be conducted in conformance with Good Clinical 
Practices.  Approximately 100 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 objective response rate 
(ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in 
Chinese subjects with advanced melanoma.  Pharmacokinetics will also be characterized in 
this study by having additional blood collected from 30 subjects.  Subjects will be evaluated 
every 6 weeks starting at Week 12 through Week 48, and after Week 48, every 12 weeks 
with radiographic imaging to assess response to treatment.  Tumor response will be assessed 
using RECIST 1.1 by the blinded independent central review (BICR).  RECIST 1.1 as 
assessed by the site investigator will be used to determine eligibility and immune-related 
RECIST (irRECIST) 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 irRECIST), unacceptable toxicity, or completion of 
35 cycles (approximately 24 months ) of treatment with MK-3475 (refer to Section 5.8 for 
further details).  Subjects who attain an investigator-determined confirmed complete 
response (CR) may consider stopping trial treatment after receiving at least 8 cycles 
(approximately 24 weeks) of treatment (Treatment Phase).  Subjects who discontinue after 
attaining a CR or who complete 35 cycles (approximately 24 months) study treatment may be 
eligible for up to 17 cycles additional (approximately 1 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 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 and 
events of clinical interest 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 Progression Free Survival (PFS) of the efficacy endpoint in 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.
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Participation in this trial will require submitting an archival tissue sample or newly obtained 
biopsy of a tumor lesion not previously irradiated for programmed cell death ligand 1 
(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.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
The trial design is depicted in Figure 1 below.
Figure 1
Trial Design Diagram
OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
At a 2 mg/kg Q3W dose of MK-3475 in Chinese subjects with advanced melanoma: 
1) Objective:  To determine the safety and tolerability.
2) Objective: To evaluate the ORR based on RECIST 1.1 assessed by the BICR.
Secondary Objective(s) & Hypothesis(es)
At a 2 mg/kg Q3W dose of MK-3475 in Chinese subjects with advanced melanoma: 
1) Objective:  To evaluate the duration of response (DOR) and PFS per RECIST 1.1 
and irRECIST by BICR, ORR per irRECIST by BICR, and OS.
2) Objective:  To evaluate the pharmacokinetic (PK) profile.
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BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with PD-L1 and programmed cell death ligand 2 (PD-L2).  Based on preclinical 
in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an 
intravenous 
(IV) 
immunotherapy 
for 
advanced 
malignancies. 
 
