Phase IB Study of Pembrolizumab (MK-3475) in Subjects With Select Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
Phase IB Study of Pembrolizumab (MK-3475) in Subjects with 
Select Advanced Solid Tumors
28-Nov-2017
NCT02054806

Product:  MK-3475 SCH 900475
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Protocol/Amendment No.: 028-04
MK-3475-028-04 FinalProtocol
28-Nov-2017
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC.,
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
Phase IB Study of Pembrolizumab (MK-3475) in Subjects with Select Advanced Solid
Tumors
IND NUMBER:  110,080
EudraCT NUMBER:  2013-004507-39
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0 
TRIAL SUMMARY.................................................................................................. 13
2.0 
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1 
Trial Diagram........................................................................................................ 16
2.2 
3.0 
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es) .............................................................. 17
3.1 
Secondary Objective(s) & Hypothesis(es)........................................................... 18
3.2 
Exploratory Objective.......................................................................................... 18
3.3 
4.0 
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
4.1 
Pharmaceutical and Therapeutic Background .................................................... 19
4.1.1 
Pre-clinical and Clinical Trials ........................................................................... 20
4.1.2 
Ongoing Clinical Trials....................................................................................... 20
4.1.3 
Rationale................................................................................................................ 20
4.2 
Rationale for the Trial and Selected Subject Population .................................... 20
4.2.1 
Rationale for Dose Selection/Regimen/Modification......................................... 21
4.2.2 
Rationale for Endpoints ...................................................................................... 22
4.2.3 
4.2.3.1 Efficacy Endpoints....................................................................................... 22
4.2.3.2 Safety Endpoints.......................................................................................... 23
4.2.3.3 Biomarker Research..................................................................................... 23
4.2.3.4 Future Biomedical Research........................................................................ 24
5.0 
METHODOLOGY ................................................................................................... 25
Entry Criteria........................................................................................................ 25
5.1 
Diagnosis/Condition for Entry into the Trial...................................................... 25
5.1.1 
Subject Inclusion Criteria.................................................................................... 25
5.1.2 
Subject Exclusion Criteria .................................................................................. 28
5.1.3 
Trial Treatment(s) ................................................................................................ 30
5.2 
Dose Selection/Modification .............................................................................. 30
5.2.1 
 
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5.2.1.1 Dose Selection (Preparation)....................................................................... 30
5.2.1.2 Dose Modification and Toxicity Management Guidelines for
Pembrolizumab............................................................................................ 30
Timing of Dose Administration.......................................................................... 35
5.2.2 
Trial Blinding/Masking....................................................................................... 37
5.2.3 
Randomization or Treatment Allocation............................................................ 37
5.3 
Stratification.......................................................................................................... 37
5.4 
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 37
5.5 
Acceptable Concomitant Medications ................................................................ 37
5.5.1 
Prohibited Concomitant Medications.................................................................. 37
5.5.2 
Rescue Medications & Supportive Care............................................................. 38
5.6 
Supportive Care Guidelines ................................................................................ 38
5.6.1 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-
related Adverse Events (irAEs) ................................................................... 41
Diet/Activity/Other Considerations..................................................................... 41
5.7 
Diet...................................................................................................................... 41
5.7.1 
Contraception...................................................................................................... 41
5.7.2 
Use in Pregnancy ................................................................................................ 43
5.7.3 
Use in Nursing Women....................................................................................... 43
5.7.4 
Subject Withdrawal/Discontinuation Criteria................................................... 43
5.8 
Discontinuation of Treatment ............................................................................. 44
5.8.1 
Subject Replacement Strategy............................................................................. 45
5.9 
Beginning and End of the Trial ........................................................................... 45
5.10 
Clinical Criteria for Early Trial Termination ................................................... 46
5.11 
6.0 
TRIAL FLOW CHART ........................................................................................... 47
Study Flow Chart.................................................................................................. 47
6.1 
Second Course Phase (Retreatment ONLY) ...................................................... 51
6.2 
7.0 
TRIAL PROCEDURES ........................................................................................... 53
Trial Procedures ................................................................................................... 53
7.1 
Administrative Procedures.................................................................................. 53
7.1.1 
7.1.1.1 Informed Consent......................................................................................... 53
7.1.1.1.1  General Informed Consent.................................................................... 53
 
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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
7.1.1.5 Prior and Concomitant Medications Review............................................... 54
7.1.1.5.1  Prior Medications.................................................................................. 54
7.1.1.5.2 Concomitant Medications..................................................................... 54
7.1.1.6 Disease Details and Treatments................................................................... 55
7.1.1.6.1 Disease Details...................................................................................... 55
7.1.1.6.2 Prior Treatment Details......................................................................... 55
7.1.1.6.3 Subsequent Anti-Cancer Therapy Status .............................................. 55
7.1.1.7 Assignment of Screening Number............................................................... 55
7.1.1.8  Assignment of Randomization Number....................................................... 55
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) ................................... 55
Clinical Procedures/Assessments........................................................................ 56
7.1.2 
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........................................................................ 56
7.1.2.3 Vital Signs.................................................................................................... 56
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 57
7.1.2.5 Tumor Imaging and Assessment of Disease................................................ 57
7.1.2.5.1 Assessment of Disease.......................................................................... 57
7.1.2.5.2 Initial Tumor Imaging........................................................................... 59
7.1.2.5.3 Tumor Imaging During Trial................................................................ 59
7.1.2.5.4 End of Treatment and Follow-up Tumor Imaging................................ 60
7.1.2.5.5 Second Course (Retreatment) Tumor Imaging..................................... 60
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling............ 61
7.1.2.7 Tumor Marker Assessment (Optional) ........................................................ 61
Laboratory Procedures/Assessments .................................................................. 62
7.1.3 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 62
 
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7.1.3.2 Pregnancy Test............................................................................................. 64
7.1.3.3 Future Biomedical Research........................................................................ 64
Other Procedures................................................................................................. 64
7.1.4 
7.1.4.1 Withdrawal/Discontinuation........................................................................ 64
7.1.4.1.1 Withdrawal From Future Biomedical Research ................................... 64
7.1.4.2 Blinding/Unblinding .................................................................................... 65
7.1.4.3 Calibration of Critical Equipment................................................................ 65
Visit Requirements.............................................................................................. 65
7.1.5 
7.1.5.1 Screening Period.......................................................................................... 65
7.1.5.2 Treatment Period Visit................................................................................. 66
7.1.5.2.1 Second Course Phase (Retreatment Period) ......................................... 66
7.1.5.3 Post-Treatment Visits................................................................................... 67
7.1.5.3.1 Safety Follow-Up Visit......................................................................... 67
7.1.5.4  Follow-up Visits........................................................................................... 68
7.1.5.4.1 Survival Status...................................................................................... 68
Assessing and Recording Adverse Events .......................................................... 68
7.2 
Definition of an Overdose for This Protocol and Reporting of Overdose to
7.2.1 
the Sponsor.......................................................................................................... 69
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 70
7.2.2 
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
7.2.3 
7.2.3.1 Serious Adverse Events ............................................................................... 70
7.2.3.2 Events of Clinical Interest............................................................................ 71
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 72
Evaluating Adverse Events................................................................................. 72
7.2.4 
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
7.2.5 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 75
8.1 
Efficacy Analyses ............................................................................................... 75
8.1.1 
Safety Analyses................................................................................................... 76
8.1.2 
Power and Sample Size....................................................................................... 76
8.1.3 
Interim Analysis.................................................................................................. 78
8.1.4 
Statistical Analysis Plan ....................................................................................... 79
8.2 
 
