A Phase II Clinical Trial of Pembrolizumab (MK-3475) in Subjects With Advanced/Unresectable or Metastatic Urothelial Cancer
Phase: PHASE2
Conditions: Urothelial Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02335424 
Document Date: 
14-May-2021
A Phase II Clinical Trial of Pembrolizumab (MK-3475) in Subjects 
with Advanced/Unresectable or Metastatic Urothelial Cancer

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.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A 
Phase 
II 
Clinical 
Trial 
of 
Pembrolizumab 
(MK-3475) 
in 
Subjects 
with 
Advanced/Unresectable or Metastatic Urothelial Cancer
IND NUMBER:  122753
EudraCT NUMBER:  2014-002206-20
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 13
Trial Design ........................................................................................................... 13
Trial Diagram........................................................................................................ 15
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 16
Primary Objective(s) & Hypothesis(es).............................................................. 16
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objective(s) & Hypothesis(es)........................................................ 17
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 18
Pre-clinical and Clinical Trials ........................................................................... 19
Ongoing Clinical Trials....................................................................................... 19
Rationale................................................................................................................ 20
Rationale for the Trial and Selected Subject Population .................................... 20
Rationale for Dose Selection/Regimen/Modification......................................... 22
Rationale for Endpoints ...................................................................................... 23
4.2.3.1
Efficacy Endpoints....................................................................................... 23
4.2.3.1.1
Primary.................................................................................................. 23
4.2.3.1.2
Secondary.............................................................................................. 23
4.2.3.1.3
Exploratory ........................................................................................... 24
Patient Reported Outcomes............................................................ 24
4.2.3.2
Safety Endpoints.......................................................................................... 24
4.2.3.3
Planned Exploratory Biomarker Research................................................... 25
4.2.3.4
Future Biomedical Research........................................................................ 27
Benefit/Risk ........................................................................................................... 27
5.0
METHODOLOGY ................................................................................................... 28
Entry Criteria........................................................................................................ 28
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Diagnosis/Condition for Entry into the Trial...................................................... 28
Subject Inclusion Criteria.................................................................................... 28
Subject Exclusion Criteria .................................................................................. 31
Trial Treatment(s) ................................................................................................ 32
Dose Modification (Escalation/Titration/Other)................................................. 33
5.2.1.1
Dose Selection (Preparation) ....................................................................... 33
5.2.1.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 33
Timing of Dose Administration.......................................................................... 38
Trial Blinding/Masking....................................................................................... 39
Randomization or Treatment Allocation............................................................ 39
Stratification.......................................................................................................... 39
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 39
Acceptable Concomitant Medications ................................................................ 39
Prohibited Concomitant Medications.................................................................. 40
Rescue Medications & Supportive Care............................................................. 41
Supportive Care Guidelines ................................................................................ 41
Diet/Activity/Other Considerations..................................................................... 41
Diet...................................................................................................................... 41
Contraception...................................................................................................... 41
Use in Pregnancy ................................................................................................ 42
Use in Nursing Women....................................................................................... 42
Subject Withdrawal/Discontinuation Criteria................................................... 42
Treatment after initial evidence of radiologic disease progression..................... 44
5.8.2
Discontinuation of Study Therapy after CR ....................................................... 46
Subject Replacement Strategy............................................................................. 46
Beginning and End of the Trial ........................................................................... 46
Clinical Criteria for Early Trial Termination ................................................... 46
6.0
TRIAL FLOW CHART ........................................................................................... 47
Initial Treatment Phase........................................................................................ 47
Second Course Phase (Retreatment)................................................................... 51
7.0
TRIAL PROCEDURES ........................................................................................... 53
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Trial Procedures ................................................................................................... 53
Administrative Procedures.................................................................................. 53
7.1.1.1
Informed Consent......................................................................................... 53
7.1.1.1.1
General Informed Consent.................................................................... 53
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 54
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 54
7.1.1.3
Subject Identification Card .......................................................................... 54
7.1.1.4
Medical History ........................................................................................... 54
7.1.1.4.1
Disease Details...................................................................................... 54
7.1.1.5
Prior and Concomitant Medications Review............................................... 54
7.1.1.5.1
Prior Medications.................................................................................. 54
Prior Treatment Details for Urothelial Cancer............................... 55
7.1.1.5.2
Concomitant Medications..................................................................... 55
Subsequent Anti-Cancer Therapy Status........................................ 55
7.1.1.6
Assignment of Screening Number............................................................... 55
7.1.1.7
Assignment of Randomization Number....................................................... 55
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 56
Clinical Procedures/Assessments........................................................................ 56
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 56
7.1.2.2
Physical Exam.............................................................................................. 56
7.1.2.2.1
Full Physical Exam ............................................................................... 56
7.1.2.2.2
Directed Physical Exam........................................................................ 57
7.1.2.3
Vital Signs.................................................................................................... 57
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 57
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 57
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 57
7.1.2.6.1
Initial Tumor Imaging........................................................................... 58
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 58
7.1.2.6.3
Bone Scans............................................................................................ 58
7.1.2.6.4
Assessment of Disease.......................................................................... 59
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling......................... 59
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7.1.2.8
Patient Reported Outcomes (PROs)............................................................. 60
Laboratory Procedures/Assessments .................................................................. 60
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 60
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 62
7.1.3.3
Future Biomedical Research........................................................................ 62
Other Procedures................................................................................................. 62
7.1.4.1
Withdrawal/Discontinuation........................................................................ 62
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 62
7.1.4.2
Blinding/Unblinding .................................................................................... 63
7.1.4.3
Calibration of Critical Equipment................................................................ 63
Visit Requirements.............................................................................................. 63
7.1.5.1
Screening...................................................................................................... 63
7.1.5.2
Treatment Period/Vaccination Visit ............................................................ 64
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 64
7.1.5.3
Post-Trial...................................................................................................... 66
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 66
7.1.5.3.2
Follow-up Visits ................................................................................... 66
7.1.5.3.3
Survival Follow-up ............................................................................... 66
7.1.5.4
Survival Status ............................................................................................. 67
Assessing and Recording Adverse Events .......................................................... 67
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 68
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 68
Immediate Reporting of Adverse Events to the Sponsor.................................... 69
7.2.3.1
Serious Adverse Events ............................................................................... 69
7.2.3.2
Events of Clinical Interest............................................................................ 70
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 71
Evaluating Adverse Events................................................................................. 71
Sponsor Responsibility for Reporting Adverse Events ...................................... 74
Trial Governance and Oversight......................................................................... 74
Scientific Advisory Committee........................................................................... 74
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 74
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Statistical Analysis Plan Summary ..................................................................... 74
Efficacy Analyses ............................................................................................... 75
Safety Analyses................................................................................................... 75
Power and Sample Size....................................................................................... 75
Biomarker/Interim Analysis................................................................................ 75
Statistical Analysis Plan ....................................................................................... 75
Responsibility for Analyses/In-House Blinding ................................................. 75
Hypotheses/Estimation ....................................................................................... 76
Analysis Endpoints ............................................................................................. 76
8.2.3.1
Efficacy Endpoints....................................................................................... 76
8.2.3.2
Safety Endpoints.......................................................................................... 76
Analysis Populations........................................................................................... 76
8.2.4.1
Efficacy Analysis Population....................................................................... 76
8.2.4.2
Safety Analysis Population.......................................................................... 77
8.2.4.3
Biomarker Discovery Population................................................................. 77
Statistical Methods.............................................................................................. 77
8.2.5.1
Statistical Methods for Efficacy Analyses................................................... 77
8.2.5.2
Statistical Methods for Safety Analyses ...................................................... 78
8.2.5.3
Statistical Methods for Biomarker Analyses ............................................... 78
8.2.5.4
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 79
8.2.5.4.1
Demographic and Baseline Characteristics .......................................... 79
Multiplicity ......................................................................................................... 79
Sample Size and Power Calculation ................................................................... 79
Subgroup Analyses and Effect of Baseline Factors............................................ 81
Interim Analyses ................................................................................................. 81
Compliance (Medication Adherence)................................................................. 81
Extent of Exposure.............................................................................................. 82
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 82
Investigational Product ........................................................................................ 82
Packaging and Labeling Information ................................................................. 82
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Clinical Supplies Disclosure................................................................................. 82
Storage and Handling Requirements.................................................................. 82
Discard/Destruction/Returns and Reconciliation .............................................. 83
Standard Policies................................................................................................... 83
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 83
Confidentiality....................................................................................................... 83
Confidentiality of Data ....................................................................................... 83
Confidentiality of Subject Records..................................................................... 83
Confidentiality of Investigator Information........................................................ 84
Confidentiality of IRB/IEC Information............................................................. 84