Keytruda™ 
(pembrolizumab) is indicated for the treatment of patients across a number of indications. 
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475.
Pharmaceutical and Therapeutic Background
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 non-small-cell lung cancer (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 
China, approximately 9418 new cases of skin melanoma were diagnosed and approximately 
6154 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 locally advanced and 
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].  
Comparing to Western countries, there is a relatively high number of more mucosal (22.6%) 
and acral melanoma (50.8%) reported in China [12]. Mucosa melanoma tends to have poor 
prognosis.  The treatment option for advanced melanoma in China is very limited and the 
standard first therapy in China is limited to dacarbazine.  More effective treatment options 
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such as ipilimumab (IPI) are not available in China.  The overall prognosis of melanoma in 
China is worse than that of western countries, so there is an urgent need for new treatment 
options in China.  
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 [13-15].  Nivolumab has an 
observed objective response rate of 28% in melanoma subjects who had not previously 
received IPI [14]; 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 [16].  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 [16-17].  The median overall survival rate in 
melanoma of MK-3475 KEYNOTE-001 was not reached for the entire study population or 
for any of the individual dose schedules at the time of the analysis.  For all subjects and dose 
schedules the fraction of subjects alive at one year was more than approximately 80% [see 
Investigators Brochure (IB)].  Drug related adverse events (AEs) were reported for 340 of 
411 (83%) in KEYNOTE-001 (all melanoma subjects: Parts B1+B2+D).  The most common 
drug-related AEs in melanoma subjects, reported in at least 10% of subjects, were: fatigue 
(36.0%), pruritus (23.8%), rash (19.7%), nausea (12.2%), diarrhea (16.3%), arthralgia 
(15.6%), and vitiligo (10.7%) (unpublished internal data: as of 18-Oct-2013).  Safety data 
from KEYNOTE-001 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 subjects. 
The US FDA approval for pembrolizumab, STN BL 125514, relies on the results of a single, 
randomized (1:1), open-label, dose-ranging, multicenter cohort (Cohort B2) within a large, 
multi-stage, multiple cohort dose-finding, activity-estimating, safety and tolerability trial, 
Study KEYNOTE-001.  This sub-study is comprised of 173 subjects with advanced or 
unresectable melanoma, who had progressed on or within 24 weeks of receiving ipilimumab 
and, if their melanoma tumor was BRAF V600 mutation-positive, had also received a prior 
BRAF inhibitor, and were randomized and received at least one dose of study treatment.  All 
subjects were required to have evidence of active disease progression at the time of 
enrollment. Key exclusion criteria included the presence of autoimmune disease, requiring 
for therapeutic corticosteroids (> 10 mg prednisone/day), and severe autoimmune adverse 
drug reactions with prior ipilimumab therapy.
For the primary efficacy endpoint of ORR, according to Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) as assessed by BICR which included both radiologists and 
oncologists, the point estimate and 95% confidence interval will be provided using exact 
binomial distribution.  
Durable objective tumor responses were observed at a similar rate with both treatment 
regimens. Merck requested approval only for the lower dose administered in Cohort B2. The 
selection of this regimen as the recommended dose is appropriate since the anti-tumor 
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activity was similar between the two arms in Cohort B with respect to both objective
response rate and duration of response.
The safety database contained all adverse event information reported in 411 subjects with 
unresectable or metastatic melanoma who received pembrolizumab administered as an 
intravenous infusion at doses of 2 mg/kg every 3 weeks or 10 mg/kg every 2 weeks or 
10 mg/kg every 3 weeks.  This safety information was supplemented by complete safety 
information from sequential dose- escalation cohorts from Study KEYNOTE-001 and by the 
serious and unexpected adverse drug reactions reported in approximately 2000 subjects 
enrolled in completed or ongoing clinical trials of pembrolizumab.
Therefore, clinical development of MK-3475 would have a great significance in patients with 
advanced melanoma including the IPI-naïve population in China.
Ongoing Clinical Trials
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.  Two ongoing, randomized studies 
with active comparators (KEYNOTE-002/ KEYNOTE-006) for melanoma are ongoing.  For 
trial details please refer to the IB.
Rationale
Rationale for the Trial and Selected Subject Population
As described in 4.1.1 Pharmaceutical and Therapeutic Background, MK-3475 has shown to 
be very well-tolerated and efficacious measured by 24% objective response rates in 
melanoma subjects at clinically approved dose [16].  Recently published data indicated that 
the ORR of anti-PD1 agents in the Asian advanced melanoma population was around 
10-24% [18] [19]. Although it is lower than that in the Caucasian population, it is still higher 
than the ORR (3.7%) of dacarbazine in first line Chinese patients [20]. Also, non-clinical 
and clinical data obtained so far supports clinical development of MK-3475 in China.  
In China, treatment options for locally advanced and metastatic melanoma have been limited 
to chemotherapeutic agents such as dacarbazine.  Outside China, there has been steady 
progress in the development of targeted therapy and immunotherapy for locally advanced and
metastatic melanoma.  BRAF inhibitors (vemurafenib and dabrafenib), anti-Cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) mAb (IPI), and MEK inhibitor (trametinib) 
were approved for treatment of locally advanced and metastatic melanoma in the past few 
years; however these newly therapies have not been approved yet in China.  Available 
treatment options for Chinese patients such as cytotoxic chemotherapies have very limited 
activity even in the first-line setting. In a phase II, randomized, double-blind multicenter trial 
in Chinese population of first-line therapy, the efficacy rate in darcabazine arm is very 
limited with ORR 3.7%, median PFS 1.5 months and median OS 8 months [20]. There is no 
standard regimen for second-line therapy.  Thus, the outcome of patients with locally 
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advanced and metastatic melanoma still remains dismal and the development of new 
effective therapy represent an urgent need.  
This is an open-label, non-randomized, multi-center, Phase Ib trial of MK-3475 in Chinese 
subjects with advanced melanoma.  Subjects with prior history chemo-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.
Rationale for Dose Selection/Regimen
The dosing regimen of MK-3475 in this study was based on US approved treatment regimen 
and lack of ethnic difference in regard to the exposure and safety.  This dose regimen was 
supported by the results from the overseas phase I study (KEYNOTE-001, refer to IB),  PK 
of MK-3475 showed slow systemic clearance, limited volume of distribution, and a long 
half-life (13-21 days).  Pharmacodynamic data (IL-2 release assay) suggested durable 
peripheral target engagement (>21 days).  These early PK and pharmacodynamic data 
provide 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 35 cycles 
(approximately 24 months) of treatment with MK-3475 in the trial.  The only exception is 
those subjects who experience a confirmed CR; these subjects may discontinue treatment 
with MK 3475 at the discretion of the investigator (see Section 5.8.1 for details). 
KEYNOTE-001 study showed 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/PD 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 
subjects with advanced melanoma (unpublished internal data).
Preliminary data also revealed lack of ethnic factor on the PK of MK-3475.
Rationale for Endpoints
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 testing 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 
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by CTCAE criteria.  Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received MK-3475, including serious adverse events 
(SAEs) and events of clinical interest (ECIs).  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0.  The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, specific immune-related 
adverse events (irAEs) will be collected.
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 melanoma.  The secondary objectives are to evaluate DOR and PFS per 
RECIST 1.1, ORR, DOR, and PFS per irRECIST, and OS in subjects with advanced 
melanoma. Response rates per RECIST 1.1 [21] and irRECIST [22] will be evaluated by 
BICR.  RECIST 1.1 as assessed by the site investigator will be used to determine eligibility 
and irRECIST 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, irRECIST will be used with the adaptations (refer to Section 7.1.2.6.4), in which a 
confirmation assessment of disease progression must be obtained at least 4 weeks after the 
initial disease assessment indicating progressive disease.  
The irRECIST 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 
Computed Tomography (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).(refer to Section 7.1.2.6.4) 
Rationale for single arm design:
The key objectives for this study are to assess the safety, efficacy in patients with advanced 
melanoma. The nature of disease is progressive, and with very limited treatment option. 
Overall response has been commonly used to assess the efficacy of anti-tumor drug in single 
arm design setting. The study population for this study is patients who failed initial 
chemotherapy. 
In China, there is no standard second-line treatment for such patient 
populations. Therefore, no comparator could be used to support a randomized trial.  In 
addition, robust efficacy has been demonstrated in clinical trials leading to US approval, and 
similar efficacy is anticipated in Chinese and can be reasonably assessed using single arm 
design initially used in supporting the first approval in US. 
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Concerning the aggressive nature of disease per se and MK-3475 has been approved oversea 
based on the robust efficacy demonstrated in previous trials, the subjects may benefit from 
this trial.  Therefore, placebo controlled study has not been considered for this study. Similar 
approach has been used to support the approval of MK-3475 in US. 
In balance of science and ethical consideration, single arm design appears appropriate to 
meet the objectives of this study.
4.2.3.3
Pharmacokinetic/Immunogenicity Endpoints
Serum samples from 30 patients will be obtained to measure pharmacokinetics of MK-3475.  
In addition, potential of the formation of anti-MK-3475 antibody will also be evaluated for 
interpretation of immunogenicity results.  The PK endpoints and time points for PK blood 
sampling are consistent with our previous studies to allow adequate description of PK in this 
patient population.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with locally advanced or metastatic melanoma will be enrolled in this 
trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be of the Chinese descent born in China, and have a Chinese home address.
2. Be willing and able to provide written informed consent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent.
4. 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.