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Responsibility for Analyses/In-House Blinding................................................. 79
8.2.1 
Hypotheses/Estimation ....................................................................................... 79
8.2.2 
Analysis Endpoints ............................................................................................. 79
8.2.3 
8.2.3.1 Efficacy Endpoints....................................................................................... 79
8.2.3.2 Safety Endpoints.......................................................................................... 80
Analysis Populations........................................................................................... 80
8.2.4 
8.2.4.1 Efficacy Analysis Populations ..................................................................... 80
8.2.4.2 Safety Analysis Populations ........................................................................ 80
Statistical Methods.............................................................................................. 81
8.2.5 
8.2.5.1 Statistical Methods for Efficacy Analyses................................................... 81
8.2.5.2 Statistical Methods for Safety Analyses ...................................................... 82
8.2.5.3 Summaries of Baseline Characteristics, Demographics, and Other
Analyses....................................................................................................... 83
8.2.5.3.1 Demographic and Baseline Characteristics .......................................... 83
Multiplicity ......................................................................................................... 83
8.2.6 
Sample Size and Power Calculations.................................................................. 83
8.2.7 
Subgroup Analyses and Effect of Baseline Factors ............................................ 86
8.2.8 
Interim Analyses ................................................................................................. 86
8.2.9 
Compliance (Medication Adherence)................................................................. 86
8.2.10 
Extent of Exposure.............................................................................................. 87
8.2.11 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL
SUPPLIES ................................................................................................................. 87
Investigational Product ........................................................................................ 87
9.1 
Packaging and Labeling Information ................................................................. 87
9.2 
Clinical Supplies Disclosure................................................................................. 87
9.3 
Storage and Handling Requirements.................................................................. 87
9.4 
Returns and Reconciliation.................................................................................. 88
9.5 
Standard Policies................................................................................................... 88
9.6 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS....................................... 88
Confidentiality....................................................................................................... 88
10.1 
Confidentiality of Data ....................................................................................... 88
10.1.1 
Confidentiality of Subject Records..................................................................... 88
10.1.2 
 
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Confidentiality of Investigator Information........................................................ 89
10.1.3 
Confidentiality of IRB/IEC Information............................................................. 89
10.1.4  
Compliance with Financial Disclosure Requirements....................................... 89
10.2 
Compliance with Law, Audit and Debarment ................................................... 90
10.3 
Compliance with Trial Registration and Results Posting Requirements ........ 92
10.4 
Quality Management System............................................................................... 92
10.5 
Data Management................................................................................................. 92
10.6 
Publications ........................................................................................................... 92
10.7 
11.0 LIST OF REFERENCES......................................................................................... 94
12.0 APPENDICES........................................................................................................... 97
Merck Code of Conduct for Clinical Trials........................................................ 97
12.1 
Collection and Management of Specimens for Future Biomedical
12.2 
Research................................................................................................................. 99
Understanding the Intent, Scope and Public Health Benefits of
12.3 
Exploratory Biomarker Research: A Guide for IRBs/IECs and
Investigational Site Staff.................................................................................... 105
ECOG Performance Status................................................................................ 116
12.4 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 117
12.5 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For
12.6 
Evaluating Response in Solid Tumors .............................................................. 118
Updated Response Assessment Criteria for High-Grade Gliomas:
12.7 
Response Assessment in Neuro-Oncology Working Group............................ 119
Design and End Points of Clinical Trials for Patients With Progressive
12.8 
Prostate Cancer and Castrate Levels of Testosterone: Recommendations
of the Prostate Cancer Clinical Trials Working Group.................................. 120
12.9 List of Abbreviations .......................................................................................... 121
13.0 SIGNATURES......................................................................................................... 124
Sponsor's Representative ................................................................................... 124
13.1 
Investigator.......................................................................................................... 124
13.2 
 
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LIST OF TABLES
Table 1  Adequate Organ Function Laboratory Values.......................................................... 27
Table 2  Trial Treatment......................................................................................................... 30
Table 3  Dose Modification and Toxicity Management Guidelines for Immune-related
AEs Associated with Pembrolizumab......................................................................... 32
Table 4  Imaging and Treatment After First Radiologic Evidence of Progressive Disease ... 36
Table 5  Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines.. 40
Table 6  Imaging and Treatment after 1st Radiologic Evidence of PD.................................. 58
Table 7  Tumor Markers and Associated Tumor Type........................................................... 61
Table 8  Laboratory Tests ....................................................................................................... 63
Table 9  Evaluating Adverse Events....................................................................................... 73
Table 10  Summary of Analysis Strategy for Key Efficacy Endpoints.................................. 76
Table 11  Decision Rules Based on Efficacy Bounds............................................................. 78
Table 12  Decision Rules Based on Futility Bounds .............................................................. 78
Table 13  Summary of Interim Analysis Strategy .................................................................. 79
Table 14  Analysis Strategy for Key Efficacy Variables........................................................ 82
Table 15  Operating Characteristics of the Sequential Monitoring Approach........................ 85
Table 16  Point Estimate and 95% CI for Hypothetical Number of Subjects with a Grade
3-5 irAE ...................................................................................................................... 86
Table 17  Product Descriptions............................................................................................... 87
 
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LIST OF FIGURES
Figure 1  Trial Design............................................................................................................. 16
Figure 2  Sequential Monitoring Rules for Efficacy and Futility........................................... 77
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s) 
Rationale
5.2.1.2
Dose Modification and
Toxicity Management
Guidelines for Pembrolizumab
Table 3: Addition of
Myocarditis as a table row and
specific actions for Grades 2, 3,
and 4 to the dose modification
table.
To clarify dose modification
for myocarditis - Program-wide
safety 
update to 
program
language
7.1.5.4.1 
6.1 and 6.2 
Survival Follow-up
Study Flow Charts
Change of subheading to
Survival Status.
Addition of paragraph to enable
survival follow-up activities
throughout the study. Removal
of redundant text.
Merging of cells for survival
status to allow continual
monitoring throughout the
study.
Program-wide update - to allow
flexibility in the entire follow-
up period beyond the current
Survival Follow-up portion and
to enable more frequent follow-
ups as necessary
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s) 
Section Title (s) 
Description of Change (s) 
Rationale
1.0
Trial Summary
Updated with program language to
include reference to the extension
study.
To allow for continued
provision of pembrolizumab to
subjects with appropriate risk-
benefit assessment
2.2
Trial Diagram
Updated to include extension
study.
5.10
Beginning and End of the Trial 
Updated with program language to
include reference to the extension
study.
5.1.2
Subject Inclusion Criteria 
Criteria 4 –insertion of “one” to
“Have one of the following
advanced (unresectable and/or
metastatic) solid tumor
indications:”
To correct an erroneous
deletion made in the previous
amendment
5.2.1.2 
5.6.1
5.6.1.1
7.1.2.1
Dose Modification and Toxicity
Management Guidelines for
Pembrolizumab
Supportive Care Guidelines
Supportive Care Guidelines for
Events of Clinical Interest and
Immune-related Adverse Events
(irAEs)
Adverse Event (AE) Monitoring
Removed cross reference to
retired ECI guidance document.
To align with program
language
 