Compliance with Financial Disclosure Requirements....................................... 84
Compliance with Law, Audit and Debarment ................................................... 85
Compliance with Trial Registration and Results Posting Requirements........ 87
Quality Management System............................................................................... 87
Data Management................................................................................................. 87
Publications ........................................................................................................... 88
11.0
LIST OF REFERENCES......................................................................................... 89
12.0
APPENDICES........................................................................................................... 94
Merck Code of Conduct for Clinical Trials........................................................ 94
Collection and Management of Specimens for Future Biomedical 
Research................................................................................................................. 96
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 102
Abbreviations ...................................................................................................... 113
ECOG Performance Status................................................................................ 116
New York Heart Association (NYHA) Functional Classification .................. 117
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 118
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors .............................................................. 119
13.0
SIGNATURES......................................................................................................... 120
Sponsor's Representative ................................................................................... 120
Investigator.......................................................................................................... 120
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values...................................................... 30
Table 2
Trial Treatment ..................................................................................................... 32
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .................................................................... 34
Table 4
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines ............................................................................................................. 37
Table 5
Imaging and Treatment After 1st Radiologic Evidence of PD............................. 45
Table 6
Laboratory Tests ................................................................................................... 61
Table 7
Evaluating Adverse Events................................................................................... 72
Table 8
Analysis Strategy for Efficacy Endpoints............................................................. 79
Table 9
Estimates and 95% CIs with 60 PD-L1 Strongly Positive Subjects..................... 80
Table 10
Estimates and 95% CIs with 75 PD-L1 Strongly Positive Subjects..................... 80
Table 11
Product Descriptions............................................................................................. 82
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LIST OF FIGURES
Figure 1
Trial Design .......................................................................................................... 16
Figure 2
Best Percent Change from Baseline in Target Lesions by Best Objective 
Response (Full Analysis Set Population, by Investigator Assessment) 
KEYNOTE-012 .................................................................................................... 21
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-052-05
14-May-2021
To update the dose modification and toxicity management 
guidelines for immune-related adverse events (irAEs).
3475-052-04
18-Sep-2019
Added language regarding the potential for subjects to be 
enrolled in an extension study if one becomes available.
3475-052-03
07-Dec-2017
Added guidelines for dose modification in the event of 
myocarditis and updated guidelines for several other 
conditions.
3475-052-02
11-Mar-2016
PD-L1 positive is prospectively defined as subjects with 
Combined Positive Score (CPS) ≥1%. Hypotheses were 
removed since the objective of the study is to estimate 
efficacy and the success of the study is determined by 
clinically meaningful ORRs and durability of the response.
3475-052-01
08-Oct-2014
To clearly state that subjects must be refractory to available 
or standard therapy for treatment of their bladder cancer in 
order to participate in the biomarker cut-point determination 
part of the study if they do not meet cisplatin-ineligible 
criteria.
3475-052-00
29-Aug-2014
Original
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change
Rationale
5.2.1.2
Immune-Related Events and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
The dose modification and 
toxicity 
management 
guidelines for irAEs and table 
were updated.
The 
dose 
modification 
and 
toxicity 
management guidelines for irAEs and table 
were updated as requested by the U.S. Food 
and Drug Administration (FDA) in an effort to 
harmonize 
the 
presentation 
of 
safety 
information 
across 
all 
FDA-approved 
programmed cell death 1/ ligand 1 (PD-1/L1) 
antibody prescribing information.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase II Trial of Pembrolizumab (MK-3475) in Subjects with Bladder 
Cancer
Trial Phase
II
Clinical Indication
1L Cisplatin-ineligible Advanced/Unresectable or Metastatic Urothelial 
Cancer
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
(Select Groups)
pembrolizumab (MK-3475) 200 mg every 3 weeks
Number of trial subjects
Approximately up to 350 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 36 months 
from the time the first subject signs the informed consent until the last 
subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final contact.  After a screening 
phase of 28 days, each eligible subject will receive treatment with 
pembrolizumab (MK-3475) on Day 1 of each 3 week cycle.  Treatment with 
pembrolizumab (MK-3475) will continue until disease progression is 
confirmed by the investigator/site radiologist, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure
requirements, subject receives 24 months of trial treatment, or administrative 
reasons. Subjects receiving pembrolizumab (MK-3475) who attain a 
complete response may consider stopping trial treatment if they meet criteria 
for holding therapy. Subjects who stop trial treatment after receiving 24 
months of trial treatment for reasons other than disease progression or 
intolerability, or subjects who attain a complete response and stop trial 
treatment may be eligible for up to one year of retreatment upon 
experiencing disease progression.  The decision to retreat will be at the 
discretion of the investigator only if the subject meets the criteria for 
retreatment after experiencing disease progression and the trial is ongoing. 
After the end of treatment each subject will be followed for 30 days for 
adverse event monitoring or before the initiation of new anti-cancer therapy, 
whichever comes first. Serious adverse events and events of clinical interest
will be collected for 90 days after the end of treatment or 30 days after the 
end of treatment if the subject initiates new anticancer therapy, whichever is 
earlier.  Subjects who discontinue for reasons other than disease progression 
will have post-treatment follow-up for disease status every 6 weeks (± 7 
days) in the first year and every 12 weeks (± 7 days) after year 1 until
disease progression is confirmed by the investigator/site radiologist, a non-
study cancer treatment is initiated, consent is withdrawn, until death, or 
becoming lost to follow-up. All subjects will be followed by telephone for 
overall survival every 12 weeks (± 7 days) until death, withdrawal of 
consent, or the end of the trial.
Once the participant has achieved the study objective or the study has ended, 
the participant is discontinued from this study and will 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 12.4.
2.0 TRIAL DESIGN
Trial Design
This is a non-randomized, multi-site, open-label trial of pembrolizumab (MK-3475) in 
subjects with advanced/unresectable (inoperable) or metastatic urothelial cancer, who have 
not received prior systemic chemotherapy (i.e., first line, 1L) and who are not eligible to 
receive cisplatin, to be conducted in conformance with Good Clinical Practices.
Approximately up to 350 subjects may be enrolled and will provide newly obtained formalin 
fixed paraffin embedded (FFPE) tumor biopsies for PD-L1 determination by 
immunohistochemistry (IHC).  PD-L1 positive/negative population is defined as subjects
with PD-L1 IHC assay result ( Combined Positive Score - CPS) higher/lower than the PD-L1 
cut-point 1%.
Samples for PD-L1 determination will be sent to a central laboratory for real time evaluation 
to ensure adequate tissue specimen is present.  Additionally, all subjects must have 
confirmed measureable disease based on RECIST 1.1 as determined by central radiology
review. All subjects will receive pembrolizumab (MK-3475) regardless of PD-L1 status. 
Subjects will be administered pembrolizumab (MK-3475) 200 mg every three weeks (Q3W).
Neoadjuvant/Adjuvant platinum based chemotherapy, with recurrence >12 months from 
completion of therapy, is permitted. 
Subjects will be evaluated at 9 weeks (± 7 days) after the first dose of trial treatment on Day 
1 Cycle 1, and every 6 weeks (± 7 days) thereafter with radiographic imaging to assess 
response to treatment. Subjects who remain on treatment beyond a year will have imaging 
performed every 12 weeks (± 7 days) thereafter. All imaging obtained on study will be 
submitted for an independent radiologist's review, who will assess the images using 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for determination of objective 
response rate (ORR) and progression-free survival (PFS). The investigator may choose to 
treat beyond RECIST 1.1 defined progression in subjects considered to be deriving clinical 
benefit and who are clinically stable.
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. Treatment with pembrolizumab (MK-3475) will continue until documented 
disease progression
by investigator/site radiologist, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, completion of 24 months of treatment with 
pembrolizumab (MK-3475), or administrative reasons. 
Subjects who attain an investigator-determined confirmed complete response (CR), may 
consider stopping trial treatment after receiving at least 24 weeks of treatment. Subjects who 
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discontinue for reasons other than disease progression or intolerability, or who discontinue 
after attaining a CR may be eligible for up to one year of retreatment after they have 
experienced radiographic disease progression. The decision to retreat will be at the discretion 
of the investigator only if no cancer treatment was administered since the last dose of 
pembrolizumab (MK-3475), the subject still meets the safety parameters listed in the 
Inclusion/Exclusion criteria and the trial remains open (refer to Section 7.1.5.2.1 for further 
details).
After the end of treatment each subject will be followed for 30 days (± 3 days) for adverse 
event monitoring or before the initiation of new anti-cancer therapy, whichever comes first. 
Serious adverse events and events of clinical interest (ECI) will be collected for 90 days after 
the end of treatment or 30 days after the end of treatment if the subject initiates new 
anticancer therapy, whichever is earlier.
Subjects who discontinue for reasons other than disease progression will have post-treatment 
follow-up for disease status every 6 weeks (± 7 days) in the first year and every 12 weeks (±7 
days) after year 1 until disease progression is confirmed by the investigator/site radiologist, a 
non-study cancer treatment is initiated, consent is withdrawn, until death, or becoming lost to 
follow-up. All subjects will be followed by telephone for overall survival every 12 weeks (± 
7 days) until death, withdrawal of consent, or the end of the trial.
The primary objective of this study is to evaluate the anti-tumor activity of pembrolizumab 
(MK-3475) as firstline (1L) therapy in subjects with advanced/unresectable (inoperable) or 
metastatic urothelial cancer who are ineligible for cisplatin-based therapy and whose tumors 
express PD-L1 protein by IHC based on ORR (RECIST 1.1) assessed by independent 
radiology review.  Data from previously conducted pembrolizumab bladder cancer trials will 
be utilized to determine a biomarker assay cut-point. In the event a cut-point cannot be 
determined from data from previous studies, additional subjects will be added to the 
beginning of this study to supplement the previously collected data in order to determine the 
assay cut-point. In this case, data from subjects in the main part of the trial to assess the 
primary endpoint will be kept separate, and will be analyzed separately once the cut-point
has been determined.
The all-patient-treated (APT) population will serve as the primary population for the analyses 
of efficacy data in this trial. Supportive analyses of efficacy will be conducted in the full 
analysis set (FAS) population as well. The APT population consists of all treated subjects. 
The FAS population consists of all enrolled subjects who receive at least one dose of study 
treatment and have measureable disease at baseline. Interim futility analysis with PD-L1 
negative subjects is planned and enrollment of PD-L1 negative subjects may be stopped after 
the interim analysis.
Participation in this trial will be dependent upon supplying tumor tissue obtained at any time 
before the first dose of study drug, as long as the subject has not received any intervening 
systemic therapy from the time the tissue was collected until the time the subject enters the 
study.
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Additionally, tumor tissue must be obtained from locations not radiated prior to biopsy; 
newly obtained formalin-fixed specimens AFTER the subject has been diagnosed with 
metastatic or muscle invasive disease will be required for determination of PD-L1 status.
Biopsies obtained PRIOR to receipt of neoadjuvant/adjuvant chemotherapy are NOT 
permitted.  Subjects who received neoadjuvant/adjuvant therapy are permitted onto the trial 
as long as therapy was completed at least 12 months prior to the diagnosis of metastatic 
disease.
Only tumor specimens obtained AFTER completion of the neoadjuvant/adjuvant therapies
and only AFTER metastatic or muscle invasive disease is observed will be used to assess 
PD-L1 status. The specimen will be evaluated at a central laboratory facility for expression 
status of PD-L1 in a retrospective manner, thus tissue availability, but not high biomarker 
expression is required for trial entry.  
Additionally, if available, archived tumor tissue specimens from prior biopsies will be 
collected for determination of PD-L1 status to compare biomarker expression in archived 
specimens against the in newly obtained tumor tissue that is collected as a requirement for 
entry into the trial.
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.
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Figure 1
Trial Design
Abbreviations: IHC = immunohistochemistry, SFU = study follow-up
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In subject with advanced/unresectable or metastatic urothelial cancer who are ineligible to 
receive cisplatin-based therapy, evaluate anti-tumor activity of pembrolizumab (MK-3475) as 
1L therapy: 
1. Objective: By objective response rate (ORR) based on RECIST 1.1 by independent 
radiology review in all subjects.
2. Objective: By ORR based on RECIST 1.1 by independent radiology review in subjects 
whose tumors are PD-L1 positive (Combined Positive Score or CPS ≥1%).
3. Objective: By ORR based on RECIST 1.1 by independent radiology review in subjects 
whose tumors are PD-L1 strongly positive (CPS cut-point determined from biomarker 
discovery population; see Section 8.2).
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Secondary Objective(s) & Hypothesis(es)
In subjects with advanced/unresectable or metastatic urothelial cancer who are ineligible to 
receive cisplatin-based therapy:
1. Objective: To evaluate the anti-tumor activity of pembrolizumab (MK-3475) as 1L 
therapy in PD-L1 strongly positive, PD-L1 positive and all subjects