Overall proportion of subjects with mucosa melanoma will be no more than 22%.
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5. Have failed the first line chemotherapy (excluding adjuvant or neoadjuvant therapy) 
or targeted therapy for melanoma.
6. 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.  
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
8. Have an anticipated life expectancy of at least 3 months.
9. Demonstrate adequate organ function as defined in Table 1, all screening labs should
be performed within 10 days of treatment initiation.
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 transfusion or 
EPO dependent within 7 days )
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
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
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal
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)
10. 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.  
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Note: Subjects will be eligible to participate regardless of the level of PD-L1 
expression.
11. 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.
12. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
13. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 - Contraception, for the course of the 
trial through 120 days after the last dose of trial drug.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
14. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 - Contraception, starting with the first dose 
of trial therapy through 120 days after the last dose of trial therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
Subject Exclusion Criteria
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 agents.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigation device 
within 4 weeks of the first dose of treatment. 
3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the 
first dose of trial treatment or who has not recovered (ie., ≤Grade 1 or at baseline) 
from adverse events due to agents administered more than 4 weeks earlier.
4. Has had chemotherapy, targeted small molecule therapy, radiotherapy within 2 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.
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5. 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.
6. Is expected to require any other form of systemic or localized antineoplastic therapy
while in study.
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
Note: Subjects with previously treated brain metastases and clinically stable CNS 
metastases are allowed to participate (clinically stable 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 metastases by MRI, (2) the subject is off steroids for at least 
two weeks, and (3) any neurologic symptoms have returned to baseline).
8. Has active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
9. Is receiving systemic steroid therapy or any other form of immunosuppressive 
therapy within 1 week prior to the first dose of trial treatment.
10. Has an active infection requiring intravenous systemic therapy.
11. 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).
12. Has a known hypersensitivity to the components of the study drug or another
monoclonal antibody.
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
14. Is known to be Human Immunodeficiency Virus (HIV)-positive (HIV 1/2 antibodies).
15. Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive 
HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and 
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay.
16. 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.
17. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
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18. 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.
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.  
Table 2
Trial Treatment/Vaccination
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
MK-3475
2 mg/kg
Q3W
IV infusion
Day 1 of each 
cycle
Experimental
Trial treatment on the day of treatment allocation/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
5.2.1.1
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 MK-3475 exposure may 
represent an immunologic etiology.  These immune-related adverse events (irAEs) may occur 
shortly after the first dose or several months after the last dose of treatment and may affect 
more than one body system simultaneously. Therefore, early recognition and initiation of 
treatment is critical to reduce complications.  Based on existing clinical trial data, most irAEs 
were reversible and could be managed with interruptions of pembrolizumab, administration 
of corticosteroids and/or other supportive care. 
For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on 
the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab are provided in Table 3.
See Section 5.6.1 for supportive care 
guidelines for MK-3475.
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to: 
Guillain-Barre 
Syndrome,
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
AE=adverse event; ALT=alanine aminotransferase; AST= aspartate aminotransferase; CTCAE= Common Toxicity Criteria for Adverse Events; 
GI=gastrointestinal; irAE=immune related adverse event; IV=intravenous; T1DM=Type 1 diabetes mellitus. 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
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Dose Modification and Toxicity Management of Infusion-Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4. 
Table 4
Pembrolizumab Infusion Reaction Dose Modification and 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 therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 
100 mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the subject’s study record.
Refer to Section 7.1.5.2.1 for details of the Second Course Phase (Retreatment Period).
Timing of Dose Administration
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.
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.
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Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated by non-random assignment. Eligible 
subjects participating in this trial will be enrolled once a treatment number is assigned to the 
subject. Treatment allocation will occur centrally using an interactive voice response system
(IVRS).
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy 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.
Allowed Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
All 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
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.
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
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; however, intranasal influenza vaccines (eg,
FluMist®) are live attenuated vaccines and are not 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.

Generally, Traditional Chinese Medicine (TCM) is not recommend to use in this 
protocol, any usage of TCM should be discussed with sponsor’s clinical director 
case by case. 
o
Note: If the TCM
have clear anti-tumor effect, or have similar 
pharmacology profile as prohibited concomitant medication listed in protocol, 
then it will not be allowed.
o
Note: Any TCM with unclear pharmacology profile or component will not be 
allowed (drug label should be provided for case by case discussion). 
o
Note: Subject is not allowed to use Traditional Chinese medicine decoction 
without prescription. 
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.
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
Supportive Care Guidelines for MK-3475
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
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events with potential immunologic etiology are outlined with the dose modification 
guidelines in Section 5.2.1.2, Table 3.  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 of the event, it is determined not to be related to MK-3475, the 
investigator does not need to follow the treatment guidance.  Refer to Table 3 in 
Section 5.2.1.2 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR
(3) has a congenital or acquired condition that prevents childbearing.
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Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
•
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
•
Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
† Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
‡ If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of trial therapy.  If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study.
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Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject 
will immediately be removed from the trial treatment.  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 trial investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If 
a male subject impregnates his female partner the trial personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and followed as described above and 
in Section 7.2.2.
Use in Nursing Women
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.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue in the study in survival 
follow-up, as long as the subject does not withdraw consent. Once a subject has discontinued
initial treatment, he/she may be eligible for retreatment if deemed medically appropriate and
the subject meets the criteria, as outlined in Section 7.1.5.2.1
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.
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) requests to 
discontinue treatment.
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
Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if 
the Sponsor approves treatment continuation).

Unacceptable adverse experiences as described in Section 5.2.1.2

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.

Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment

Recurrent Grade 2 pneumonitis

Completed 35 treatments (approximately 2 years) of MK-3475
Note: 35 treatments (approximately 2 years) of study medication is calculated from 
the date of first dose. Subjects who stop MK-3475 after receiving 35 doses may be 
eligible for up to 17 cycles (1 year) additional study treatment if they progress after 
stopping study treatment provided they meet the requirements detailed in 
Section 7.1.5.2.1.