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Section Number (s) 
Section Title (s)
Description of Change (s) 
Rationale
7.2.3.2
8.1.2
8.2.3.2
8.2.5.2
Events of Clinical Interest
Safety Analyses
Safety Endpoints
Statistical Methods for Safety
Analysis
6.1 and 6.2
7.1.2.5.1
7.1.2.5.4
7.1.2.5.5
7.1.5.4
Study Flow Charts
Assessment of Disease
End of Treatment and Follow-up
Tumor Imaging
Second Course (Retreatment)
Tumor Imaging
Follow-up Visits
Schedule of imaging/visits in the
1st course phase follow-up period
extended from every 8 weeks to
every 12 weeks after Month 6. 
In the second course phase
imaging frequency extended to
every 12 weeks throughout.
To reduce the burden on
subjects
6.0
7.1.2.7
Trial Flow Chart
Tumor Marker Assessment
(Optional)
In 6.1 and 6.2: footnote #j and q,
and Section 7.1.2.7:
Removed the timing of tumor
marker data collection and
clarified that data collection will
occur at the same time as post-
treatment imaging
To increase clarity following
changes to follow-up imaging
schedule
12.5 
Common Terminology Criteria
for Adverse Events V4.0
(CTCAE)
The nonfunctioning website link
to CTCAE V4.0 updated to a
functioning link
To provide a functioning
website link
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Pembrolizumab (MK-3475 [SCH 900475]) Solid All Comers
TrialPhase
1B
Clinical Indication
The treatment of subjects with any of the following advanced
(unresectable and/or metastatic) solid tumor indications:
A1 Colon or Rectal Adenocarcinoma
A2 Anal Canal Squamous Cell Carcinoma
A3 Pancreas Adenocarcinoma
A4 Esophageal Squamous Cell Carcinoma or Adenocarcinoma
(Including GE Junction)
A5 Biliary Tract Adenocarcinoma (Gallbladder and Biliary Tree but
excluding Ampulla of Vater Cancers)
A6 Carcinoid Tumors
A7 Neuroendocrine Carcinomas (Well or moderately differentiated
Pancreatic Neuroendocrine Tumor)
B1 ER Positive HER2 Negative Breast Cancer
B2 Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma
B3 Endometrial Carcinoma
B4 Cervical Squamous Cell Cancer
B5 Vulvar Squamous Cell Carcinoma
C1 Small Cell Lung Cancer
C2 Mesothelioma (Malignant Pleural Mesothelioma)
D1 Thyroid Cancer (Papillary or Follicular Subtype)
D2 Salivary Gland Carcinoma
D3 Nasopharyngeal Carcinoma
E1 Glioblastoma Multiforme
E2 Leiomyosarcoma
E3 Prostate Adenocarcinoma
Trial Type
Interventional
Type of control
No treatment control
Route of administration  
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab 10 mg/kg IV every 2 weeks (Q2W)
Number of trial subjects 
Approximately 440 subjects will be enrolled.
Estimated duration of trial 
The sponsor estimates that the trial will require approximately
24 months from the time the first subject signs the informed consent until
the last subject’s last visit.
Duration of Participation  
Each subject will participate in the trial from the time the subject signs
the Informed Consent Form (ICF) through the final protocol-specified
contact.  After a screening phase of 28 days, eligible subjects will receive
treatment on Day 1 of each 2-week dosing cycle.  Treatment with
MK-3475 will continue until documented confirmed disease progression,
unacceptable adverse event(s), intercurrent illness that prevents further
administration of treatment, investigator’s decision to withdraw the
subject, subject withdraws consent, pregnancy of the subject,
 
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noncompliance with trial treatment or procedure requirements; subject
receives 24 months of study medication, or administrative reasons. 
Subjects who attain a complete response may consider stopping trial
treatment if they meet criteria for holding therapy.  Subjects who stop
trial treatment after receiving 24 months of study medication for reasons
other than disease progression or intolerability or who attain a complete
response and stop trial treatment may be eligible for up to 1 year of
retreatment after experiencing disease progression.  The decision to
retreat will be at the discretion of the investigator only if they meet the
criteria for retreatment and the trial is ongoing.  After the end of
treatment, each subject will be followed for 30 days for adverse event
(AE) monitoring (serious adverse events [SAEs] will be collected for
90 days after the end of treatment).  Subjects who discontinue for reasons
other than disease progression will have post-treatment follow-up for
disease status until disease progression, initiating a non-study cancer
treatment, withdrawing consent, or becoming lost to follow-up.  All
subjects will be followed by telephone for overall survival until death,
withdrawal of consent, or the end of the study.
Once the subject has achieved the study objective or study has ended, the
subject is discontinued from this study and will be enrolled in an
extension study to continue protocol defined assessments and treatment.
A list of abbreviations used in this document can be found in Section 12.9.
2.0 TRIAL DESIGN
Trial Design
2.1 
This is a multicenter, nonrandomized, multi-cohort trial of pembrolizumab (MK-3475) in
subjects with Programmed Death - Ligand 1 (PD-L1) positive advanced solid tumors. 
Subjects will be enrolled into 1 of the following 20 solid tumor cohorts:
A1 
Colon or Rectal Adenocarcinoma
A2 
Anal Canal Squamous Cell Carcinoma
A3 
Pancreas Adenocarcinoma
A4 
Esophageal Squamous Cell Carcinoma or Adenocarcinoma (Including GE
Junction)
A5 
Biliary Tract Adenocarcinoma (Gallbladder and Biliary Tree but excluding
Ampulla of Vater Cancers)
A6 
Carcinoid Tumors
A7 
Neuroendocrine Carcinomas (Well or moderately differentiated Pancreatic
Neuroendocrine Tumor)
B1 
ER Positive HER2 Negative Breast Cancer
B2 
Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma
B3 
Endometrial Carcinoma
B4 
Cervical Squamous Cell Cancer
B5 
Vulvar Squamous Cell Carcinoma
 