By duration of response (DOR) based on RECIST 1.1 by independent radiology 
review.

By progression-free survival (PFS) based on RECIST 1.1 by independent radiology 
review and overall survival (OS).

By PFS rate based on RECICST 1.1 by independent radiology review and OS rate at 
6 and 12 months.
2. Objective: To establish a cut-point for PD-L1 strongly positive status if this is not 
determined by other biomarker discovery populations, investigate the association 
between PD-L1 protein expression by IHC and anti-tumor activity.
3. Objective: To determine the safety and tolerability of  pembrolizumab (MK-3475) as 1L 
therapy.
Exploratory Objective(s) & Hypothesis(es)
In subjects with advanced/unresectable or metastatic urothelial cancer who are ineligible to 
receive cisplatin-based therapy:
1. Objective: To investigate the relationship between candidate efficacy/resistance 
biomarkers and anti-tumor activity of pembrolizumab (MK-3475) utilizing pre- and post-
treatment tumor biopsies and blood sampling in PD-L1 strongly positive, PD-L1 positive 
and all subjects, respectively.
2. Objective: To explore the PK profile of pembrolizumab (MK-3475) 200 mg Q3W as 1L 
therapy in PD-L1 strongly positive, PD-L1 positive and all subjects, respectively.
3. Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline using the EORTC QLQ-C30, in PD-L1 strongly positive, PD-L1 positive and all 
subjects, respectively.
4. Objective: To characterize utilities using the EuroQol EQ-5D, in PD-L1 strongly 
positive, PD-L1 positive and all subjects, respectively.
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5. Objective:  To Evaluate anti-tumor activity of pembrolizumab (MK-3475) as 1L therapy 
in PD-L1 strong positive, PD-L1 positive and all subjects by ORR, DOR and PFS based 
on modified RECIST 1.1 by independent radiology review.
Note: If a strongly positive cut-off with clinical utility beyond 1% cannot be identified from 
the biomarker analysis, the objectives with strongly positive subjects will not be pursued.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (previously known as MK-3475 and SCH 9000475) is a potent and highly 
selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 
8].  The structure of murine PD-1 has been resolved [9].  PD-1 and family members are type 
I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [7; 10; 11; 12].  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [13; 14].  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells [15; 16].  Expression has also been shown during thymic 
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development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17]   The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors [18; 19; 20; 13].  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-
cell activation triggered through the T-cell receptor.  PD-L1 is expressed at low levels on 
various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments.  PD-L2 is thought to control immune T-cell activation 
in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in 
peripheral tissues [13].  Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in subjects with melanoma (MEL) 
[21].  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
Pre-clinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [22; 23; 24; 25; 26; 27].  Experiments have confirmed the in 
vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, a number of advanced solid tumor indications and hematologic malignancies.  For 
study details please refer to the Investigator’s Brochure.
An open-label Phase I trial (KEYNOTE-012) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475) in advanced solid tumors 
including triple negative breast cancer, head and neck cancer, urothelial cancer and gastric 
cancer.  Subjects with advanced urothelial cancer who express PD-L1 in the tumor and 
surrounding microenvironment were enrolled into an initial cohort and treated with 
pembrolizumab (MK-3475) at 10 mg/kg every 2 weeks.  Promising preliminary anti-cancer
activity has been observed in these subjects.  These data show a best objective response of 
25% (7 of 28 subjects in the full analysis set).   Thirty-three (33) subjects were included in 
the safety analysis of the urothelial cohort and of these subjects, 97% experienced 1 AE, 
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and 58% reported a drug-related AE.  At least one Grade 3-5 AE was reported in 57% of 
subjects, with 12% reporting a drug-related Grade 3-5 AE.  
Rationale
Rationale for the Trial and Selected Subject Population
Urothelial (transitional cell) cancer describes a range of tumors that arise from the urothelial 
endothelium, which includes the bladder, renal pelvis, ureter, and urethra. The worldwide 
incidence of bladder cancer exceeds 300,000 cases annually, ranking it as the seventh most 
common cancer worldwide [28]. Urothelial carcinoma is the predominant histologic type of 
bladder cancer in the United States and Western Europe, where it accounts for approximately 
90 percent of bladder cancers. In other areas of the world, nonurothelial histologies are more 
frequent.
Cisplatin-based combination chemotherapy is standard first-line treatment for patients with 
advanced bladder cancer based on randomized trials [29; 30; 31; 32; 33; 34]. The median 
survival with these regimens is 13 to 15 months, and 5% to 15% of patients attain long-term 
survival. However, cisplatin ineligibility is common because of renal dysfunction (creatinine 
clearance < 60 mL/min) or performance status of 2, or both. Furthermore, hearing loss, Grade 
2 neuropathy, heart failure, and age-associated diminished renal function may also confer 
cisplatin ineligibility [35; 36; 37].
Carboplatin is often substituted for cisplatin in such patients, but it is associated with inferior 
outcomes, as demonstrated in a meta-analysis of randomized Phase II trials [36; 38]. A 
Phase 
III 
trial 
comparing 
gemcitabine/carboplatin 
(GC) 
with 
MCAVI 
(methotrexate/carboplatin/vinblastine) in cisplatin-ineligible patients demonstrated a median 
survival of only 8 to 9 months with both regimens [39]. Notably, those with both poor renal 
function and poor performance status fared especially poorly with combination 
chemotherapy in this trial.  Thus, there remains a significant unmet medical need for well-
tolerated active therapies in this population.  According to the National Comprehensive 
Cancer Network guidelines, clinical trials of potentially less toxic therapies are recommended 
for this population of patients.
This study administers pembrolizumab (MK-3475) as 1st line therapy.  Based on the known 
toxicity profile of pembrolizumab (MK-3475), it is unlikely that initial treatment with 
pembrolizumab will preclude subsequent treatment with gemcitabine/carboplatin, or other 
regimens, for those patients who desire such treatment.  Results from KEYNOTE-012 
demonstrate that nearly half of pembrolizumab treated patients experienced tumor shrinkage 
with very limited toxicity, and suggest that an initial trial with pembrolizumab may be 
reasonable and worthwhile for cisplatin ineligible patients (Figure 2).
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Figure 2
Best Percent Change from Baseline in Target Lesions by Best Objective Response
(Full Analysis Set Population, by Investigator Assessment) KEYNOTE-012
For the individual patient, it is potentially possible that receiving a regimen such as 
gemcitabine/carboplatin earlier in the disease course may be better than receiving it later.  
However, in oncology, it has been uncommon to observe differences in overall disease 
outcomes based on the sequence of treatments.  For example, patients initially allocated to a 
placebo treatment in a clinical trial and then crossed over to active treatment, in general, have 
an overall survival outcome similar to those first allocated to an active treatment.  
Cross over in a clinical trial with a placebo arm represents a form of delayed treatment where 
the patient is first allocated to an ineffective treatment.  However, in the majority of cases, 
such an approach does not have an adverse impact on patient outcomes.  In fact, cross over is 
commonly prohibited in such clinical trials for the reason that receipt of treatment, whether 
early or late in the disease course, yields a similar result, thus confounding a clinical trial 
designed to detect a difference between treatments.  The observation of significant activity 
with pembrolizumab (MK-3475) further decreases the possibility that sequence of treatment 
could adversely impact the overall clinical course of a patient.  These considerations suggest 
that it is reasonable to treat patients with pembrolizumab (MK-3475) before administering an 
alternative regimen such as gemcitabine/carboplatin.
In light of the relatively limited benefit from cytotoxic chemotherapy in subjects with  
advanced/unresectable (inoperable) 
or metastatic urothelial cancer who cannot receive 
cisplatin, and the promising results with pembrolizumab (MK-3475) and other anti-PD-1 
pathway agents [40], pembrolizumab (MK-3475) will be evaluated as monotherapy in this 
population.
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Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab across all indications and regardless of tumor type. As outlined below, this 
dose is justified by: 

Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer, covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg Q3W 
vs. 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), and three studies 
compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5 to 7.5 fold difference in exposure. The 2 mg/kg (or 
200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-/exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
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Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary
The primary efficacy objective of this trial is to evaluate the anti-tumor activity of 
pembrolizumab (MK-3475) (200 mg Q3W) as 1L therapy
in subjects with 
advanced/unresectable (inoperable)  or metastatic urothelial cancer who are ineligible for 
cisplatin-based therapy.  Objective response rate (ORR) based on RECIST 1.1 as assessed by 
independent radiology review will be used as the primary  efficacy endpoint.  The 
requirement that subjects have measurable disease will be assessed by the central vendor.
RECIST 1.1 will also be used by the local site to make treatment decisions.  For this purpose,
RECIST 1.1 will be adapted to account for the unique tumor response profile seen with 
treatment of pembrolizumab (MK-3475) (Refer to Section 5.2.2.1).
In the first line treatment of advanced/unresectable (inoperable) or metastatic urothelial 
cancer, response rates (RRs) generally observed with other single agents have ranged from 
12%-28% [31; 41; 42; 43; 44; 45; 46].  The one exception was a study with paclitaxel where 
a RR of 42% was observed [47].  Despite the high RR with paclitaxel, the median duration of 
response approximated 7 months, where the median number of 3 week cycles administered in 
responding patients was 8.  In addition, results in all of these studies were obtained in 
cisplatin eligible patients, rather than cisplatin ineligible patients who will be enrolled in this 
study.  A limitation of the existing literature is a general lack of comparable information for 
cisplatin ineligible patients, thus necessitating reference to results with cisplatin eligible 
patients as the best source of data to provide context.
Results observed with pembrolizumab in bladder and other cancers have shown extended 
durations of response not typically observed with existing agents.  Duration of response has 
been recognized as an important goal and is cited as one of the primary reasons for the use 
of, for example, IL-2 in renal cell carcinoma.  
The RR results obtained in this trial will be compared to an historical RR of 30%.  A 30% 
RR is at the high end of RRs observed with existing agents tested in the first line setting in 
populations actually more likely to respond than the cisplatin ineligible patients included in 
this trial.  Considering the effect of pembrolizumab on duration of response and the 
population of cisplatin ineligible patients being studied, a RR of 30% is considered clinically 
important.  
4.2.3.1.2 Secondary
PD L1 Expression
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab (MK-3475).
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4.2.3.1.3 Exploratory
Patient Reported Outcomes
EORTC QLQ-C30, EQ-5D and Health Economic Assessment are not pure efficacy or safety 
endpoints because they are affected by both disease progression and treatment tolerability.
EORTC QLQ-C30
EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects. It has been 
translated and validated into 81 languages and used in more than 3,000 studies worldwide.  It 
contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom 
scales (fatigue, nausea, pain) and additional single symptom items. It is scored on a 4 point 
scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The EORTC QLQ-C30 instrument 
also contains 2 global scales that use 7 point scale scoring with anchors (1=very poor and 
7=excellent). This assessment will be completed at various time points as specified in the 
study Flow Chart, beginning with Cycle 1 until 30 days post-treatment discontinuation.
eEuroQoL-5D
The eEuroQol-5D (eEQ-5D) is a standardized instrument for use as a measure of health 
outcome.  The eEQ-5D will provide data for use in economic models and analyses including 
developing health utilities or QALYs.  The five health state dimensions in this instrument 
include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression [48].  Each dimension has three levels: no problems, some problems, 
extreme problems.  The eEQ-5D also includes a graded (0 to 100) vertical visual analog scale 
on which the subject rates his or her general state of health at the time of the assessment.  The 
eEQ-5D will always be completed by subjects first before completing the EORTC QLQ-C30 
and is to be completed at various time points as specified in the study Flow Chart, beginning 
with Cycle 1 until 30 days post-treatment discontinuation. 
Health Economic Assessment
The health economic assessment (HEA) form will be completed via an interview with the 
subject by qualified site personnel. The objective of the HEA form is for the site personnel to 
collect information from subjects on all the non-study related health care contacts made 
throughout the study.  The HEA is to be completed at various time points as specified in the 
Trial Flow Chart, beginning with Cycle 2 until 30 days post-treatment discontinuation. 
4.2.3.2
Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab (MK-3475) in subjects with advanced/unresectable (inoperable) or metastatic 
urothelial cancer.  The primary safety analysis will be based on subjects who experienced 
toxicities as defined by CTCAE criteria.  Safety will be assessed by quantifying the toxicities 
and grades experienced by subjects who have received pembrolizumab (MK-3475), 
including serious adverse events (SAEs) and events of clinical interest (ECIs).  
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Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 7.2.3.2. 
4.2.3.3
Planned Exploratory Biomarker Research
Subjects will be required to have newly obtained core or excisional tumor biopsies (fine 
needle aspiration is not acceptable) of sufficient quality to support the secondary biomarker 
objective: “To investigate the correlation between PD-L1 protein expression
by 
immunohistochemistry (IHC) and anti-tumor activity of pembrolizumab (MK-3475) as 1L 
therapy in subjects with advanced/unresectable (inoperable) or metastatic urothelial cancer 
who are ineligible for cisplatin-based therapy”.  If a relationship between PD-L1 expression 
by IHC is found, a cut-point associated with optimal predictive value will be determined.
If needed, additional data from this trial may be used to supplement external data in order to 
determine a cut-point.  In such a circumstance, the subject data utilized to supplement the 
external data will not be included in the data utilized to assess the primary endpoint in this 
trial and the sample size of the PDL1-positive population required for assessment of the 
primary endpoint will not be altered from that currently specified.
The tissue specimens will be evaluated at a central laboratory for expression status of PD-L1
in a retrospective analysis from subjects enrolled in the study, thus tissue availability, but not 
high biomarker expression is required for trial entry.  Therefore, subjects will be enrolled 
onto this trial irrespective of PD-L1 expression (including subjects whose tumors do not 
express PD-L1).  Additionally, if available, archived tumor tissue specimens from prior 
biopsies will be collected for determination of PD-L1 status to compare biomarker
expression in archived specimens against that in newly obtained tumor tissue that is collected 
as a requirement for entry into the trial.  Previous unpublished data has suggested 
discordance between newly obtained and archived specimens. The collection of archived 
specimens will help determine if this limitation occurs with bladder cancer samples.
Tumor PD-L1 IHC results from NSCLC subjects treated with pembrolizumab (MK-3475)
showed that pretreatment tumor PD-L1 expression was a statistically significant predictor of 
response. In subjects with evaluable tumor PD-L1 expression, confirmed responses by 
RECIST v1.1 (and immune related response criteria - irRC) occurred in subjects with tumors 
strongly positive for PD-L1 [49], suggesting that PD-L1 may be a predictive biomarker of 
anti-PD-1 activity.  Recent preliminary data presented at the 2014 American Society of 
Clinical Oncology (ASCO) annual meeting demonstrated the value of PD-L1 expression in 
predicting response to MPDL3280a (Roche’s anti-PDL1 antibody) in patients with urothelial 
cancer [40].
Additional biomarker research to identify factors important for pembrolizumab (MK-3475) 
therapy may also be pursued. For example, tumor and blood samples (including serum and 
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plasma) from this trial may undergo proteomic, genomic, metabolomic and transcriptional
analyses. Additional research may evaluate factors important for predicting responsiveness 
or resistance to pembrolizumab (MK-3475) therapy and other immunologic targets.
Assays may include but are not be limited to:
Immunohistochemistry
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab (MK-3475). Other exploratory biomarkers (e.g. PD-1 expression, markers of 
T-cell phenotype) may also be evaluated.
Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material (biopsy specimens, 
peripheral blood) will be completed to assess expression of approximately 700 genes and 
attempt to define a gene set critical for clinical response to pembrolizumab (MK-3475). The 
hypothesis to be tested is that pembrolizumab (MK-3475) induces responses in tumors that 
reflect an inflamed/ immune phenotype based on gene expression signatures capturing PD-
L1 & interferon-gamma transcriptional programs. Global profiling will also be pursued.
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., IL-10).  microRNA profiling may also be 
pursued in serum samples.
Proteomic analysis
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood.  Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab (MK-3475) therapy, as well as levels of PD-L1 
IHC or protein in the tumor.  Blood would be a less invasive compartment compared to 
tumor from which to measure PD-L1 protein biomarker.  In addition to this specific protein 
biomarker, both tissue and blood derivatives can be subjected to proteomic profiling studies 
using a variety of platforms that could include but are not limited to immunoassay, Liquid 
chromatography/Mass Spectrometry.  This approach could identify novel protein biomarker 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or can detect the presence of specific T-cell clones within the tumor 
microenvironment or in the peripheral blood. There is a potential that the hypermutated state 
and/or increased T-cell clonality may correlate with response to pembrolizumab (MK-3475) 
therapy, and/or that the converse, ‘hypomutated’ state or lack of dominant T-cell clones may 
correlate with non-response.
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In addition, understanding genetic determinants of drug response is an important endeavor 
during medical research. This research will evaluate whether genetic variation within a 
clinical trial population correlates with response to the treatment(s) under evaluation. If 
genetic variation is found to predict efficacy or adverse events, the data might inform optimal 
use of therapies in the patient population.
4.2.3.4
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens specifically collected 
for future biomedical research during this clinical trial.   This research may include genetic 
analyses (DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, 
plasma) and/or the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
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5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects of at least 18 years of age with advanced/unresectable (inoperable) or 
metastatic transitional cell cancer who are ineligible for cisplatin-based therapy will be 
enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial. The 
subject may also provide consent/assent for Future Biomedical Research. However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
2. Be ≥18 years of age on day of signing informed consent.
3. Have histologically or cytologically-confirmed diagnosis of advanced/unresectable 
(inoperable) or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or 
urethra. Both transitional cell and mixed transitional/non-transitional cell histologies
are allowed.  Subjects with non-urothelial cancer of the urinary tract are not allowed.
4. Be considered cisplatin-ineligible to receive cisplatin-based combination therapy, 
based on having at least one of the following criteria: 
a.
ECOG performance status of 2 (the proportion of ECOG 2 subjects will be 
limited to approximately 50% of the total population)
b. Creatinine clearance (calculated or measured) < 60 mL/min but >30 mL/min
Note: Subjects with a creatinine clearance (calculated or measured) < 30 
mL/min or on dialysis are excluded from the trial.
c.
CTCAE v.4, Grade >2 audiometric hearing loss (25dB in two consecutive 
wave ranges)
d. CTCAE v.4, Grade >2 peripheral neuropathy
e.
NYHA Class III heart failure (Appendix 12.6)
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5. Have received no prior systemic chemotherapy for advanced/unresectable 
(inoperable) or metastatic urothelial cancer
a.
Adjuvant platinum based chemotherapy, following radial cystectomy, with 
recurrence > 12 months from completion of therapy is permitted
b. Neoadjuvant platinum based chemotherapy, with recurrence > 12 months 
since completion of therapy is permitted.
Note: 
Low-dose 
chemotherapy 
(e.g., 
low 
dose 
cisplatin, 
cisplatin+5FU, 
mytomycin+5FU, or cisplatin+paclitaxel) given concurrent with radiation to the primary 
tumor site is not considered as systemic therapy. 
6. Have provided tissue for biomarker analysis from a newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated (mandatory).  Adequacy of the 
biopsy specimen for PD-L1 biomarker analysis must be confirmed by the central 
laboratory.
7. Have measureable disease based on RECIST 1.1 as determined by central review. 
Tumor lesions situated in a previously irradiated area are considered measureable if 
progression has been demonstrated in such lesions.
8. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale, as assessed 
within 10 days prior to treatment initiation.  
9. Demonstrate adequate organ function as defined in Table 1. All screening labs should 
be performed within 10 days of treatment initiation.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L 
Renal
Creatinine OR
Measured 
or 
calculateda
creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5xULN OR
≥30 mL/min for subjects with 
creatinine levels >1.5x institutional ULN
Hepatic
Total bilirubin
≤1.5xULN OR
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5xULN
AST (SGOT) and ALT (SGPT)
≤2.5xULN  OR
≤5xULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT) or PTT
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
≤1.5xULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
a Creatinine clearance should be calculated per institutional standard. For subjects with a baseline 
calculated creatinine clearance below normal institutional laboratory values, a measured baseline 
creatinine clearance should be determined.
10. Female subject of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
11. Female subjects of childbearing potential must be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for >1 year.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
12. Male subjects must 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.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
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Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local therapy administered with curative intent.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks prior to the first dose of treatment.
3. Has had a prior anti-cancer monoclonal antibody (mAb) for direct anti-neoplastic 
treatment within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 
1 or at baseline) from adverse events due to agents administered more than 4 weeks 
earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent.
Note: Subjects with neuropathy or ≤ Grade 2 alopecia are an exception to this 
criterion and may qualify for the study.
Note: If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.
5. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. A
history
of
prostate
cancer
that
was
identified incidentally following
cystoprostatectomy for bladder cancer is acceptable, provided that the following
criteria are met: stage T2N0M0 or lower; and Gleason score ≤6, and undetectable
PSA.  
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable [without evidence of progression by imaging (confirmed by 
CT scan if CT used at prior imaging, or confirmed by MRI if MRI was used at prior 
imaging) for at least four weeks prior to the first dose of trial treatment and any 
neurologic symptoms have returned to baseline], have no evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability.
7. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
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replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.   
8. Has evidence of interstitial lung disease or active non-infectious pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or 
with an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, 
CD137).
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
16. Has received a live virus vaccine within 30 days of planned start of trial treatment.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject.
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.  
Table 2
Trial Treatment
Drug, Vaccine, 
Biologic, 
Device, etc.
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
pembrolizumab 
(MK-3475)
200 mg
Q3W
IV infusion
Day 1 of each 3 
week cycle
Experimental
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Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Modification (Escalation/Titration/Other)
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 & Rationale.  Details on preparation and administration of pembrolizumab (MK-
3475) are provided in the Pharmacy Manual.
5.2.1.2
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3. 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis
Grade 2
Withhold
   Administer 
corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
   Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4
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 participants 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)
   Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
   Participants 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.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring 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
T1DM 
or 
Hyperglycemia
New onset T1DM 
or
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of β-cell 
failure
Withhold a
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer 
anti-
hyperglycemic in participants 
with hyperglycemia
   Monitor participants 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 
discontinue a
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 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid disorders
Nephritis 
and 
renal dysfunction
Grade 2
Withhold
   Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold 
or 
discontinue b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b     Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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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 pembrolizumab
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 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. 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.
Timing of Dose Administration
Trial treatment
should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. Trial treatments will be administered on an 
outpatient basis, unless the subject is hospitalized for an unrelated reason. Pembrolizumab 
(MK-3475)
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Pembrolizumab (MK-3475) 200 mg will be administered as a 30 minute IV infusion every 3 
weeks. Treatment cycle intervals may be increased due to toxicity as described in Section 
5.2.1.2.  Sites should make every effort to target infusion timing to be as close to 30 minutes 
as possible.  However, given the variability of infusion pumps from site to site, a window of -
5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab (MK-3475) dose 
calculation, reconstitution, preparation of the infusion fluid, and administration.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS).  Subjects will be assigned to pembrolizumab (MK-
3475) in an unblinded fashion.  
Subjects participating in this trial will be allocated by non-random assignment.
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.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
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All concomitant medications received within 30 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab (MK-3475)

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Sponsor.  

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, intranasal 
influenza, rabies, BCG, and typhoid vaccine.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  Subjects who require
corticosteroids to manage drug-related adverse events must be at an equivalent dose 
of ≤10 mg per day of prednisone to resume dosing with MK-3475. Furthermore, an 
inability to reduce the corticosteroid dose for managing a drug-related adverse event 
to the equivalent of ≤10 mg prednisone per day within 12 weeks of last MK-3475 
dose should prompt discussion between the investigator and Sponsor regarding the 
subject’s ability to continue on treatment in the trial.
o Note: Temporary use of prophylactic corticosteroids to avoid allergic reactions 
(e.g. IV contrast dye or transfusions) is permitted.
o Note: Use of intermittent inhaled steroids or local injection of corticosteroids is 
permitted upon consultation with the sponsor.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
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Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications, which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.1.2, . Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the Investigator determines 
the events to be related to pembrolizumab. 
Note: If after the evaluation the event is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to in Section 5.2.1.2 for 
dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
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 (MK-3475) may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if pembrolizumab (MK-3475) has transient adverse effects on the composition of 
sperm.  Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 
methods of birth control or are considered highly unlikely to conceive.  Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 
years of age and has not had menses for greater than 1 year will be considered 
postmenopausal), or 3) not heterosexually active for the duration of the study.  The two birth 
control methods can either be two barrier methods or a barrier method plus a hormonal 
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method to prevent pregnancy. Subjects should start using birth control from study Visit 1 
throughout the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the 
subject.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.2.2-Reporting of 
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab 
(MK-3475), the subject will immediately be removed from the study.  The site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.   If a male subject impregnates his female partner the study personnel at the site 
must be informed immediately and the pregnancy reported to the Sponsor and followed as 
described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether pembrolizumab (MK-3475) is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
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withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  Once a 
subject has discontinued treatment, even though he/she continues to be monitored in the trial, 
he/she may be allowed to begin treatment again if deemed medically appropriate.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Section 5.8.1.
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 
5.8.1 below.

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Completed 24 months of treatment with pembrolizumab (MK-3475)
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab (MK-3475) after 24 months may be eligible for up to one 
year of additional study treatment if they progress after stopping study treatment 
provided they meet the requirements detailed in Section 7.1.5.2.1.   

Administrative reasons
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The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment or 30 days after the end of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, as described in Section 7.2.3.1).  
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
Treatment after initial evidence of radiologic disease progression
Immunotherapeutic agents such as pembrolizumab (MK-3475) may produce antitumor 
effects by reactivating endogenous cancer-specific immune responses, which may be 
functionally exhausted.  The response patterns seen with such therapies may extend beyond 
the typical time course of responses seen with cytotoxic agents, and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions.  
Standard RECIST criteria may not provide an accurate or complete response assessment of 
immunotherapeutic agents such as pembrolizumab (MK-3475).   Therefore, RECIST 1.1 will 
be used with the following adaptation:
If radiologic imaging by local/site assessment shows PD, tumor assessment may be repeated 
by the site 4 weeks later in order to confirm PD with the option of continuing treatment per 
below while awaiting radiologic confirmation of progression.  If repeat imaging shows SD, 
PR or CR, treatment may be continued as per treatment calendar.  If repeat imaging still 
meets the threshold for PD (≥ 20% increase in tumor burden compared to nadir) but shows a 
reduction in tumor burden compared to the previous time point, treatment may be continued 
as per treatment calendar after consultation with Sponsor.
If repeat imaging confirms 
progressive disease without reduction in tumor burden compared to the previous time point, 
subjects will be discontinued from study therapy.  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 Procedures Manual).
The decision to continue study treatment after the 1st evidence of disease progression is at 
the Investigator’s discretion based on the clinical status of the subject as described in Table 5
below.  Confirmatory imaging maybe performed as early as 28 days later; alternatively, the 
scan performed at the next scheduled time point (every 42 days ± 7 days) may be used as 
confirmation. Subjects may receive study treatment while waiting for confirmation of PD if 
they are clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status
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
Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention

Subjects exhibiting toxicity from trial therapy as outlined in Section 5.2.1.2 and 7.2 
may NOT continue to receive trial therapy.
Table 5
Imaging and Treatment After 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologic 
evidence of PD 
Repeat imaging at >
4 weeks at site to 
confirm PD
May continue study 
treatment 
at 
the 
Investigator’s 
discretion 
while 
awaiting 
confirmatory 
scan 
by site
Repeat imaging at >
4 weeks to confirm 
PD per physician 
discretion only
Discontinue 
treatment
Repeat 
scan 
confirms PD (no 
reduction in tumor 
burden from prior 
scan)
No 
additional 
imaging required
Discontinue 
treatment
No 
additional 
imaging required
N/A
Repeat 
scan 
confirms 
PD 
(reduction in tumor 
burden from prior 
scan)
Continue regularly 
scheduled imaging 
assessments
Continue 
study 
treatment 
after 
consultation 
with 
Sponsor
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment 
if 
condition 
has 
improved 
and/or 
clinically stable per 
Investigator 
and 
Sponsor’s 
discretion
Repeat scan shows 
SD, PR or CR
Continue regularly 
scheduled imaging 
assessments 
Continue 
study 
treatment 
at 
the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment 
if 
condition 
has 
improved 
and/or 
clinically stable per 
Investigator’s 
discretion
NOTE: If a subject with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory scan (as assessed by the 
investigator/site radiologist), an exception may be considered to continue treatment upon 
consultation with the Sponsor.
Additional information is included in the Site Imaging Manual.    
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5.8.2
Discontinuation of Study Therapy after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab (MK-3475) and had at 
least two treatments with pembrolizumab (MK-3475) beyond the date when the initial CR 
was declared.  Subjects who then experience radiographic disease progression may be 
eligible for up to one year of additional treatment with pembrolizumab (MK-3475) at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab (MK-3475), the subject meets the safety parameters listed in the 
Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at the same 
dose and schedule at the time of initial discontinuation.  Additional details are provided in 
Section 7.1.5.2.1.  Response or progression in this Second Course Phase will not count 
towards the ORR as the primary endpoint in this trial.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).  Upon study completion, participants are discontinued and enrolled in a 
pembrolizumab extension study.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
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a. In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 weeks; 
however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 5.2.1.2.  If the interval is increased, all 
procedures except imaging should be performed based on the new dosing schedule.  Imaging should be performed at 9 weeks (63 ± 7 days) after the first dose of trial treatment 
on Day 1 Cycle 1, and every 6 weeks thereafter (42 days ± 7 days) regardless of any treatment delays.  After 12 months, imaging frequency should be reduced to every 12 weeks 
(84 ± 7 days).  
b. 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 6 weeks (42 ± 7 days) in the first year and every 12 weeks (84 ± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression as 
assessed by the investigator/site radiologist, (3) death, or (4) the end of the study, whichever occurs first.
c. After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a scheduled study visit or 
study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a death event previously recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted.  Study personnel will access IVRS/IWRS to obtain randomization number and study drug assignment. 
Cycle 1 treatment must be given within 3 days of randomization number assignment in IVRS/IWRS.
e. Written informed consent must be obtained prior to performing any protocol specified procedure.  Please note there is no specific study window for acquiring the “newly 
obtained” tissue specimen and it may be obtained any time before the first dose of study drug, as long as the subject has not received any intervening systemic therapy from the 
time the tissue was collected until the time the subject enters the study. Written consent should be obtained prior to acquiring the biopsy specimen for the study.  Results of a test 
performed prior to the subject signing consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the window specified for 
screening procedures (e.g., within 28 days for tumor imaging assessments or within 10 days the first dose of trial treatment for required lab tests).  Screening number will be 
assigned when the study informed consent is signed.
f. Signing the informed consent for future biomedical research (FBR) sample is optional.  Detailed instructions for the collection and management of specimens for FBR are 
provided in the Procedures Manual and Section 12.2.  
g. Prior medications – Record all medications taken within 30 days of Cycle 1. Concomitant medications – Enter new medications started during the trial through the Safety 
Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
h. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.  
i. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days after 
the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial treatment.
j. Full PE at screening visit; Direct PE for all other visits.
k. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening visit only. Vital signs will be collected at screening, 
prior to the administration of each dose of trial treatment at every cycle, at treatment discontinuation, and at follow-up.
l. ECOG performance status at screening to be performed within 10 days prior to Day 1 of Cycle 1. ECOG performance status will also be performed prior to the administration of 
each dose of trial treatment at every cycle, at treatment discontinuation, and at follow-up.
m. 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.
n. 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.
o. Laboratory tests for screening are to be performed within 10 days prior to Day 1 of Cycle 1.  See Section 7.1.3 for details regarding laboratory tests.
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p. After Cycle 1, predose lab samples can be collected up to 72 hours prior to the scheduled time point.  Thyroid function tests (T3, FT4 and TSH) and urinalysis should be 
repeated every 2 cycles after Cycle 6 up to one year of treatment. CBC and Chemistry tests should be collected predose on Day 1 of every 3 week cycle after Cycle 6.  For 
subjects with a baseline estimated creatinine clearance below the normal institutional laboratory range, a baseline measured creatinine clearance should be performed. See 
Section 7.1.3 for details regarding laboratory tests. A persistent elevated alkaline phosphatase should prompt consideration for the presence of bony metastatic disease.
q. Unresolved abnormal labs that are drug-related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
r. Blood for serum and blood for plasma correlative studies is to be collected only predose at Cycle 1. See Procedures Manual. Any leftover samples from the correlative blood 
studies will be stored for future biomedical research if the subject signs the FBR consent
s. Whole blood sample for RNA/DNA correlative studies should be collected predose at Cycles 1, 2, and 3, and again at treatment discontinuation.. See Procedures Manual. Any 
leftover samples from the correlative blood studies will be stored for future biomedical research if the subject signs the FBR consent.
t. This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the 
IRB/IEC does not approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future biomedical research 
if the subject signs the FBR consent.
u. The initial tumor imaging at screening will be performed within 28 days prior to the first dose of trial treatment. Scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. Measureable disease based on 
RECIST 1.1 must be confirmed by central review before enrollment. All subjects will have a baseline bone scan performed at screening. Bone scans at baseline must be sent to 
central imaging vendor for review with initial tumor imaging to determine eligibility.  Subjects with positive bone scans at baseline will be followed with additional scans 
performed at 9 weeks (± 7 days) after the first dose of trial treatment on Day 1 Cycle 1, and then every 6 weeks (± 7 days) thereafter or more frequently if clinically 
indicated.  For subjects with new symptoms suggestive of osseous metastasis, a bone scan should be obtained. Additionally, plain X-ray evaluation should  be obtained for 
symptomatic sites with negative bone scan evaluations. Refer to Section 7.1.2.6.3 of the protocol and site imaging manual.
v. The first on-study imaging time point will be performed at 9 weeks (± 7 days) after the first dose of trial treatment on Day 1 Cycle 1, and then every 6 weeks (± 7 days) 
thereafter or more frequently if clinically indicated.  After 12 months, imaging frequency should be reduced to every 12 weeks (± 7 days).  Imaging timing should follow 
calendar days and should not be adjusted for delays in cycle starts or extension of pembrolizumab (MK-3475) cycle frequencies.  The same imaging technique should be used in 
a subject throughout the trial.  On-study scans should be submitted immediately to the central imaging vendor; and progressive disease should be confirmed by the 
investigator/site radiologist prior to subject discontinuation from trial.  
w.In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation (i.e., date 
of discontinue ± 4 week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory.
x. Baseline tumor tissue for biomarker analysis from a newly obtained core or excisional biopsy (FNA not adequate) (mandatory) must be provided to the central vendor prior to 
randomization number assignment, and an archival tissue sample (if available) will also be collected. Adequacy of the biopsy specimen for PD-L1 biomarker analysis must be 
confirmed by the central laboratory before enrollment. Detailed instructions for tissue collection, process and shipment are provided in the Procedures Manual.  If the subject 
signs the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for FBR.  
y. For electronic patient reported outcomes (ePROs) it is most relevant and strongly recommended that ePROs are administered prior to drug administration, adverse event 
evaluation and disease status notification; an exception to this recommendation may occur at the treatment discontinuation visit where patients may have already been notified of 
their disease status or an AE evaluation is known prior to them arriving to the clinic.   ePROs are to be administered starting with EQ-5D, followed by EORTC QLQ-C30, and 
HEA.  Health economic assessment (HEA) to be completed by trained personnel prior to all other study procedures.  All ePROs are to be performed prior to Cycle 1, Cycle 2, 
Cycle 3, Cycle 4  and every 2 cycles thereafter (e.g., Cycle 6, Cycle 8, Cycle 10) up to a year or  End of Treatment, whichever comes first, and the 30-day post-treatment 
discontinuation follow-up visit.  If the subject does not completed the ePROs the MISS_MODE form must be completed to capture the reason the assessment was not 
performed. 
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a. In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment cycles are 3 
weeks; however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 5.2.1.2.  If the interval is 
increased, all procedures except imaging should be performed based on the new dosing schedule.  Imaging should always be performed every 6 weeks (42 days ± 7 days)
regardless of any treatment delays.  After 12 months, imaging frequency should be reduced to every 12 weeks (± 7 days).  
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (+7 days) in the first year and every 12 weeks (± 7 days) after year 1 until (1) the start of new anti-cancer treatment, (2) disease progression as 
assessed by the investigator/site radiologist, (3) death, or (4) the end of the study, whichever occurs first.
c. After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated 
survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding participants that have a death event 
previously recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted.
e. Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on pembrolizumab (MK-3475) for reasons other than disease 
progression or intolerability may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1.  
f. Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 
7.2.
g. Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
h. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.  
i. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 
days after the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only SAEs and ECIs that are related to trial 
treatment.
j. Full PE at Cycle 1; Directed PE for all other visits. 
k. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only. Vital signs will be collected prior to the 
administration of each dose of trial treatment at every cycle, at treatment discontinuation, and at follow-up.
l. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of the retreatment phase.  If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines.
m.Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
n. Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab (MK-3475).  See 
Section 7.1.3 for details regarding laboratory tests.
o. After Cycle 1, predose lab samples can be collected up to 72 hours prior to the scheduled time point. Thyroid function tests (T3, FT4 and TSH) should be repeated every 2 
cycles after Cycle 5 up to one year of treatment. CBC and Chemistry tests should be collected predose on Day 1 of every 3 week cycle after Cycle 6.  See Section 7.1.3 for 
details regarding laboratory tests. A persistent elevated alkaline phosphatase should prompt consideration for the presence of bony metastatic disease.
p. A scan must be performed within 28 days prior to restarting treatment with pembrolizumab (MK-3475).  Imaging should continue to be performed every 6 weeks (42 ± 7 
days) from the first retreatment dose or more frequently if clinically indicated. Imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts or extension of MK-3475 cycle frequencies.  The same imaging technique should be used in a subject throughout the trial. On-study scans should be submitted 
immediately to the central imaging vendor; and progressive disease should be confirmed by the investigator/site radiologist prior to subject discontinuation from trial.  
q. In subjects who discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., date of discontinue ± 4 week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation 
isn’t mandatory.