Discontinuation of treatment may be considered for subjects who have attained a
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), 
receiving at least 2 doses of MK-3475 beyond the date when the initial CR was
declared. 
Subjects who stop MK-3475 with stable disease (SD), partial response (PR), or CR, 
may be eligible for up to 1 year (17 cycles) of MK-3475 if they experience disease 
progression per irRECIST after stopping MK-3475.  This retreatment is termed the 
Second Course Phase (Retreatment) and is described in detail 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

The subject is lost to follow-up

Administrative reasons
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).
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems, 
or the number of discontinuations for administrative reasons is too high.
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TRIAL FLOW CHART
Treatment Phase
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
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
Survival Status 3)
<- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ->
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
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) 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)
HIV, HBsAg, HCV-Ab, HCV-RNA
X
Laboratory Procedures/Assessments: analysis performed by central laboratory
Pharmacokinetics 13) 14)
X
X
X
X
X
Anti-MK-3475 Antibodies 13)
X
X
X
X
X
Efficacy Measurements
Tumor Imaging 15)
X
X
X
X
X19)
X
Digital Photography (if applicable) 16)
X
X
X
X
X
Tumor Tissue Collection 17)
X
BRAF Testing 18)
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).  
2) In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue post treatment follow up 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) In subjects that experience documented disease progression or start a new anti-cancer therapy, contact should be made (e.g. by telephone) approximately every 12 weeks to 
assess for survival status. Additional survival follow-up contact between regularly performed calls may be performed based on pre-defined analyses in the protocol and/or for 
other data analyses purposes (for example, database locks).  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor 
notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status 
(excluding subjects that have a death event previously recorded).
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 30 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 (PEs) at predose on the day of the study treatment visit. A full PE will be performed at screening and every 3 cycles after Cycle 5. Directed PEs 
will be performed at other visits where full PE is not performed.
8) Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
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.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
10) 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.  
11) 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.
12) Unresolved abnormal labs that are drug related AEs should be followed until resolution or become non-clinically relevant.  Labs do not need to be repeated after the end of 
treatment if labs are within normal range.
13) PK analysis will be performed in 30 subjects. Both PK and anti- MK-3475 antibody for subjects who receive MK-3475; Pre-dose trough PK and anti- MK-3475 antibody 
samples will be collected at Cycles 1, 2, 4, 6, 8 and every 4 cycles thereafter. All pre-dose trough samples should be drawn within 24 hours before infusion of MK-3475.  
14) Among 30 subjects, additional post-dose peak PK samples will be drawn within 30 minutes after end of MK-3475 infusion at Cycles 1 and 8.  An additional single PK sample 
should be drawn at 24 hours (Day 2), between 72 and 168 hours (Day 4-8) and 336 hours (Day 15) after Cycle 1 dosing. Procedures for sample collection are described in the 
Procedures Manual. 
15) 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.  Tumor imaging will be performed every 6 weeks 
(±7 day window) starting at Week 12 through Week 48. Following Week 48, tumor imaging may be performed approximately every 12 weeks (±7 days; or whenever clinically 
indicated) while the patient remains on study therapy at the discretion of the investigator. Timing of imaging scans should follow the calendar and not be adjusted for treatment 
delays. Patients with an objective response or disease progression should have repeat imaging at least 4 weeks later to confirm the objective response or disease progression. CT 
scans are the required modality for measureable disease unless a patient has a clinical condition e.g. severe contrast allergy, or the lesions are significantly better visualized 
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through the use of an MRI. The same imaging technique has to be used in a patient throughout the study. CTs should include the chest, abdomen, and pelvis. Pulmonary 
radiographic imaging for pneumonitis will be performed based on symptoms, the chest CT performed for tumor imaging may 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.
17) 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. Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.  
18) BRAF V600 mutation analysis should be performed locally by the sites or at the central lab during screening in subjects without documented BRAF status.
19) In subjects who discontinue trial treatment, tumor imaging should be performed at the time of treatment discontinuation (±4 weeks).  If a previous scan was obtained within 4 
weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory.  In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
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Second Course Phase (Retreatment ONLY)
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)
-17(48)
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
Survival Status 3)
<- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ->
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
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) 8)
X
Coagulation Parameters 9), 10)
X
Hematology and Chemistry 10)
X
X
X
X
X
X
X
X
X
X 11)
Urinalysis 10)
X
X
X
X 11)
FT3, FT4 and TSH 10)
X
X
X
X
X
X 11)
HIV, HBsAg, HCV-Ab, HCV-RNA
X
Efficacy Measurements
Tumor Imaging 12)
X
X
X
X
X 14)
X
Digital Photography (if applicable) 13)
X
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).
2) In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue post treatment follow up 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)
In subjects that experience documented disease progression or start a new anti-cancer therapy, contact should be made (e.g. by telephone) approximately every 12 weeks to 
assess for survival status. Additional survival follow-up contact between regularly performed calls may be performed based on pre-defined analyses in the protocol and/or for 
other data analyses purposes (for example, database locks).  Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor 
notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status 
(excluding subjects that have a death event previously recorded).
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 30 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 (PEs) at predose on the day of the study treatment visit. A full PE will be performed at predose of the first dose of trial retreatment and every 
3 cycles after Cycle 5. Directed PEs will be performed at other visits where full PE is not performed.
7) Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.
8) 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.
9) Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy. Any subject receiving anticoagulant 
therapy should have coagulation factors monitored closely throughout the trial.
10) 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.
11) Unresolved abnormal labs that are drug related AEs should be followed until resolution or become non-clinically relevant.  Labs do not need to be repeated after the end of 
treatment if labs are within normal range.
12) 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.  Tumor imaging will be performed every 6 weeks
(±7 day window) starting at Week 12 through Week 48. Following Week 48, tumor imaging may be performed approximately every 12 weeks (or whenever clinically indicated) 
while the patient remains on study therapy at the discretion of the investigator. Timing of imaging scans should follow the calendar and not be adjusted for treatment delays. 
Patients with an objective response or disease progression should have repeat imaging at least 4 weeks later to confirm the objective response or disease progression. CT scans 
are the required modality for measureable disease unless a patient has a clinical condition e.g. severe contrast allergy, or the lesions are significantly better visualized through the 
use of an MRI. The same imaging technique has to be used in a patient throughout the study. CTs should include the chest, abdomen, and pelvis. Pulmonary radiographic 
imaging for pneumonitis will be performed based on symptoms, the chest CT performed for tumor imaging may be used for pulmonary radiographic evaluation