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C1 
Small Cell Lung Cancer
C2 
Mesothelioma (Malignant Pleural Mesothelioma)
D1 
Thyroid Cancer (Papillary or Follicular Subtype)
D2 
Salivary Gland Carcinoma
D3 
Nasopharyngeal Carcinoma
E1 
Glioblastoma Multiforme
E2 
Leiomyosarcoma
E3 
Prostate Adenocarcinoma
Approximately 440 subjects will be enrolled in this trial to examine the safety and efficacy in
these cohorts to the 10 mg/kg dose of pembrolizumab administered every 2 weeks.  Subjects
will be evaluated every 8 weeks (56 days ±7 days) with radiographic imaging to assess
response to treatment.  After 6 months, radiography imaging will be evaluated every
12 weeks (84 days ±7 days).  Response evaluation criteria in solid tumors (RECIST) 1.1 will
be used as the primary efficacy endpoint of response rate. 
RECIST 1.1 will be adapted as described in Section 4.2.3.1 due to the tumor response
patterns seen with pembrolizumab treatment (e.g., tumor flare), and this adapted RECIST
will be used by the sites for treatment decisions.  Adverse events (AEs) will be monitored
throughout the trial and graded in severity according to the guidelines outlined in the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) version 4.0.  Treatment with pembrolizumab will continue until documented
disease progression, unacceptable AEs, 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, 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.  In addition, subjects who discontinue after at least 24 months of therapy for
reasons other than disease progression or intolerability, or who discontinue after attaining a
CR and had at least 2 treatments beyond initial CR, may be eligible for up to 1 year of
retreatment if they subsequently experience 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, the subject still meets the safety
parameters listed in the Inclusion/Exclusion criteria and the trial remains open (refer to
Section 7.1.5.2.1 for further details).  After the end of treatment, each subject will be
followed for 30 days for adverse event monitoring (serious adverse events will be collected
for 90 days after the end of treatment).  Subjects who discontinue treatment for reasons other
than disease progression will have post-treatment follow-up of disease status until disease
progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost
to follow-up.  All subjects will be followed by telephone contact for overall survival (OS)
until death, withdrawal of consent or the end of the study, whichever comes first.
 
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The primary objective of the trial is to evaluate a preliminary signal of potential anti-tumor
activity of pembrolizumab in subjects with PD-L1 positive advanced solid tumors. 
Secondary objectives include safety and tolerability, progression-free survival (PFS), OS and
response duration. 
Participation in this trial will be dependent upon supplying tissue from an archival tissue
sample or newly obtained biopsy of a tumor lesion not previously irradiated (tumors
progressing in a prior site of radiation are allowed for PD-L1 characterization, other
exceptions may be considered after Sponsor consultation).  This specimen will be evaluated
at a central laboratory for expression status of PD-L1 by immunohistochemistry (IHC).  Only
subjects with PD-L1 positive tumors will be enrolled in the trial. 
This study will be conducted in conformance with Good Clinical Practices (GCP)s.
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
2.2 
The trial design is depicted in Figure 1.
Figure 1  Trial Design
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1 
(1) Objective: 
To evaluate preliminary signals of potential anti-tumor activity of
pembrolizumab in subjects with a given histopathologic type of PD-L1 positive advanced
solid tumor based on RECIST 1.1 as determined by the investigator in the tumor
indications below.
Hypotheses:  Intravenous administration of single agent pembrolizumab to subjects with
a given PD-L1 positive solid tumor type will result in a clinically meaningful best overall
response rate (ORR) greater than 10% based on RECIST 1.1 criteria. 
The primary objective will be tested separately in each tumor indication listed below:
A1 
Colon or Rectal Adenocarcinoma
A2 
Anal Canal Squamous Cell Carcinoma
A3 
Pancreas Adenocarcinoma
A4 
Esophageal Squamous Cell Carcinoma or Adenocarcinoma (Including GE
Junction)
A5 
Biliary Tract Adenocarcinoma (Gallbladder and Biliary Tree but excluding
Ampulla of Vater Cancers)
A6 
Carcinoid Tumors
A7 
Neuroendocrine Carcinomas (Well or moderately differentiated Pancreatic
Neuroendocrine Tumor)
B1 
ER Positive HER2 Negative Breast Cancer
B2 
Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma
B3 
Endometrial Carcinoma
B4 
Cervical Squamous Cell Cancer
B5 
Vulvar Squamous Cell Carcinoma
C1 
Small Cell Lung Cancer
C2 
Mesothelioma (Malignant Pleural Mesothelioma)
D1 
Thyroid Cancer (Papillary or Follicular Subtype)
D2 
Salivary Gland Carcinoma
D3 
Nasopharyngeal Carcinoma
E1 
Glioblastoma Multiforme
E2 
Leiomyosarcoma
E3 
Prostate Adenocarcinoma
 
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Secondary Objective(s) & Hypothesis(es)
3.2 
Across-Indication Secondary Objective
(1) Objective:  To determine the safety and tolerability of pembrolizumab across selected
PD-L1 positive advanced solid tumors.
Within-Indication Secondary Objectives
The following secondary objectives will be evaluated separately in each of the 20 disease
indications listed in Section 3.1.
(1) Objective:  To evaluate the PFS in subjects with a given PD-L1 positive advanced solid
tumor type receiving pembrolizumab.
(2) Objective:  To evaluate the OS in subjects with a given PD-L1 positive advanced solid
tumor type receiving pembrolizumab.
(3) Objective:  To evaluate the duration of response (DOR) in subjects with a given PD-L1
positive advanced solid tumor type receiving pembrolizumab.
Exploratory Objective
3.3 
Across-Indication Exploratory Objectives
The following exploratory objectives will be evaluated across all 20 disease indications:
(1) Objective: To evaluate potential anti-tumor activity of pembrolizumab in subjects with a
given immune signature
(2) Objective: To investigate the relationship between other candidate efficacy/resistance
biomarkers and anti-tumor activity of pembrolizumab utilizing tumor tissue and blood
sampling.
Within-Indication Exploratory Objectives
The following exploratory objectives will be evaluated separately for each of the 20 disease
indications listed in Section 3.1:
(1) Objective:  To evaluate the anti-tumor activity of pembrolizumab in subjects with a
given PD-L1 positive advanced solid tumor type using continuous tumor measurements.
(2) Objective:  To explore the relationship between PD-L1 continuous IHC scale score and
anti-tumor activity of pembrolizumab in subjects with a given advanced solid tumor type. 
(3) Objective (optional):  To evaluate the anti-tumor activity of pembrolizumab in subjects
with a given PD-L1 positive advanced solid tumor type based on RECIST 1.1 as
determined by central radiology review, response assessment in neuro-oncology (RANO)
criteria for the glioblastoma multiforme (GBM) cohort, and Prostate Cancer Clinical
Trials Working Group 2 (PCWG2) for the prostate cancer cohort.
 