r. Unresolved labs for drug related AEs should be followed until resolution.  Labs do not need to be repeated at the end of trial treatment if labs are within normal range.
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7.0 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 or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. A medical 
history will be obtained by the investigator or qualified designee. Medical history will
include all active conditions, and any condition diagnosed within the prior 10 years that are
considered to be clinically significant by the Investigator. Details regarding the subject’s 
urothelial cancer will be recorded separately and not listed as medical history.
7.1.1.4.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding the
subject’s urothelial cancer.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial. Prior treatment for urothelial cancer will be recorded 
separately and not listed as a prior medication.
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Prior Treatment Details for Urothelial Cancer
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded a
defined in Section 7.2.
Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the
first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after treatment allocation.  Once a randomization number is assigned to a subject, it 
can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
All subjects will be assigned a randomization number, however all subjects will receive the 
same pembrolizumab (MK-3475) 200 mg every three weeks (Q3W) as trial treatment by 
non-random assignment in unblinded fashion.
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7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab (MK-3475) doses require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff. The
total volume of pembrolizumab (MK-3475) infused will be compared to the total volume 
prepared to determine compliance to each dose of pembrolizumab (MK-3475) administered.
The instructions for preparing and administering pembrolizumab (MK-3475) will be 
provided in the Pharmacy Manual.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Appendix 12.7).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab (MK-3475) all AEs of unknown 
etiology associated with pembrolizumab (MK-3475) exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (termed immune-related adverse events, or irAEs); see the separate ECI guidance 
document in the administrative binder regarding the identification, evaluation and 
management of potential irAEs.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.  
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or clinical designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history. A full physical exam should be performed as specified in the Trial Flow Chart.  
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
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7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
dosing on Day 1 of each treatment cycle.  New clinically significant abnormal findings 
should be recorded as AEs.
7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart.  Vital signs should include temperature, pulse, respiratory rate, weight 
and blood pressure.  Height will be measured at screening only.  
7.1.2.4
12-Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at 
screening.  Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Appendix 12.5) at 
screening, prior to dosing on Day 1 of each treatment cycle and at discontinuation of trial 
treatment as specified in the Trial Flow Chart.
7.1.2.6
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central vendor can be found in the 
imaging section of the Site Imaging Manual (SIM). Tumor imaging may be performed by 
computed tomography (CT) (preferred) or magnetic resonance imaging (MRI), but the same 
imaging technique should be used in a subject throughout the trial. Bone scans will also be 
utilized to assess osseous metastases. Additionally, plain X-ray evaluation will be obtained 
for symptomatic sites with negative bone scan evaluations.
Real-time determination of measurable disease by central review at screening will be used to 
determine subject eligibility. The central imaging vendor will receive all images at the 
timepoints specified in the Study Flow Chart from the sites. Real-time determination of 
measurable disease by central review at screening will be used to determine subject 
eligibility.  The central imaging vendor will receive all images at the timepoints specified in 
the Study Flow Chart from the sites. In addition, additional imaging (including other 
modalities) that are obtained at an unscheduled time point to determine disease progression, 
as well as imaging obtained for other reasons but captures radiologic progression, should be 
submitted to the central imaging vendor as well.
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7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.  The central imaging vendor must review the baseline scan to determine subject 
eligibility per RECIST 1.1.  The baseline imaging scan should be submitted to the central 
imaging vendor immediately. Bone scans will be performed at baseline for all subjects. Bone 
scans at baseline must be sent to central imaging vendor immediately for review with initial 
tumor imaging to determine eligibility.
Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality, meet the requirements specified in the 
imaging manual, and performed within 28 days prior to the first dose of trial treatment.  
Subjects who enter the study with stable brain metastases should continue to have brain 
imaging as clinically indicated.
7.1.2.6.2 Tumor Imaging During Trial
The first imaging assessment should be performed at 9 weeks (63 days ± 7 days) after the 
first dose of trial treatment on Day 1 Cycle 1. Subsequent imaging should be performed 
every 6 weeks (42 days ± 7 days), more frequently if clinically indicated.  Subjects who 
remain on treatment for a year will have imaging performed every 12 weeks (84 ± 7 days).  
Imaging should not be delayed for delays in cycle starts or extension of pembrolizumab 
(MK-3475) cycle intervals.  
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date the response was first documented.  The scan for confirmation of 
response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan (6 weeks later), whichever is clinically indicated.  
Imaging should continue to be performed until disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the SPONSOR, whichever 
occurs first.  Disease progression may be confirmed at least 4 weeks after the first scan 
indicating progressive disease in clinically stable subjects.  Subjects who have unconfirmed 
disease progression may continue on treatment until progression is confirmed provided they 
have met the conditions detailed in Section 5.8.1.
7.1.2.6.3 Bone Scans
Bone scans will be performed at baseline for all subjects. Bone scans at baseline must be 
sent to central imaging vendor for review with initial tumor imaging to determine eligibility.
Subjects with positive bone scans at baseline will be followed with additional scans 
performed at 9 weeks (± 7 days) after the first dose of trial treatment on Day 1 Cycle 1, and 
then every 6 weeks (± 7 days) thereafter or more frequently if clinically indicated. Subjects 
with new symptoms concerning of osseous metastasis (e.g., new persistently elevated 
alkaline phosphatase) a bone scan should be obtained. Additionally, plain X-ray evaluation 
should be obtained for symptomatic sites with negative bone scan evaluations. New osseous 
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uptake, upon confirmation with CT or per institutional standard, will be assessed for 
progression per RECIST 1.1. Lytic/mixed lesions with soft tissue component may be 
included in the evaluation of disease burden if it meets measurability criteria, while blastic 
lesions are considered non-measurable, in accordance with RECIST 1.1.
7.1.2.6.4 Assessment of Disease
For the purposes of the primary study endpoints, RECIST 1.1 (Appendix 12.8) will be 
applied by the central imaging vendor as the primary measure for assessment of tumor 
response. All scans, including confirmatory scans, should be submitted to the central imaging 
vendor for retrospective evaluation and should  be submitted in a timely fashion.  
Sites should also assess tumor response and progression per modified RECIST and this data 
will be collected in the clinical database.   Site assessment of tumor response and progression 
will be used for all subject decision making in the trial. Subjects who have unconfirmed 
progressive disease will be managed as detailed in Section 5.8.1, and these criteria may be 
applied at the discretion of the investigator.
Imaging during the follow-up period is to be repeated every 6 weeks (42 ± 7 days), or every 
12 weeks (84 ± 7 days) after the first year following the initiation of trial therapy, for subjects 
who discontinue trial treatment for reasons other than disease progression until the subject 
experiences confirmed disease progression or starts a new anti-neoplastic therapy.  
Review by the central imaging vendor based on RECIST 1.1 will be used to determine 
subject eligibility.  Confirmatory scans performed per modified RECIST will be evaluated by 
local reading for the purpose clinical decision-making. Real-time analysis of subject 
eligibility by RECIST 1.1 will be conducted. Retrospective analysis of treatment response 
by RECIST 1.1 and modified RECIST will also be performed by a central imaging vendor.  
7.1.2.7
Tumor Tissue Collection and Correlative Blood Sampling
A “newly obtained” core or excisional biopsy (fine needle aspirate not adequate) must be 
submitted to a central lab for characterization of PD-L1 expression. PD-L1 expression will be 
evaluated retrospective in this trial.  The tumor tissue must be received by the central vendor 
and be deemed adequate for evaluation prior to subject randomization number assignment. 
The “newly obtained” tissue sample may be obtained at any time before the first dose of 
study drug, as long as the subject has not received any intervening systemic therapy from the 
time the tissue was collected until the time the subject enters the study.
Participation in this trial will be dependent upon supplying tumor tissue from locations not 
radiated prior to biopsy. Biopsies obtained PRIOR to receipt of neoadjuvant/adjuvant 
chemotherapy is NOT permitted.  Subjects who received neoadjuvant/adjuvant therapy are 
permitted onto the trial as long as therapy was completed at least 12 months prior to the 
diagnosis of metastatic disease. Only tumor specimens obtained AFTER completion of the 
neoadjuvant/adjuvant therapies, and only AFTER metastatic or muscle invasive disease is 
observed will be used to assess PD-L1 status.
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If a tumor biopsy is to be obtained from an intended target lesion during eligibility 
assessment, the biopsy should be performed prior to obtaining the baseline scan.   Otherwise, 
a new baseline scan should be obtained.
Additionally, if available, archived tumor tissue specimens from prior biopsies will be 
collected for determination of PD-L1 status to compare biomarker expression in archived 
specimens against the in newly obtained tumor tissue that is collected as a requirement for 
entry into the trial.
Whole blood sample for RNA/DNA correlative studies should be collected predose at Cycles 
1, 2, and 3, and again at treatment discontinuation. Blood for serum and blood for plasma 
correlative studies is to be collected only predose at Cycle 1. 
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
7.1.2.8
Patient Reported Outcomes (PROs)
The EuroQol EQ-5D and EORTC QLQ-C30 questionnaires will be administered by trained 
site personnel and completed electronically by subjects in the following order: EuroQol EQ-
5D first then EORTC QLQ-C30 at the time points specified in the Trial Flow Chart. It is 
most relevant and strongly recommended that ePROs are administered prior to drug 
administration, adverse event evaluation and disease status notification; an exception to this 
recommendation may occur at the treatment discontinuation visit where patients may have 
already been notified of their disease status or an AE evaluation is known prior to them 
arriving to the clinic.   
The health economic assessment (HEA) form will be completed via an interview with the 
subject by qualified site personnel after the subject completes all other questionnaires.  The 
form captures all non-study related health care contacts made throughout the study
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 (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry 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)a
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
aPTT
WBC 
(total 
and 
differential)d
Aspartate 
aminotransferase (AST)
Specific gravity 
Total 
thriiodothyronine 
(T3) (or Free T3)b
Red Blood Cell Count
Carbon dioxide (CO2 or 
bicarbonate)b
Microscopic 
exam, 
if 
abnormal results are noted
Free tyroxine (Free T4)
Absolute 
Neutrophil 
Count
Calcium
Urine pregnancy testa
Thyroid 
Stimulating 
Hormone (TSH)
Absolute 
Lymphocyte 
Count
Chloride
PK
for pembrolizumab 
(MK-3475) 
Creatininec 
(GFR can also be used in 
place
of creatinine or 
CrCl)
Anti-pembrolizumab 
(MK-3475) Antibodies 
Glucose
Blood 
for 
correlative 
studies
Phosphorus
Blood for FBR
Potassium
Blood for Genetics
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Blood Urea Nitrogen e
Uric acid
a Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, 
a serum pregnancy test will be required.
b If considered standard of care in your region
c For subjects with a baseline calculated creatinine clearance below the normal institutional laboratory range, a 
baseline measured creatinine clearance should be performed.
d For WBC results Absolute or %  acceptable per their institutional standard.
e Blood Urea Nitrogen is preferred; if not available urea may be tested
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Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable prior to each dose of trial treatment. The results from thyroid function
tests (T3/or FT3, FT4, and TSH) are not required to be available nor reviewed prior to each 
dose of trial treatment after Cycle 1, unless clinical suspicion of thyroid dysfunction is 
observed.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
The accumulation of robust PK and ADA data has allowed for the adequate characterization  
of the clinical pharmacology of pembrolizumab across indications. Therefore, upon approval 
of Amendment 3, each site is to stop the collection of PK and ADA samples for all subjects. 
Blood samples for PK and ADA collected prior to Amendment 3 may be stored only at this 
time. Analysis will be performed if required.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future use