13) 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.
14) In subjects who discontinue trial treatment, tumor imaging should be performed at the time of treatment discontinuation (±4 weeks).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory.  In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
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TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
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.
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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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator.  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
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 therapy.  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.
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.
7.1.1.6
Disease Details and Treatments
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
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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.
Prior Treatment Details
The investigator will review all prior cancer treatments for melanoma including systemic 
treatments, radiation and surgeries.
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 treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
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 require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
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Administration of trial medication will be witnessed by the investigator and/or trial staff.  
The total volume of 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
7.1.2.1
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 a potentially immunologic etiology (irAE).  See Section 5.6.1 
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.
7.1.2.3
Vital Signs, Height and Weight
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart - Section 6.0.  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  
Subjects must be resting in a sitting position for approximately 10 minutes prior to obtaining 
vital signs. Height will be measured at screening only.
If blood pressure is >150/100 mmHg in a subject without a history of hypertension, or 
increased >20 mmHg (diastolic) from baseline measurement in a subject with a previous 
history of hypertension, the assessment should be repeated in 10 minutes for confirmation. 
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7.1.2.4
12-lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at 
screening.  Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) as 
specified in the Trial Flow Chart.
7.1.2.6
Tumor Imaging and Assessment of Disease
Processes for image collection and transmission to the central vendor can be found in the 
Procedure Manual.  The Site Imaging Manual will provide details on acquisition parameters 
and image transmission practices required for this trial. Tumor imaging is strongly preferred 
to be acquired by CT. Magnetic resonance imaging (MRI) should be used only when CT is 
contraindicated or for imaging of the brain. The same imaging technique regarding modality 
and the use of contrast should be used in a subject throughout the trial to optimize the 
visualization of existing and new tumor burden.
Initial Tumor Imaging
To meet screen criteria, initial tumor imaging must be performed within 4 weeks prior to 
treatment.  This scan will be considered the baseline assessment for the study.  The site 
investigator must review screening images to confirm the subject has at least one target 
lesion per standard RECIST 1.1.
Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality and performed within 4 weeks prior to randomization.
Tumor Imaging During Trial
The first on-study imaging assessment should be performed at 12 weeks from the date of first 
dose of MK-3475. Subsequent imaging should be performed every 6 weeks (± 7 days) 
starting at Week 12 through Week 48. After Week 48, the frequency of imaging will be 
every 12 weeks (± 7 days).  Imaging may be more frequent if clinically indicated. Imaging 
should not be delayed for delays in cycle starts.
Note: The exact same image acquisition and processing parameters should be used 
throughout the study.
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (i.e. 6 weeks later), whichever is clinically indicated.  Subjects will 
then return to regular scheduled imaging, starting with the next scheduled imaging time 
point. Subjects who obtain a confirmation scan do not need to undergo the next scheduled 
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tumor imaging if it is < 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.
At the time of the initial PD by RECIST 1.1 imaging scans should be sent to central vendor 
to verify progressive disease.  If PD is verified, the investigator may choose to continue 
treatment if the patient is clinically stable and repeat imaging in 4 weeks to confirm PD (by 
the site) by irRECIST.  Imaging should continue to be performed until documented disease 
progression, the start of new anti-cancer treatment, withdrawal of consent, death, or the end 
of the trial, whichever occurs first.  For subjects receiving MK-3475 per irRECIST disease 
progression should be confirmed at least 4 weeks after the first scan indicating PD in 
clinically stable subjects.  Subjects who have unconfirmed disease progression may continue 
on treatment until progression is confirmed provided they have met the conditions detailed in 
Section 7.1.2.6.2.
In clinically stable subjects, disease progression may be confirmed by the site at least 
4 weeks after the first scan indicating PD.
End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 weeks). If a previous scan was obtained within 4 weeks 
prior to the date of discontinuation, then a scan at treatment discontinuation is not mandatory. 
In subjects who discontinue trial treatment due to documented disease progression, this is the 
final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging every 
12 weeks (± 7 days) to monitor disease status until the start of a new anticancer treatment, 
disease progression, death, or the end of the trial, whichever occurs first.
Second Course (Retreatment) Tumor Imaging
A scan must be performed within 4 weeks prior to restarting treatment with pembrolizumab. 
Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility. Imaging should be submitted to the central imaging vendor for retrospective 
review.
The first on-trial imaging assessment should be performed at Week 12 (±7 days) after the 
restart of treatment.  Subsequent tumor imaging should be performed every 6 weeks 
(±7 days) from Week 12 through Week 48; after Week 48, tumor imaging may be performed 
approximately every 12 weeks, or more frequently if clinically indicated.
If tumor imaging shows initial PD per RECIST 1.1, tumor assessment should be repeated 
≥4 weeks later in order to confirm PD with the option of continuing treatment while awaiting 
radiologic confirmation of progression.  Subjects who obtain a confirmation scan do not need 
to undergo scheduled tumor imaging if it is <4 weeks later and may wait until the next 
scheduled imaging time point if clinically stable.
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Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating PD in clinically stable subjects. Additional irRECIST detail is described 
in Section 7.1.2.6.6.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. 
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging every 
12 weeks (±7 days) until either the start of a new anticancer treatment, disease progression, 
death, or the end of the trial, whichever occurs first.
Assessment of Disease
Standard RECIST 1.1 will be applied by the central imaging vendor as the primary measure 
for assessment of tumor response, date of disease progression, and as a basis for all protocol 
guidelines related to disease status. Scans showing site-assessed PD should be submitted to 
the central imaging vendor immediately. The site will be notified when the imaging vendor 
verifies disease progression using RECIST 1.1.
Immune-related RECIST (irRECIST)
Following PD by RECIST 1.1, sites will assess tumor response and progression per 
immune-related RECIST (irRECIST) for subjects receiving MK-3475 as this data will be 
collected in the clinical database. Tumor imaging should also be submitted to central 
imaging vendor for assessment of tumor response per irRECIST as this data will be collected 
in clinical database as well.
irRECIST is RECIST 1.1 adapted for use with immunotherapies as described in the 
Procedure Manual and irRECIST Tip Sheet.  
When feasible, subjects treated with pembrolizumab should not be discontinued until 
progression is confirmed by the local site investigator/radiology assessment. This allowance 
to continue treatment despite initial radiologic PD takes into account the observation that 
some subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. Subjects that are deemed 
clinically unstable are not required to have repeat tumor imaging for confirmation of PD. 
Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing nontarget lesion(s)