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4.0 BACKGROUND & RATIONALE
Background
4.1 
Refer to the Investigator’s Brochure for detailed background information on
pembrolizumab/MK-3475.
Pharmaceutical and Therapeutic Background
4.1.1 
The importance of intact immune surveillance in controlling outgrowth of neoplastic
transformation has been known for decades [1].  Accumulating evidence shows a correlation
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in
various malignancies [2] [3] [4] [5] [6].  In particular, the presence of CD8+ T-cells and the
ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells seems to correlate with improved
prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune
responses, including autoimmune reactions.  PD-1 (encoded by the gene programmed cell
death 1 [PDCD1]) is an immunoglobulin (Ig) superfamily member related to clusters of
differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) which
has been shown to negatively regulate antigen receptor signaling upon engagement of its
ligands (PD-L1 and/or PD-L2) [7] [8].  The structure of murine PD-1 has been resolved [9]. 
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-
type (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 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 zeta-chain-associated protein kinase (ZAP70) which are involved in the CD3 T-cell
signaling cascade [7] [10] [11] [12].  The mechanism by which PD-1 down modulates T-cell
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an
overlapping set of signaling proteins [13] [14].  PD-1 was shown to be expressed on activated
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer
cells [15] [16].  Expression has also been shown during thymic development on CD4-CD8-
(double negative) T-cells as well as subsets of macrophages and dendritic cells [17].  The
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a
variety of cell types, including non-hematopoietic tissues as well as in various tumors [18]
[19] [20] [13].  Both ligands are type I transmembrane receptors containing both
immunoglobulin variable domain  (IgV) and immunoglobulin constant domain (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
 
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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.
Pembrolizumab (previously known as SCH 900475) is a potent and highly selective
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block
the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Pre-clinical and Clinical Trials
4.1.2 
Therapeutic studies in mouse models have shown that administration of antibodies blocking
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads
ultimately to tumor rejection, either as a mono-therapy or in combination with other
treatment modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively
promoted CD8+ T-cell infiltration into the tumor and the presence of interferon gamma,
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).
Ongoing Clinical Trials
4.1.3 
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung
cancer, head and neck cancer, urothelial cancer, triple negative breast cancer, gastric cancer
and hematologic malignancies.  For study details please refer to the Investigator’s Brochure.
Rationale
4.2 
Rationale for the Trial and Selected Subject Population
4.2.1 
Details regarding specific benefits and risks for subjects participating in this clinical trial may
be found in the accompanying Investigators Brochure and Informed Consent documents.
This is a multicenter, nonrandomized, multi-cohort trial of pembrolizumab in PD-L1 positive
subjects with advanced solid tumors.  Subjects will be enrolled into 1 of 20 solid tumor
indications as outlined in Section 2.1.  Given that immune checkpoints such as the PD-1/PD-
L1 axis may be relevant in a variety of solid tumors in addition to the ones previously
studied, exploration as to which of these tumors might be more responsive to PD-1 inhibition
is being pursued in this protocol.  Twenty indications with a significant unmet medical need
in the metastatic/refractory setting for which there is internal PD-1/PD-L1 data were chosen
 
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for study. This indication discovery effort may lead to a better understanding of which tumor
types may be more responsive to pembrolizumab.
Participation in this trial will be dependent upon supplying tissue from an archival tissue
sample or newly obtained core or excisional biopsy of a tumor lesion to evaluate for PD-L1
expression by IHC.  If an archival specimen is PD-L1 negative but a newly obtained biopsy
is positive, the subject would be eligible. The specimen will be evaluated at a central
laboratory for expression status of PD-L1.  Only subjects with PD-L1 positive tumors will be
enrolled in the trial.  PD-L1 predicting potential response to anti-PD-1 therapy is based on
the results from Topalian  et al [28] who examined PD-L1 expression in the archival
specimens of 42 of the 296 subjects treated with the PD-1 inhibitor nivolumab.  Of those
17 subjects whose tumor cells did not stain positive for PD-L1 using a 5% threshold of tumor
cell surface expression, no objective response by RECIST 1.1 was observed.  But among the
25 subjects whose tumor cells were considered positive for PD-L1, 9 responded (36%). 
Therefore, it is hypothesized that PD-L1 expression may be a predictive biomarker of anti-
PD-1 activity, and this selection criterion will be utilized in this study as a necessary element
for study enrollment.
Rationale for Dose Selection/Regimen/Modification
4.2.2 
An open-label Phase I trial (KEYNOTE-001) is being conducted to evaluate the safety and
clinical activity of single agent pembrolizumab.  The dose escalation portion of this trial
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered once every 2 weeks
(Q2W) in subjects with advanced solid tumors.  All 3 dose levels were well tolerated and no
dose-limiting toxicities were observed.  This first in human study of pembrolizumab showed
evidence of target engagement and objective evidence of tumor size reduction at all dose
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No maximum tolerated dose (MTD) has been
identified to date.  10 mg/kg Q2W, the highest dose tested in KEYNOTE-001, will be the
dose and schedule utilized in this protocol.
Pharmacokinetic (PK) data analysis of pembrolizumab administered Q2W showed slow
systemic clearance, limited volume of distribution, and a long half-life (refer to Investigator’s
Brochure).  Pharmacodynamic data (interleukin-2 release assay) suggested that peripheral
target engagement is durable (>21 days).  This early PK and pharmacodynamic data provide
scientific rationale for testing a once every 3 weeks (Q3W) or more frequent dosing
schedule. 
 
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Rationale for Endpoints
4.2.3 
4.2.3.1 Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of
pembrolizumab in subjects with PD-L1 positive advanced solid tumors.  Response rates per
RECIST 1.1 will be evaluated.
RECIST 1.1 [29] as assessed by the investigator will be used as the primary response rate
efficacy endpoint.  RECIST 1.1 will also be used by the local site to determine eligibility and
make treatment decisions. 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may
produce antitumor effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial
increase in tumor burden or even the appearance of new lesions.  Standard RECIST may not
provide an accurate response assessment of immunotherapeutic agents such as
pembrolizumab.  Therefore, RECIST 1.1 will be used with the following adaptations:
If radiologic imaging shows initial progressive disease (PD), tumor assessment should be
repeated ≥4 weeks later in order to confirm PD with the option of continuing treatment per
below while awaiting radiologic confirmation of progression.  If repeat imaging shows a
reduction in the tumor burden compared to the initial scan demonstrating PD, treatment may
be continued / resumed.  If repeat imaging confirms progressive disease, subjects will be
discontinued from study therapy (exception noted in Section 7.1.2.5.1).  In determining
whether or not the tumor burden has increased or decreased, investigators should consider all
target lesions as well as non-target lesions (please refer to the Procedure Manual).
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating
physician whether to continue a subject on study treatment until repeat imaging is obtained a
minimum of 4 weeks later.  This clinical judgment decision should be based on the subject’s
overall clinical condition, including performance status, clinical symptoms, and laboratory
data.  Subjects may receive pembrolizumab treatment while waiting for confirmation of PD if
they are clinically stable as defined by the following criteria:
• Absence of signs and symptoms indicating disease progression
• No decline in Eastern Cooperative Oncology Group (ECOG) performance status
• Absence of rapid progression of disease
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression)
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed.  This
allowance to continue treatment despite initial radiologic progression takes into account the
 