Leftover tumor tissue

Leftover biomarker samples
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. Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab (MK-3475) may discontinue treatment with the option of 
restarting treatment if they meet the criteria specified in Section 7.1.5.2.1.  After 
discontinuing treatment following assessment of CR or 24 months of treatment, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) 
and then proceed to the Follow-up Period of the study (described in Section 7.1.5.3.2).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
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obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual and Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Approximately 28 days prior to randomization number assignment, potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1.  
Screening procedures may be repeated after consultation with the Sponsor.
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 
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frame.  Screening procedures are to be completed within 28 days prior to the first dose trial 
treatment except for the following:

Informed Consent Form (ICF) signed prior to completing any protocol specified 
procedure.

Laboratory tests and evaluation of ECOG status 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).

Initial tumor imaging must be performed within 28 days of the first dose of study.

A “newly obtained” tissue sample may be obtained at any time before the first dose of 
study drug, as long as the subject has not received any intervening systemic therapy 
from the time the tissue was collected until the time the subject enters the study. See 
Section 7.1.2.7 for additional details regarding tumor tissue requirements.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.2
Treatment Period/Vaccination Visit
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.  
7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab (MK-3475) with SD or better may be eligible for up to 
one year of additional pembrolizumab (MK-3475) therapy if they progress after stopping 
study treatment.  This retreatment is termed the Second Course Phase of this study and is 
only available if the study remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab (MK-3475) after attaining an 
investigator-determined confirmed CR according to RECIST 1.1

Was treated for at least 24 weeks with pembrolizumab (MK-3475) 
before discontinuing therapy

Received at least two treatments with pembrolizumab (MK-3475) 
beyond the date when the initial CR was declared
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OR
o
Subject had SD, PR or CR and stopped pembrolizumab (MK-3475) treatment 
after 24 months 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 pembrolizumab (MK-3475)

Did not receive any anti-cancer treatment since the last dose of pembrolizumab (MK-
3475)

Have a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrate adequate organ function as detailed in Section 5.1.2

Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  

Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

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. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.
Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab (MK-3475).  Treatment will be administered for up to one 
additional year.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.
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7.1.5.3
Post-Trial
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days (± 3 
days) after the last dose of trial treatment or before the initiation of a new anti-cancer 
treatment, whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit 
should be recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution 
of the AE to Grade 0-1 or until the beginning of a new anti-cancer therapy, whichever occurs 
first.  SAEs and ECIs that occur within 90 days of the end of treatment or before initiation of 
a new anti-cancer treatment should also be followed and recorded.  
Subjects who are eligible for retreatment with pembrolizumab (MK-3475) (as described in 
Section 7.1.5.2.1) may have up to two safety follow-up visits, one after the Treatment Period 
and one after the Second Course Phase.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (42 ±7 days) by
radiologic imaging to monitor disease status. After 1 year, the imaging time point will occur 
every 12 weeks (84 ± 7 days).  Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression determined by 
the investigator/site radiologist, death, end of study, or if the subject begins retreatment with 
pembrolizumab (MK-3475) as detailed in Section 7.1.5.2.1.  Information regarding post-
study anti-cancer treatment will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab (MK-3475) according 
to the criteria in Section 7.1.5.2.1 will move from the Follow-up Phase to the Second Course 
Phase when they experience disease progression.  Details are provided in Section 6.2 – Trial 
Flow Chart for Retreatment with pembrolizumab (MK-3475).
7.1.5.3.3 Survival Follow-up
Once a subject stops receiving trial treatment, they will be followed for survival. Initially 
these data will be collected at the Safety Follow-up visit and 3-month Follow-up visits, and 
any subsequent visits for imaging that may occur until PD is confirmed or starting a new 
anti-cancer therapy. Once the subject stops the imaging assessments for this protocol every 6 
weeks or then every 12 weeks (84 ± 7 days) after 1 year (e.g. for PD or starting a new anti-
cancer therapy), the subject moves into the survival follow-up phase and should be contacted 
by telephone every 12 weeks (± 7 days) to assess for survival status, until death, withdrawal 
of consent, or end of the study, whichever occurs first. Post-study treatments and the 
subject’s response to them will also be collected.
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7.1.5.4
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.
Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a 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 
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 
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section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose of pembrolizumab (MK-3475) will be defined as 
1,000 mg or greater (≥5x the indicated dose) No specific information is available on the 
treatment of overdose of pembrolizumab (MK-3475). In the event of overdose, the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated.
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.
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 
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(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
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 
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 
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guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
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3. Additional adverse events:
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-Related 
Adverse Event Guidance Document”).  This document can be found in the administrative 
binder and provides guidance regarding identification, evaluation and management of ECIs 
and irAEs.  
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days after 
the initiation of a new anticancer therapy, whichever is earlier, need to be reported to the 
SPONSOR within 24 hours of the event, regardless of attribution to study treatment, 
consistent with standard SAE reporting guidelines and either by electronic media or paper.  
Sponsor Contact information can be found in the administrative binder.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.  
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.
Trial Governance and Oversight
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes made to primary and/or key 
secondary objectives, or the statistical methods related to those objectives, then the protocol 
will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to unblinding, 
will be documented in a supplemental 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
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
The primary and secondary objectives of this study include evaluations of the clinical 
efficacy of pembrolizumab (MK-3475) as 1L therapy in subjects with advanced/unresectable 
(inoperable)  or metastatic urothelial cancer who are ineligible for cisplatin-based therapy, in 
all subjects, PD-L1 positive, and PD-L1 strongly positive (if applicable) populations, by 
objective response rates, response duration, PFS, and OS. The PD-L1 positive/negative 
population is defined as patients with PD-L1 IHC assay CPS score of at least/lower than the 
pre-specified PD-L1 positive cut-point of 1%. The PD-L1 strongly positive is defined as 
patients with CPS score of at least the PD-L1 strongly positive cut-point determined using 
the biomarker discovery population (first 100 enrolled excluding subjects not evaluable). If a 
PD-L1 strongly positive cut-off with clinical utility cannot be determined, only the all 
subjects and PD-L1 positive populations will be evaluated. 
Analyses examining the association between PD-L1 expression and clinical efficacy to 
determine PD-L1 cut-point determination will be discussed in 8.2.5.3. The biomarker 
discovery population consists of the first 100 subjects enrolled; data from the biomarker 
discovery population will not contribute to efficacy evaluations for the PD-L1 strongly 
positive population.
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Efficacy Analyses
The all-patients-treated (APT) population will serve as the primary population for the 
analyses of efficacy data in this trial. ORR based on RECIST 1.1 assessed by independent 
radiology review is the primary efficacy endpoint. A point estimate and a 95% confidence 
interval (as determined by the upper and lower 97.5% one-sided confidence bounds) based 
on the exact binomial distribution will be provided in all subjects, PD-L1 positive, and PD-
L1 strongly positive populations. No hypothesis testing will be performed. An outline of the 
efficacy analysis strategy is presented in Table 8. 
Safety Analyses
The APT population will be used for safety analyses. Safety will be summarized for all 
subjects treated.
Power and Sample Size 
The sample size of this study is driven by the requirement for adequate efficacy evaluation 
for the PD-L1 strongly positive population. It is expected that ~350 subjects will be enrolled, 
which will provide enough subjects for the PD-L1 strongly positive population.
Biomarker/Interim Analysis
The biomarker analysis to establish the PD-L1 strongly positive cutpoint is planned. An 
interim futility analysis is planned for the PD-L1 negative population within the biomarker 
discovery population. See 8.2.9 for more details.
Statistical Analysis Plan
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 non-randomized single-arm clinical trial. The 
trial has primary objectives in the subset of subjects that is PD-L1 positive, defined as a PD-
L1 CPS score ≥1%, and PD-L1 strongly positive, defined as the PD-L1 CPS score ≥the 
optimal cut-point determined from data obtained from the biomarker discovery population. 
The study team will remain blinded to PD-L1 scores for individual patients throughout the 
study period until database lock for the primary study report; interim analyses related to PD-
L1 scores will be conducted by a sponsor unblinded statistician.
The clinical biostatistics department will generate the allocation schedule for study treatment 
assignment. Allocation will be implemented in an interactive voice response system (IVRS).
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Hypotheses/Estimation
Objectives of the study are stated in Section 3.0. There is no hypothesis and the efficacy 
objectives are related only to estimation.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
8.2.3.1
Efficacy Endpoints
The primary efficacy endpoint is objective response rate (ORR), defined as the proportion of 
subjects in the analysis population who have complete response (CR) or partial response 
(PR) using RECIST 1.1 criteria assessed by independent radiology review at any time during 
the study. 
Secondary efficacy endpoints include:

Duration of response (DOR) (RECIST 1.1 by independent radiology review).

Overall survival (OS) and progression free survival (PFS) (RECIST 1.1 by 
independent radiology review).

PFS (RECIST 1.1 by independent radiology review) rate and OS rate at 6 months and 
12 months. 
8.2.3.2
Safety Endpoints
A description of safety measures is provided in Section 4.2.3.2.  
The primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who have 
received MK-3475, including serious adverse events (SAEs) and events of clinical interest
(ECIs).  Immune-related ECIs, as described in Section 7.2.3.2, will be collected.  Other 
safety endpoints include laboratory safety assessments, ECOG performance status, vital signs 
and physical examinations.
Analysis Populations
8.2.4.1
Efficacy Analysis Population
The APT population, which consists of all enrolled subjects who receive at least one dose of 
study treatment, will serve as the primary population for the analyses of efficacy data in this 
trial. Supportive analyses of efficacy will be conducted in the full analysis set (FAS)
population, which consists of all enrolled subjects who receive at least one dose of study 
treatment and have measureable disease at baseline.
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The biomarker discovery population, subjects in this trial used for the determination of the 
PD-L1 strongly positive cut-point, will be excluded from efficacy analyses for the PD-L1 
strongly positive population. These subjects will still be included in the efficacy analyses for 
all and PD-L1 positive subjects.
8.2.4.2
Safety Analysis Population
The APT population will be used for the analysis of safety data.  At least one laboratory or 
vital sign measurement obtained subsequent to at least one dose of study treatment is 
required for inclusion in the analysis of each specific parameter.  To assess change from 
baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
8.2.4.3
Biomarker Discovery Population
The biomarker analysis will be based on all subjects within the first 100 enrolled by time that 
are deemed clinically evaluable, which is defined as any subjects who received at least one 
dose of study drug and had week 9 and week 15 scans, or discontinued due to 
radiographic/clinical progression or death before reaching week 15. The biomarker discovery
population will be identified through routine review of accumulating data.
Statistical Methods
Statistical methods for efficacy and safety analyses are described in sections 8.2.5.1 and 
8.2.5.2, respectively. 
8.2.5.1
Statistical Methods for Efficacy Analyses
Efficacy will be available for PD-L1 strongly positive subjects, PD-L1 positive subjects, and 
all subjects. The first 100 study subjects (biomarker discovery population) will be evaluated 
for biomarker cut-point determination. The biomarker discovery population will be excluded 
from the primary and secondary objectives for the PD-L1 strongly positive subjects.
For the primary efficacy endpoint, the ORR based on RECIST 1.1 by independent radiology 
review, the point estimate, and 95% confidence interval (as determined by the upper and 
lower 97.5% one-sided confidence bounds) will be provided using an exact binomial 
distribution (Clopper and Pearson method). Subjects without response data will be counted as 
non-responders.
Duration of responses (DOR) based on RECIST 1.1 by independent radiology review will be 
summarized descriptively using Kaplan-Meier medians and quartiles. Only the subset of 
subjects who show a complete response or partial response will be included in this analysis. 
For PFS and OS, Kaplan-Meier (KM) curves, median estimates, and survival rates at 6 and 
12 months based on the KM curves (95% CI is based on Greenwood's formula) will be 
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provided. Subjects without efficacy evaluation data or without survival data will be censored 
at Day 1. 
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 8.
8.2.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Summary statistics (counts, 
percentage, mean, standard deviation, etc.) will be provided for the safety endpoints as 
appropriate. The 95% confidence interval for the incidence rate of Grade 2 or higher adverse 
events with an immune etiology and the incidence rate of Grade 3-5 AEs will be provided.  
8.2.5.3
Statistical Methods for Biomarker Analyses
The evaluation   of a general positive association between CPS and ORR will be investigated 
via standard logistic regression as well as generalized additive models. The potential to 
achieve a cut-off greater than CPS = 1% for defining a PD-L1 strongly positive population 
will involve a review of how the positive predictive value (PPV, response rate in those above 
a cut-off), negative predictive value (NPV, non-response rate in those below the cut-off), and 
fraction of patients defined as strongly positive change as a function of increasing cut-offs 
and whether there is evidence for a relative improvement in clinical utility relative to the 1% 
CPS cut-off.  A PD-L1 strongly positive cut-off that maintains high NPV (e.g. near or above 
90%) while achieving meaningful enrichment of response and largely capturing patients 
showing durable clinical benefit is sought.  The profiles of PPV, NPV, and the percentage of 
patients above a given cut-off along with intervals quantifying the uncertainty in those 
profiles will be estimated as a function of potential cut-offs.  Receiver operating 
characteristic curve analysis will also be used to understand the sensitivity and specificity 
profile and examine cut-offs that might be suggested based on the ROC curve and their 
appropriateness with regard to PPV and NPV. CPS ranges for any promising cut-offs will 
also have to be gauged in the context of practical implementation and interpretation by 
pathologists in clinical practice.
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Table 8
Analysis Strategy for Efficacy Endpoints
Endpoint/Variable‡
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Objectives:
RECIST1.1 ORR by independent 
radiology 
review 
for 
PD-L1 
strongly positive subjects, PD-L1 
positive subjects, and all subjects
Exact method based on 
binomial distribution
APT/FAS
Subjects with missing 
data are considered 
non-responders
Secondary Objectives:
Duration of Response, RECIST1.1 
by independent radiology review, 
for 
PD-L1 
strongly 
positive 
subjects, PD-L1 positive subjects, 
and all subjects
Summary 
statistics 
/Kaplan-Meier method
APT/FAS
Non-responders 
are 
excluded in analysis
Progression-free 
survival, 
RECIST1.1
by 
independent 
radiology 
review, 
for 
PD-L1 
strongly positive subjects, PD-L1 
positive subjects, and all subjects
Summary 
statistics 
/Kaplan-Meier method
APT/FAS
Censored 
at 
last 
assessment
Overall 
survival, 
for 
PD-L1 
strongly positive subjects, PD-L1 
positive subjects, and all subjects
Summary 
statistics 
/Kaplan-Meier method
APT/FAS
Censored 
at 
last 
assessment
95% confidence interval is determined by the upper and lower 97.5% one-sided confidence bounds.
8.2.5.4
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.4.1 Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs for each cohort.  
No statistical hypothesis tests will be performed on these characteristics.  The number and 
percentage of subjects screened, randomized, primary reasons for screening failure, and 
discontinuation will be displayed.  Demographic variables (e.g., age, gender), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
Multiplicity
This is an estimation study. 95% confidence intervals of ORR will be provided. No 
multiplicity adjustment will be applied.
Sample Size and Power Calculation
The sample size is driven by the primary efficacy estimation for PD-L1 strongly positive 
subjects. Table 9 and Table 10 shows 95% CIs at different true ORR rates (number of 
events), for 60 and 75 PD-L1 strongly positive subjects, respectively.
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Table 9
Estimates and 95% CIs with 60 PD-L1 Strongly Positive Subjects
Sample Size
Number of ORR Event
Proportion
Lower Limit
Upper Limit
Width of 95% CI
60
12
0.2
0.108
0.323
0.215
60
13
0.217
0.121
0.342
0.221
60
14
0.233
0.134
0.36
0.227
60
15
0.25
0.147
0.379
0.231
60
16
0.267
0.161
0.397
0.236
60
17
0.283
0.174
0.414
0.24
60
18
0.3
0.188
0.432
0.244
60
19
0.317
0.203
0.45
0.247
60
20
0.333
0.217
0.467
0.25
60
21
0.35
0.231
0.484
0.253
60
22
0.367
0.246
0.501
0.255
Table 10
Estimates and 95% CIs with 75 PD-L1 Strongly Positive Subjects
Sample Size
Number of ORR Event
Proportion
Lower Limit
Upper Limit
Width of 95% CI
75
20
0.267
0.171
0.381
0.21
75
21
0.280
0.182
0.396
0.214
75
22
0.293
0.194
0.41
0.216
75
23
0.307
0.205
0.424
0.219
75
24
0.320
0.217
0.438
0.221
75
25
0.333
0.229
0.452
0.223
75
26
0.347
0.24
0.465
0.225
75
27
0.360
0.252
0.479
0.227
75
28
0.373
0.264
0.493
0.229
75
29
0.387
0.276
0.506
0.23
75
30
0.400
0.288
0.52
0.232
Up to 350 subjects will be enrolled. Assuming a 33% prevalence rate of PD-L1 strongly 
positive subjects and 100 for biomarker discovery population, there is 88% chance to have at 
least 75 PD-L1 strongly positive subjects and 99.9% chance to have at least 60 PD-L1 
strongly positive subjects in the confirmation group. 
For all and PD-L1 positive subjects, the expected sample sizes (350 and 225, respectively) 
are adequate for efficacy estimation. Thus, if strongly PD-L1 positive cannot be determined, 
the study may stop enrollment after ~225 subjects are enrolled.
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Subgroup Analyses and Effect of Baseline Factors
To determine whether the treatment effect is consistent across various subgroups, the 
estimate (with a nominal 95% CI) for the primary endpoint will be estimated and plotted 
within each category of the following classification variables for all subjects, PD-L1 positive 
subjects, and PD-L1 strongly positive subjects, respectively:

Age category (≤65 vs. >65 years)

Sex (female vs. male)

Race (white vs. non-white)

ECOG status (0 / 1 vs. 2 and 0 vs 1 / 2)

Geographic region of enrolling site (East Asia vs. non-East Asia and EU vs. non-EU)

Presence or absence of liver metastases at baseline

Baseline hemoglobin (≥ 10 g/dL vs. <10 g/dL)

Naïve vs. prior adjuvant/neoadjuvant chemotherapy

Bajorin risk score
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Interim Analyses
A biomarker analysis is planned where data from a subset of subjects (the biomarker 
discovery population) will be used to determine the PD-L1 strongly positive cut-point. The 
biomarker discovery population consists of the evaluable subjects among the first 100 
subjects enrolled into the study. Analysis will be conducted according to the SAP (section 
8.2.5.3). More subjects may be allocated to the biomarker discovery population, if necessary. 
In addition, an interim efficacy evaluation for the PD-L1 negative population will be 
performed using the biomarker discovery population data. Enrollment of PD-L1 negative 
(CPS < 1%) population may be stopped if the ORR is low and substantial enrollment 
remains. The futility analysis will be based on the evaluable PD-L1 negative subjects in the 
biomarker discovery population (up to the first 25 subjects). If the number of PD-L1 negative 
subjects in the biomarker subgroup is less than 20, additional PD-L1 negative subjects may 
be included until the number reaches at least 20. The non-binding rule for futility is the upper 
limit of the 95% CI (two-sided) of the ORR estimate is less than 20% (need at least 1 
response in N < 26 subjects, and at least 2 responses in N=26 to 40 subjects).
Compliance (Medication Adherence)
A day within the study will be considered an On-Therapy day if the subject receives the 
study medication infusion. The number of Days on Therapy is the total number of days from 
the first day of study medication to the date of the last dose of study medication. 
Summary statistics for the number of Days on Therapy will be provided by treatment group 
for the APT population.
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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 
the APT population.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.  
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
pembrolizumab (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.
All supplies will be provided open label.  Pembrolizumab (MK-3475) will be provided as 
non-kitted single vials or as single vials in a kit box.  
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.
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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, or local discard and destruction if 
appropriate.   Where local discard and destruction is appropriate, the investigator is 
responsible for ensuring that a local discard/destruction procedure is documented.
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 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.
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Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
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Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
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.
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, 
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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.
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 
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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 Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
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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, 
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 
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the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1.
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.
2.
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.  
3.
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.
4.
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.  
5.
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.
6.
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.  
7.
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.
8.
Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.  
9.
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7.
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.  
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12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.  
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.  
14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.  
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.  
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.  
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.  
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et 
al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58:449-59.  
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.  
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.  
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value 
of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-
24.  
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.  
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24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.  
25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ 
cell infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in 
neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 
2010;59:909-19.  
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.  
28. Jemal A, Bray F, Center MM, Ferlay J, Ward E, and Forman D. Global Cancer 
Statistics. CA Cancer J Clin 2011;61:69-90.
29. Logothetis C.J., Dexeus F.H., Finn L., et al. A prospective randomized trial comparing 
MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin 
Oncol, 8 (1990), pp. 1050–1055.
30. Von der Maase H., Hansen S.W., Roberts J.T., et al. Gemcitabine and cisplatin versus 
methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder 
cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin 
Oncol, 18 (2000), pp. 3068–3077.
31. Saxman S.B., Propert K.J., Einhorn L.H., et al. Long-term follow-up of a phase III 
intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and 
doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. 
J Clin Oncol, 15 (1997), pp. 2564–2569.
32. Loehrer Sr. P.J., Einhorn L.H., Elson P.J., et al. A randomized comparison of cisplatin 
alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with 
metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol, 10 (1992), pp. 
1066–1073.
33. Sternberg C.N., De Mulder P, Schornagel J.H., et al. Seven year update of an EORTC 
phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic 
M-VAC in advanced urothelial tract tumors. Eur J Cancer, 42 (2006), pp. 50–54.
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34. Von der Maase H., Sengelov L., Roberts J.T., et al. Long-term survival results of a 
randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, 
doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol, 23 (2005), pp. 
4602–4608.
35. Galsky M.D., Hahn N.M., Rosenberg J., et al. A consensus definition of patients with 
metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lncet 
Oncol, 12 (2011), pp. 211–214.
36. Galsky M.D., Hahn N.M.,. Rosenberg J, et al. Treatment of patients with metastatic 
urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol, 29 (2011), pp. 
2432–2438.
37. Dash A., Galsky M.D., Vickers A.J., et al. Impact of renal impairment on eligibility for 
adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the 
bladder. Cancer, 107 (2006), pp. 506–513.
38. Galsky M.D., Chen G.J., Oh W.K., et al. Comparative effectiveness of cisplatin-based 
and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. 
Ann Oncol, 23 (2012), pp. 406–410.
39. De Santis M., Bellmunt J., Mead G., et al. Randomized phase II/III trial assessing 
gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with 
advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC 
study 30986. J Clin Oncol, 30 (2012), pp. 191–199.
40. Powles T, Vogelzang N, Fine G, Eder J, Braiteh F, Loriot Y, et al.  Inhibition of PD-L1 
by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer 
(UBC). ASCO 2014 Abstract #5011, Jun 2014.
41. Waxman J, Barton C.  Carboplatin-based chemotherapy for bladder cancer. Cancer Treat 
Rev. 1993;19 Suppl C:21-5.
42. Sternberg CN, de Mulder P, Fossa S, Kaye S, Roberts T, Pawinsky A, Daamen S.  
Lobaplatin in advanced urothelial tract tumors. The Genitourinary Group of the 
European Organization for Research and Treatment of Cancer (EORTC).  Ann Oncol. 
1997 Jul;8(7):695-6.
43. De Wit R, Kaye SB, Roberts JT, Stoter G, Scott J, Verweij J. Oral piritrexim, an 
effective treatment for metastatic urothelial cancer.  Br J Cancer. 1993 Feb;67(2):388-
90.
44. Witte RS, Elson P, Khandakar J, Trump DL.  An Eastern Cooperative Oncology Group 
phase II trial of trimetrexate in the treatment of advanced urothelial carcinoma.  Cancer. 
1994 Feb 1;73(3):688-91. 
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45. McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF.  
Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell 
carcinoma. J Clin Oncol. 1997 May;15(5):1853-7.
46. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA.  Phase II study of single-agent 
gemcitabine in previously untreated patients with metastatic urothelial cancer.  J Clin 
Oncol. 1997 Nov;15(11):3394-8].
47. Roth BJ, Dreicer R, Einhorn LH, Neuberg D, Johnson DH, Smith JL, Hudes GR, 
Schultz SM, Loehrer PJ. Significant activity of paclitaxel in advanced transitional-cell 
carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology 
Group.  J Clin Oncol. 1994 Nov;12(11):2264-70.
48. Finkelstein DM (1986). A proportional hazards model for interval-censored failure time 
data. Biometrics 42, 845-54.
49. Bjordal K, Ahlner-Elmquist MA, Tollesson E, Jensen AB, Razavi D, Maher EJ, et al. 
Development of a European Organization for Research and Treatment of Cancer 
(EORTC) questionnaire module to be used in quality of life assessments in head and 
neck cancer patients. Acta Oncologica. 1994;33(8):879-885.
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12.0 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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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and tumor tissue specimen(s) collected in the current trial will be used to study 
various causes for how subjects may respond to a drug/vaccine.  The DNA  and tumor 
tissue specimen(s) will be stored to provide a resource for future trials conducted by 
Merck focused on the study of biomarkers responsible for how a drug/vaccine enters and 
is removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may 
interact with, or other aspects of disease.  The specimen(s) may be used for future assay 
development and/or drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
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To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
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Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
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administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial.
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
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It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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Abbreviations
Abbreviation/Term
Definition
1L
First Line
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
APaT
All Patients as Treated
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ß-HCG
Beta Human Chorionic Gonadotropin
CBC
Complete Blood Count
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
DAP
Data Analysis Plan
DNA
Deoxyribonucleic acid
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
ePRO
Electronic Patient Reported Outcomes
ERC
Ethics Review Committee
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin Fixed Paraffin Embedded
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Abbreviation/Term
Definition
FNA
Fine Needle Aspirate
GC
Gemcitabine/Carboplatin
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HEA
Health Economic Assessment
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention To Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
KM
Kaplan-Meier
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum Tolerated Dose
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective response Rate
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Abbreviation/Term
Definition
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
PFS
Progression Free Survival
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PT
Prothrombin Time
PS
Performance Status
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable Disease
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOC
Standard of Care
SOP
Standard Operating Procedures
T3
Total thriiodothyronine
T4
Free tyroxine 
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
V-type
Ig Variable-type
WBC
White Blood Cell
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
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New York Heart Association (NYHA) Functional Classification
Class
Functional Capacity: How a patient with cardiac disease feels 
during physical activity
I
Patients with cardiac disease but resulting in no limitation of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea or anginal pain. 
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea or anginal pain. 
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea or anginal pain. 
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort increases.
* As published in: The Criteria Committee of the New York Heart Association. (1994). 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). 
Boston: Little, Brown & Co. pp. 253–256.
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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/reporting/ctc.html).
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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.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
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13.0
SIGNATURES
Sponsor's Representative
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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