Development of new lesion(s)
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If imaging shows progressive disease (PD), tumor assessment may be repeated by the site at 
least 4 weeks later in order to confirm PD with the option of continuing treatment until this 
scan is obtained for clinically stable subjects (see Table 5). Figure 2 illustrates the imaging 
flow involving verification of PD for clinically stable subjects. Clinically stable is defined by 
the following criteria:

Absence of signs and symptoms indicating clinically significant disease progression, 
including worsening of laboratory variables

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Table 5
Imaging and Treatment after First Radiologic Evidence of Progressive Disease 
(PD)
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD by 
RECIST 1.1 
which has been 
verified by the 
central imaging 
vendor
Repeat imaging at 
4 weeks to 
confirm PD
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory scan
by site by 
irRECIST
Repeat imaging at 
4 weeks to 
confirm PD per 
physician discretion 
only
Discontinue 
treatment
Repeat scan 
confirms PD by 
irRECIST at the 
local site
No additional 
imaging required
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required
N/A
Repeat scan shows 
SD, PR or CR by 
RECIST1.1 at the 
local site
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. Next 
tumor image should 
occur according to 
the regular imaging 
schedule.
CR=complete response; irRECIST=immune-related response evaluation criteria in solid tumors; N/A=not 
applicable; PD=progressive disease; PFS=progression-free survival; PR=partial response; SD=stable disease
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Figure 2
Imaging and Treatment for Clinically Stable Subjects after First Radiologic 
Evidence of PD Assessed by the Site 
In determining whether or not the tumor burden has increased or decreased, investigators 
should consider all target lesions as well as non-target lesions (please refer to the irRECIST 
Tip Sheet).  Subjects that are deemed clinically unstable are not required to have repeat 
imaging for confirmation.  If radiologic progression is confirmed, it is recommended that the 
subject be discontinued from trial treatment unless, in the investigator’s opinion, the subject 
is deriving benefit from treatment. Clinically stable subjects as defined above may continue 
to receive trial therapy after discussion with the Sponsor. 
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Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
If a subject has unconfirmed progression of disease and is clinically stable, it is at the 
discretion of the investigator to continue treating the subject with the assigned treatment per 
protocol until progression of disease is confirmed at least 28 days from the date of the scan 
suggesting progression of disease. If progression is not confirmed on the subsequent scan, the 
subject should continue to receive study therapy and radiographic scans obtained to monitor 
for disease status every 6 weeks (± 7 days) starting at 12 weeks through 48 weeks, or every 
12 weeks (± 7 days) after week 48.
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the 
following occur (as assessed by irRECIST): 

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
The same imaging technique, acquisition, and processing parameters should be used in a 
subject throughout the trial. Details are provided in the Site Imaging Manual.
NOTE: In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 12 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, whichever occurs first. See the Trial Flow 
Charts in Section 6.0 and Section 7.1.5.3 for information about the Follow-up Visits.
7.1.2.7
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 
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digital photographs and the process for transmitting photographs to the central vendor is 
located in the Procedures Manual.
7.1.2.8
Tumor Tissue Collection
Participation in this trial will require submitting tumor sample from a newly obtained 
formalin-fixed specimen from locations not radiated prior to biopsy; no new systemic 
antineoplastic therapy may be administered between the PD-L1 biopsy and initiating study 
medication. The specimen will be evaluated at a central laboratory facility for expression 
status of PD-L1 by IHC in a retrospective manner. Both PD-L1 positive and negative 
subjects as determined by the central laboratory facility will be enrolled in this trial.
Newly-obtained 
specimens 
are 
defined 
as 
formalin-fixed 
paraffin 
embedded 
(FFPE)-preserved blocks of tissue collected at screening.
Note: A fine needle aspirate (FNA) or cytologic specimen will not be acceptable. Core 
needle or excisional biopsies, or resected tissue is required. 
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.
If the subject signs the FBR consent, any leftover tissue that would ordinarily be discarded at 
the end of the main study will be retained for FBR.  Details regarding time points for 
collection of tumor tissue are outlined in the Study Flow Chart – Section 6.1. 
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial, including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per subject can be found in Procedure Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.
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Table 6
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 Ab**
HCV RNA**
Glucose
IgG
Phosphorus
Potassium
Sodium
Magnesium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen or Urea
*
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) 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. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within the normal range.
PT/INR and aPTT will be collected as coagulation parameters.
TSH, FT3, and FT4 will be measured for thyroid function test.
Testing for HIV 1/2 antibodies, HBsAg, and HCV-Ab, 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.
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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. Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines.
7.1.3.2
Pharmacokinetic/ Immunogenicity Evaluations
To further evaluate MK-3475 immunogenicity and MK-3475 exposure in this indication, and 
also to evaluate exposure of the proposed dosing regimen, sample collections for analysis of 
anti-drug antibodies (ADA) and PK are currently planned as shown in the Trial Flow Chart.  
Blood samples will be obtained to measure pharmacokinetics of serum MK-3475 as 
monotherapy.  The MK-3475 serum maximum concentration (Cmax) and minimum 
concentration (Ctrough) at planned visits and times will be summarized. Blood samples for PK 
and ADA collection may be stored only at this time. Further analysis may be performed if 
required. If ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, 
it may be reduced or discontinued. 
Blood Collection for Serum MK-3475
The time points for PK blood sampling are described in Section 6 – Trial Flow Chart.  
Sample collection, storage and shipment instructions for the serum samples will be provided 
in the Procedures Manual. PK samples should be drawn according to the PK collection 
schedule for subjects who receive MK-3475.  
Blood Collection for Serum Anti-MK-3475 Antibodies
The time points for Anti-MK-3475 Antibodies blood sampling are described in Section 6 –
Trial Flow Chart.  Sample collection, storage and shipment instructions for the serum 
samples will be provided in the Procedures Manual. Anti-MK-3475 antibody samples should 
be drawn according to the ADA collection schedule for subjects who receive MK-3475. 
Simultaneous PK sampling is required for interpretation of ADA analysis or until start of a 
new anti-cancer therapy, whichever occurs first.
Other Procedures
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.
7.1.4.2
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 as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Laboratory equipment – as required for inclusion labs and trial assessments.
•
Imaging equipment – as required for study objectives.
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Site 
Imaging Manual (SIM) and irRECIST Tip Sheet.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
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) 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-Ab, 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.
Second Course Phase (Retreatment Period)
Subjects who stop MK-3475 with SD or better may be eligible for up to 17 additional cycles 
(approximately 1 year) of pembrolizumab (MK-3475) treatment if they progress after 
stopping trial treatment from the initial treatment phase and with SPONSOR approval.  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 RECIST1.1.