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observation that some subjects can have a transient tumor flare in the first few months after
the start of immunotherapy, but with subsequent disease response.  Subjects that are deemed
clinically unstable are not required to have repeat imaging for confirmation of progressive
disease.
A retrospective central review may be performed for subjects using RECIST 1.1 criteria to
assess best overall response.  Response activity by RECIST 1.1 in GBM subjects may be
retrospectively confirmed using central review RANO criteria [30], and similarly prostate
cancer subject radiologic activity may be retrospectively confirmed using central PCWG2
criteria [31]. 
4.2.3.2 Safety Endpoints
The secondary safety objective of this study is to characterize the safety and tolerability of
pembrolizumab in subjects with PD-L1 positive advanced solid tumors.  The 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, including SAEs and events of clinical interest (ECIs). 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant
medications administered will be recorded.  AEs will be analyzed including but not limited to
all AEs, SAEs, fatal AEs, and laboratory changes.  Furthermore, specific immune-related
adverse events (irAEs) will be collected and designated as immune-related ECIs (irECI) as
described in Section 7.2.3.2.
4.2.3.3 Biomarker Research
Additional biomarker research to identify factors important for pembrolizumab therapy will
also be pursued. For example, tumor and blood samples from this study may  undergo
proteomic, genomic and transcriptional analyses. Additional research may evaluate factors
important for predicting responsiveness or resistance to pembrolizumab therapy and other
immunologic targets. 
Assays may include, but are not limited to:
Transcriptional Analyses of Gene Expression Signatures
Objective: To assess the association between anti-tumor activity from pembrolizumab with
several gene expression signatures related to PD-1/PD-L1 signaling
Messenger ribonucleic nucleic acid (mRNA) transcript profiling will be performed to assess
gene expression and to evaluate specific gene sets that may correlate with clinical response to
pembrolizumab.
 
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Genetic Analysis
Objective: To assess the association between anti-tumor activity from genetic alterations that
may indicate a specific genotype reflective of greater dependency on PD-1/PD-L1
checkpoint function or other immune checkpoint signaling pathways.
Deoxyribonucleic acid (DNA) isolated from blood or tumor tissue will be analyzed in order
to identify genetic alterations and to evaluate specific genetic alterations that may correlate
with clinical response to pembrolizumab. These and other additional biomarker or genomic
research to identify factors important for pembrolizumab therapy  (for example, human
leukocyte antigen genotype) may also be pursued.
Multiparametric (2-Color) IHC
Spatial association of PD-1+ TILs and PD-L1+ cells (tumor and myeloid cells) suggests
“induction” of PD-L1.  By assessing both of the required elements, i.e. PD-L1 positive cells
and PD-1+ T cells, a 2-color IHC assay may be a better predictor of response than PD-L1
positivity alone.  These and other additional biomarker analyses may also be pursued to
identify factors important for pembrolizumab therapy.
Additional exploratory analyses may be done when possible on available tumor specimens to
evaluate other immune related checkpoints, genes, and cytokines, and their relationship to
clinical responses to pembrolizumab therapy.
4.2.3.4 Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on blood and tumor tissue specimens
collected during this clinical trial.  This research may include genetic analyses (DNA), gene
expression profiling (ribonucleic acid [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.
 
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5.0 METHODOLOGY
Entry Criteria
5.1 
Diagnosis/Condition for Entry into the Trial
5.1.1 
Male/Female subjects with a PD-L1 positive advanced solid tumor (as prespecified in
Section 2.1) of at least 18 years will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2 
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/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 the day of signing informed consent.
3. Have histologically or cytologically-documented, locally-advanced, or metastatic
solid malignancy that is incurable and has either (a) failed prior standard therapy, (b)
for which no standard therapy exists, or (c) standard therapy is not considered
appropriate by the subject and treating physician. There is no limit to the number of
prior treatment regimens.
4. Have one of the following advanced (unresectable and/or metastatic) solid tumor
indications:
A1 
Colon or Rectal Adenocarcinoma
A2 
Anal Canal Squamous Cell Carcinoma
A3 
Pancreas Adenocarcinoma
A4 
Esophageal Squamous Cell Carcinoma or Adenocarcinoma (Including GE
Junction)
A5 
Biliary Tract Adenocarcinoma (Gallbladder and Biliary Tree but excluding
Ampulla of Vater Cancers)
A6 
Carcinoid Tumors
A7 
Neuroendocrine Carcinomas (Well or moderately differentiated Pancreatic
Neuroendocrine Tumor)
B1 
ER Positive HER2 Negative Breast Cancer a, d
B2 
Ovarian Epithelial, Fallopian Tube or Primary Peritoneal Carcinoma
B3 
Endometrial Carcinoma b
B4 
Cervical Squamous Cell Cancer
B5 
Vulvar Squamous Cell Carcinoma
C1 
Small Cell Lung Cancer
C2 
Mesothelioma (Malignant Pleural Mesothelioma)
 