Was treated for at least 8 cycles 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 
35 administrations (approximately 2 years) of trial treatment 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. A scan documenting PD should 
be performed within 4 weeks prior to starting Second Course treatment.

Did not receive any anti-cancer treatment since the last dose of MK-3475.

Have a performance status of 0 or 1 on the ECOG Performance Scale.

Demonstrate adequate organ function as detailed in Section 5.1.2.

Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have 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.  
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
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 17 additional cycles
(approximately 1 year) of pembrolizumab (MK-3475) treatment.  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
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.
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 as specified in the Trial Flow Chart (Section 
6.0).  The Sponsor may request survival status to be assessed at additional time points during 
the course of the study (not to exceed approximately 12 weeks).  Every effort should be made 
to collect information regarding disease status 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.   
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Survival Follow-up
Once a subject experiences confirmed disease progression (by site assessment) or starts a 
new anti-neoplastic therapy, the subject moves into the survival follow-up phase and should 
be contacted by telephone approximately every 12 weeks to assess for survival status until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
7.1.5.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee review, interim and/or final analysis. Upon Sponsor notification, all 
subjects who do not/will not have a scheduled study visit or study contact during the Sponsor 
defined time period will be contacted for their survival status (excluding subjects that have a 
previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/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 
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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).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for ≥1000 mg of pembrolizumab. No specific information is available on the treatment 
of overdose of pembrolizumab. In the event of overdose, study treatment 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).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
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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. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
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protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
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 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
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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).
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.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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Table 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
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E-9).  Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in a supplemental SAP (sSAP) and referenced in the 
Clinical Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly 
identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.  
Study Design Overview
Phase Ib Study of MK-3475 in Chinese Subjects with Advanced 
Melanoma
Treatment Assignment
MK-3475 2 mg/kg every 3 weeks (Q3W)
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR based on RECIST 1.1 assessed by the BICR
Statistical Methods for Key 
Efficacy Analyses
The centrally reviewed RECIST 1.1 ORR will be evaluated by 
providing the point estimate and 95% confidence interval using an exact 
method based on binomial distribution.
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentage, mean, standard deviation, etc.) 
will be provided for the safety endpoints as appropriate.  
Interim Analyses
No interim analyses are planned in this trial.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power 
The planned sample size is approximately 100 subjects. 
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
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 Sponsor will generate the treatment numbers for this protocol, and the assignment of 
treatment number will be implemented in IVRS (see section 7.1.1.8).
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Hypotheses/Estimation
Objectives of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint

Objective response rate (ORR) per RECIST 1.1 assessed by the BICR
The ORR is defined as the proportion of subjects in the analysis population who have CR or 
PR using RECIST 1.1 criteria at any time during the study.  Response for the primary 
analysis will be determined by the BICR.
Secondary Efficacy Endpoints
Duration of Response (DOR) - per RECIST 1.1 and per irRECIST assessed by the BICR: 
For subjects who demonstrated CR or PR, response duration is defined as the time from 
first documented evidence of CR or PR until disease progression or death. Subjects who 
died without documented disease progression would be counted as event (PD) at the
death date. Response duration for subjects who have not progressed or died at the time of 
analysis will be censored at the date of their last tumor assessment.
Progression-free Survival (PFS) - per RECIST 1.1 and per irRECIST assessed by the 
BICR: PFS is defined as the time from the first day of study treatment to the first 
documented disease progression or death due to any cause, whichever occurs first
Objective response rate (ORR) per irRECIST assessed by the BICR
Overall survival (OS): is defined as the time from the first day of study treatment to death 
due to any cause. Subjects without documented death at the time of the final analysis will 
be censored at the date of the last follow-up
Safety Endpoints
A description of safety measures is provided in Section 7.0.
Analysis Populations
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the population for the analysis of ORR, 
and PFS 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,
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
Lack of baseline data for those analyses that require baseline data (i.e. failure to have
measurable disease per RECIST 1.1 at baseline scan).
The analysis population for OS is All Subjects as Treated (ASaT) population.
The analysis population for DOR consists of responders.
The efficacy analysis will be conducted at the time when all subjects are enrolled and have 
either discontinued/ have progression disease or have at least 24 weeks of follow-up since 
first dose of last enrolled subjects, whichever occurs first.
Details on the approach to handling missing data are provided in Section 8.6 Statistical 
Methods.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all allocated subjects who received at least one 
dose of study treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 Statistical Methods.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.
For the primary efficacy endpoint of ORR, the point estimate, and 95% confidence interval 
will be provided using exact binomial distribution. Subjects in the primary analysis 
population (FAS) without response data will be counted as non-responder.
For PFS, DOR and OS endpoints, Kaplan-Meier (KM) curves and median estimates from the 
KM curves will be provided as appropriate. Censoring rules for DOR are summarized in 
Table 8.
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Table 8
Censoring Rules for DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new anti-cancer 
therapy initiated
Last adequate assessment before new 
anti-cancer therapy initiated
Censor 
(non-event)
Death or progression after ≥ 2 
consecutive missed adequate disease 
assessments
Last adequate assessment prior to ≥ 
2 missed adequate disease 
assessments
Censor 
(non-event)
Death or  progression after ≤1 missed 
adequate disease assessments
Death or progression
End of response 
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.  
Table 9 summarizes the efficacy analyses.
Table 9
Analysis Strategy for Efficacy Variables
Endpoint/Variable‡
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary Endpoint 
ORR

RECIST 1.1, BICR
Exact method 
based
on binomial
distribution 
(Clopper-
Pearson method)
FAS
Subjects with 
missing data are 
considered non-
responders
Secondary Endpoints
DOR

RECIST 1.1, BICR

irRECIST, BICR
Summary 
statistics using 
Kaplan-Meier 
method
All 
responders
Non-responders 
are excluded from 
analysis
PFS

RECIST 1.1, BICR

irRECIST, BICR
Summary 
statistics using 
Kaplan-Meier 
method
FAS
Censored at last 
assessment
ORR

irRECIST, BICR
Exact method 
based
on binomial
distribution 
(Clopper-
Pearson method)
FAS
Subjects with 
missing data are 
considered non-
responders
OS
Summary 
statistics using 
Kaplan-Meier 
method
ASaT
Censored at last 
known alive date
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests and vital signs. 
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate. The summary statistics of count and percentage will be 
provided for the incidence rate of any AE, any serious AE, any Grade 3-5 AE, any 
drug-related AE, any serious and drug-related AE, any Grade 3-5 and drug-related AE, dose
interrupted due to AE, discontinuation due to AE, any immune-related AE (irAE), death and
specific AEs.
The summary statistics of mean and standard deviation will be provided for change from 
Baseline Results (Labs and Vital Signs) within each treatment cycle. The summary statistics
of count and percentage will be provided for laboratory worsening from Baseline in terms of 
CTCAE grades.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
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.
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.
Interim Analyses
No interim analyses are planned in this trial.
Multiplicity
There will be no hypothesis testing performed in this study. For the primary and secondary 
objectives in this study, no adjustment to control for Type I error is planned.
Sample Size and Power Calculations
In this study, approximately a total of 100 subjects with advanced melanoma will be enrolled.
With a sample size of 100, the 95% confidence intervals for an observed objective response 
rate of 5%, 10%, 15% and 20% are listed in Table 10. 
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Table 10
Two-sided 95% CI of ORR with 100 Evaluable Subjects
Number of observed 
responders
ORR estimates
95% CI of ORR (%)
95% CI Width (%)
5
5%
(1.6, 11.3)
9.7
10
10%
(4.9, 17.6)
12.7
15
15%
(8.6, 23.5)
14.9
20
20
(12.7, 29.2)
16.5
Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate for the primary and secondary endpoints will be provided within each category of 
each subgroup.  The following are examples of classification variables: 

ECOG ( 0 vs. 1)

Liver metastasis (yes vs. no)

PD-L1 (negative vs. positive)

Subjects with advanced mucosal melanoma(yes vs. no)

LDH (normal vs. high)

BRAF status (negative vs. positive)
In addition, a Forest plot will be produced, which provides the estimated point estimates and 
confidence intervals for the treatment effect across the categories of subgroups listed above.
Compliance (Medication Adherence)
Drug accountability data for MK-3475 will be collected during the study. Any deviation from
protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure 
for ASaT population.
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
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Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
MK-3475 100 mg/ 4mL
Solution for Infusion
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label vials every 3 weeks (Q3W).  
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and
disclosures.
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If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
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The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
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.
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Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
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standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
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, 
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due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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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.
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. Chi Z, Li S, Sheng X, Si L, Cui C, Han M, Guo J. Clinical presentation, histology, and 
prognoses of malignant melanoma in ethnic Chinese: a study of 522 consecutive cases. 
BMC Cancer. 2011;11:85. doi: 10.1186/1471-2407-11-85.
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13. 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.
14. 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.
15. 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.
16. 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.
17. Topalian S, et al. Survival, Durable Tumor Remission, and Long-Term Safety in 
Patients With Advanced Melanoma Receiving Nivolumab.  J Clin Oncol. 2014;32
18. Jinhyun Cho, Soomin Ahn, Kwai Han Yoo, et al. Treatment outcome of PD-1 immune 
checkpoint inhibitor in Asian metastatic melanoma patients: correlative analysis with 
PD-L1 immunohistochemistry. Invest New Drugs .2016; 34:677–684
19. Naoya Yamazaki, Tatsuya Takenouchi, Manabu Fujimoto, et al. Phase 1b study of 
pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with 
advanced melanoma (KEYNOTE-041). Cancer Chemother Pharmacol. 2016; DOI 
10.1007/s00280-016-3237-x (Published online: 11March 2017)
20. Chuanliang Cui, Lili Mao, Zhihong Chi, et al. A Phase II, Randomized, Double-blind, 
Placebo-controlled Multicenter Trial of Endostar in Patients with Metastatic Melanoma. 
The American Society of Gene & Cell Therapy.2013; 21(7): 1456-1463
21. 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.
22. 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.
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APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of 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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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov).
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
*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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Clinical Study Conduct System
Clinical study conduct system in China is provided in Attachment by Chinese language.
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List of Abbreviations
Abbreviation/Term
Definition
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
ß-HCG
Beta Human Chorionic Gonadotropin
BICR
Blinded Independent Central Review
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DNA
Deoxyribonucleic acid
DOR
Duration of Response
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
ERC
Ethics Review Committee
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FNA
Fine Needle Aspirate
FT3
Free Triiodothyronine
FT4
Free Thyroxine 
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
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Abbreviation/Term
Definition
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
IPI
Ipilimumab
irAEs
Immune-related Adverse Events
irRECIST
Modification of RECIST 1.1
IRB
Institutional Review Board
IV
Intravenous
Kg
Kilogram
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
mcL
Microliters
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed Cell Death-1
PD-L1
Programmed Cell Death Ligand 1
PD-L2
Programmed Cell Death Ligand 2
PFS
Progression Free Survival
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/Pharmacodynamic
PR
Partial Response
PT
Prothrombin Time
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
Q3W
Every 3 Weeks
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SIM
Site Imaging Manual
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Abbreviation/Term
Definition
SOP
Standard Operating Procedures
T1DM
Type 1 Diabetes Mellitus
TCM
Traditional Chinese Medicine
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
US
United States
WBC
White Blood Cell
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SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – 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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