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D1 
Thyroid Cancer (Papillary or Follicular Subtype)
D2 
Salivary Gland Carcinoma b
D3 
Nasopharyngeal Carcinoma
E1 
Glioblastoma Multiforme c
E2 
Leiomyosarcoma
E3 
Prostate Adenocarcinoma d
a Note:  ER positive HER2 negative status for breast cancer cohort defined by local
standards.
b Note:  All carcinoma subtypes are allowed however sarcomas or mesenchymal
tumors are excluded.
c Note:  Glioblastoma multiforme subjects with any prior bevacizumab treatment are
NOT eligible (exceptions may be considered after consultation with the
sponsor).
d Note: Subjects with prostate cancer who are currently on luteinizing-hormone-
releasing hormone (LHRH) analogs and breast cancer subjects receiving
LHRH analogs for ovarian suppression to avoid menses are eligible for this
study and may continue to take the LHRH analogs while participating in
this study.
5. Have provided tissue for biomarker analysis from an archival tissue sample or newly
obtained core or excisional biopsy of a tumor lesion not previously irradiated (tumors
progressing in a prior site of radiation are allowed for PD-L1 characterization, other
exceptions may be considered after Sponsor consultation). 
6. Have a PD-L1 positive tumor as determined by IHC at a central laboratory from
either an archived formalin-fixed, paraffin embedded (FFPE) tumor sample or a
newly obtained biopsy.
7. Have measurable disease based on RECIST 1.1. Tumor lesions situated in a
previously irradiated area are considered measurable if progression has been
demonstrated in such lesions. 
8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
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 
CrCla)
≤1.5xULN OR
≥60 mL/min for subject 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) 
≤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
aCreatinine clearance (CrCl) should be calculated per institutional standard.
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper
limit of normal.
10. Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required. 
11. Female subjects of childbearing potential must be willing to use an adequate method
of contraception as outlined in Section 5.7.2 - Contraception, for the course of the
trial through 120 days after the last dose of trial drug.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
12. Male subjects of childbearing potential must agree to use an adequate method of
contraception as outlined in Section 5.7.2 –Contraception starting with the first dose
of 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
5.1.3 
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigation device
within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.  The use of physiologic doses of corticosteroids may be approved after
consultation with the Sponsor.
Note:  Systemic steroid therapy allowed for subjects in the GBM cohort as long as ≤
dexamethasone 4 mg, or its steroid equivalent (other exceptions may be considered
after sponsor consultation).
3. Has had a prior anti-cancer mAb within 4 weeks prior to study Day 1 or who has not
recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to mAbs 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 AEs due to a previously administered agent.
Note:  Subjects with ≤ Grade 2 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. 
Note:  Subjects in the GBM cohort are not eligible if they have had radiation therapy
to their only sites of measurable central nervous system (CNS) disease within
12 weeks prior to study Day 1.
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.
6. Has known active CNS metastases and/or carcinomatous meningitis.  Subjects with
previously treated brain metastases may participate provided they are stable (without
evidence of progression by imaging for at least 4 weeks prior to the first dose of trial
treatment and any neurologic symptoms have returned to baseline), have no evidence
of new or enlarging brain metastases, and are not using steroids for at least 7 days
prior to trial treatment.  This exception does not include carcinomatous meningitis
which is excluded regardless of clinical stability.
 
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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
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment. 
8. Has evidence of interstitial lung disease or a history of (non-infectious) pneumonitis
that required steroids or has current 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 pre-screening or screening visit
through 120 days after the last dose of trial treatment.
13. Has previously  participated in any other pembrolizumab trial, or received prior
therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab or any
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways). 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
Hepatitis C virus (e.g., HCV RNA [qualitative] is detected).
16. Has received a live vaccine within 30 days of planned start of study therapy. 
Examples of live vaccines include, but are not limited to, the following:  measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however, intranasal
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
17. Is or has an immediate family member (spouse or children) 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.
 
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Trial Treatment(s)
5.2 
The study drug dose and schedule to be used in this trial are outlined below in Table 2.
Table 2  Trial Treatment
Drug 
Dose/Potency
Dose
Frequency
Route of
Administration
Regimen/
Treatment
Period 
Use
Pembrolizumab 
10 mg/kg 
Q2W  
IV infusion  
Day 1 of each 
cycle
Experimental
The pembrolizumab dosing interval may be withheld due to toxicity as described in Section 5.2.1.2.
Trial treatment should begin on the day of randomization or as close as possible to the date
on which the subject is allocated/assigned.
All trial treatments will be administered on an out-patient basis.
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the
trial site, subsidiary or designee, depending on local country operational or regulatory
requirements.
The investigator shall take responsibility for and shall take all steps to maintain appropriate
records and ensure appropriate supply, storage, handling, distribution and usage of trial
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1 
5.2.1.1 Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background and Rationale. 
The dose amount required to prepare the pembrolizumab infusion solution will be based on
the subject’s weight in kilograms (kg).  Details on the dose calculation, preparation and
administration are provided in the Pharmacy Manual.
5.2.1.2 Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with
pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic
etiology.  These irAEs may occur shortly after the first dose or several months after the last
dose of pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical trial data, most irAEs were reversible and could be managed with
 
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interruptions of pembrolizumab, administration of corticosteroids and/or other supportive
care.  For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other
causes.  Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be
included as part of the evaluation.  Based on the severity of irAEs, withhold or permanently
discontinue pembrolizumab and administer corticosteroids. Dose modification and toxicity
management guidelines for irAEs associated with pembrolizumab are provided in Table 3;
additional guidance is provided Section 5.6.1.
For subjects whose dose was withheld due to toxicity, subjects may resume pembrolizumab
upon resolution of toxicity to Grade 0-1 or baseline. This dose would be considered Day 1 of
the next cycle and should be in alignment with the new schedule.
 
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Table 3  Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related
AEs
Toxicity grade or
conditions
(CTCAEv4.0)
Action taken to
pembrolizumab
irAE management with
corticosteroid and/or other
therapies
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold
 Administer corticosteroids (initial
dose of 1-2 mg/kg prednisone or
equivalent) followed by taper
 Monitor subjects for signs and symptoms of
pneumonitis
 Evaluate subjects with suspected
pneumonitis with radiographic imaging and
initiate corticosteroid treatment
 Add prophylactic antibiotics for
opportunistic infections
Grade 3 or 4, or
recurrent Grade 2
Permanently
discontinue
Diarrhea / Colitis 
Grade 2 or 3 
Withhold 
 Administer corticosteroids (initial
dose of 1-2 mg/kg prednisone or
equivalent) followed by taper
 Monitor subjects for signs and symptoms of
enterocolitis (ie, diarrhea, abdominal pain,
blood or mucus in stool with or without
fever) and of bowel perforation
(ie, peritoneal signs and ileus).
 Subjects with ≥ Grade 2 diarrhea suspecting
colitis should consider GI consultation and
performing endoscopy to rule out colitis.
 Subjects with diarrhea/colitis should be
advised to drink liberal quantities of clear
fluids.  If sufficient oral fluid intake is not
feasible, fluid and electrolytes should be
substituted via IV infusion.
Grade 4 
Permanently
discontinue
 
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Immune-related
AEs
Toxicity grade or
conditions
(CTCAEv4.0)
Action taken to
pembrolizumab
irAE management with
corticosteroid and/or other
therapies
Monitor and follow-up
AST / ALT
elevation or
Increased
bilirubin a
Grade 2
Withhold 
 Administer corticosteroids (initial
dose of 0.5-1 mg/kg prednisone or
equivalent) followed by taper
 Monitor with liver function tests (consider
weekly or more frequently until liver
enzyme value returned to baseline or is
stable
Grade 3 or 4 
Permanently
discontinue
 Administer corticosteroids (initial
dose of 1-2 mg/kg prednisone or
equivalent) followed by taper
Type 1 diabetes
mellitus (T1DM)
or
Hyperglycemia
Newly onset 
T1DM or
Grade 3 or 4
hyperglycemia
associated with
evidence of -cell
failure
Withhold
 Initiate insulin replacement
therapy for subjects with T1DM
 Administer anti-hyperglycemic in
subjects with hyperglycemia
 Monitor subjects for hyperglycemia or other
signs and symptoms of diabetes.
Hypophysitis 
Grade 2 
Withhold 
 Administer corticosteroids and
initiate hormonal replacements as
clinically indicated. 
 Monitor for signs and symptoms of
hypophysitis (including hypopituitarism and
adrenal insufficiency)
Grade 3 or 4 
Withhold or
permanently
discontinue b
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
discontinueb
Hypothyroidism  
Grade 2-4
Continue
 Initiate thyroid replacement
hormones (eg, levothyroxine or
liothyroinine) per standard of care
 Monitor for signs and symptoms of thyroid
disorders.
Nephritis and 
Renal
dysfunction
Grade 2
Withhold
 Administer corticosteroids
(prednisone 1-2 mg/kg or
equivalent) followed by taper.
 Monitor changes of renal function
Grade 3 or 4 
Permanently
discontinue
 
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Immune-related
AEs
Toxicity grade or
conditions
(CTCAEv4.0)
Action taken to
pembrolizumab
irAE management with
corticosteroid and/or other
therapies
Monitor and follow-up
Myocarditis 
Grade 1 or 2 
Withhold
 Based on severity of AE
administer corticosteroids
 Ensure adequate evaluation to confirm
etiology and/or exclude other causes
Grade 3 or 4 
Permanently
discontinue
All other
immune-related
AEs
Intolerable/ 
persistent Grade 2
Withhold
 Based on type and severity of AE
administer corticosteroids
 Ensure adequate evaluation to confirm
etiology and/or exclude other causes
Grade 3
Withhold or
discontinue based
on the type of
event.  Events that
require
discontinuation
include and not
limited to: 
Gullain-Barre
Syndrome,
encephalitis
Grade 4 or
recurrent Grade 3
Permanently
discontinue
a. For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative
to baseline and lasts for at least 1 week then subjects should be discontinued.
b. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE:
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM). 
 
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Dose modification and toxicity management of infusion-reactions related to
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after
drug infusion and generally resolve completely within 24 hours of completion of infusion.
Dose modification and toxicity management guidelines on pembrolizumab associated
infusion reaction are provided in Section 5.6.1 (Table 5).
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 trial therapy (e.g., elective
surgery, unrelated medical events, subject vacation, and/or holidays).  Subjects should be
placed back on trial therapy within 12 weeks of the scheduled interruption, unless otherwise
discussed with the Sponsor.  The reason for interruption should be documented in the
subject's trial record.
Timing of Dose Administration
5.2.2 
Study drug 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).  Study drug may be
administered up to 3 days before or after the scheduled Day 1 of each cycle due to
administrative reasons.
All study drug will be administered on an outpatient basis.
Pembrolizumab will be administered as a 30 minute IV infusion every 2 weeks (treatment
cycle intervals may be withheld 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 dose calculation,
preparation of the infusion solution, and administration.
Continuing Study Drug Administration After Initial Evidence of Radiologic Disease
Progression
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by
potentiating endogenous cancer-specific immune responses.  The response patterns seen with
such an approach may extend beyond the typical time course of responses seen with
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor
burden or even the appearance of new lesions. 
If initial radiologic imaging shows PD, tumor assessment should be repeated ≥4 weeks later
in order to confirm PD with the option of continuing treatment per below while awaiting
 
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radiologic confirmation of progression.  If repeat imaging shows a reduction in the tumor
burden compared to the initial scan demonstrating PD, treatment may be continued as per
treatment calendar.  If repeat imaging confirms progressive disease, subjects will be
discontinued from study therapy (exception noted in Section 7.1.2.5.1).  In determining
whether or not the tumor burden has increased or decreased, Investigators should consider all
target lesions as well as non-target lesions (please refer to the Procedures Manual).
When feasible, subjects should not be discontinued until progression is confirmed; however,
the decision to continue study treatment after the 1st evidence of disease progression is at the
Investigator’s discretion based on the clinical status of the subject as described in Table 4
below.  Subjects may receive study treatment while waiting for confirmation of PD if they
are clinically stable as defined by the following criteria:
• Absence of signs and symptoms (including worsening of laboratory values) indicating
disease progression
• No decline in ECOG performance status
• Absence of rapid progression of disease
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression)
requiring urgent alternative medical intervention
Table 4  Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment 
Imaging
Treatment
1st radiologic
evidence of PD
Repeat imaging
at >4 weeks to
confirm PD
May continue
study treatment at
the Investigator’s
discretion while
awaiting
confirmatory scan
Repeat imaging
at >4 weeks to
confirm PD if
possible
Discontinue
treatment
Repeat scan
confirms PD
No additional
imaging
required
Discontinue
treatment
(exception noted
in Section
7.1.2.5.1)
No additional 
imaging required
N/A
Repeat scan
shows SD, PR
or CR
Continue
regularly
scheduled
imaging
assessments
every 8 weeks
(after 6 months,
imaging
assessments
every 12 weeks)
Continue study
treatment at the
Investigator’s
discretion
Continue
regularly
scheduled
imaging
assessments
every 8 weeks
(after 6 months,
imaging
assessments
every 12 weeks)
May restart
study treatment
if condition has
improved and/or
clinically stable
per
Investigator’s
discretion
CR=completed response; N/A=not applicable; SD=stable disease; PD=progressive disease; PR=partial response
 
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Trial Blinding/Masking
5.2.3 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the
treatment administered.
Randomization or Treatment Allocation
5.3 
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
5.4 
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the
investigator and/or the subject's primary physician.  However, the decision to continue the
subject on trial therapy or vaccination schedule requires the mutual agreement of the
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1 
All treatments that the investigator considers necessary for a subject’s welfare may be
administered at the discretion of the investigator in keeping with the community standards of
medical care.  All concomitant medication will be recorded on the electronic case report form
eCRF 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 eCRF.
All concomitant medications received within 28 days before the first dose of trial treatment
and 30 days after the last dose of trial treatment should be recorded.  Concomitant
medications administered after 30 days after the last dose of trial treatment should be
recorded for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
5.5.2 
Subjects are prohibited from receiving the following therapies during the Screening and
Treatment Phase (including retreatment for post-complete response relapse) of this trial:
 Anti-cancer systemic chemotherapy or biological therapy
Note:  Subjects with glioblastoma multiforme with any prior bevacizumab treatment
are not eligible (exceptions may be considered after consultation with the sponsor).
Note: Subjects with prostate cancer who are currently on LHRH analogs and
subjects with breast cancer receiving LHRH analogs for ovarian suppression to
avoid menses are eligible for this study and may continue to take the LHRH analogs
while participating in this study.
 
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 Immunotherapy not specified in this protocol
 Chemotherapy not specified in this protocol
 Investigational agents other than pembrolizumab
 Radiation therapy
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be
allowed after consultation with Sponsor. 
 Live vaccines within 30 days prior to the first dose of trial treatment and while
participating in the trial.  Examples of live vaccines include, but are not limited to, the
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and
typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are generally killed
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-
Mist®) are live attenuated vaccines, and are not allowed
 Glucocorticoids for any purpose other than to modulate symptoms from an adverse
event. 
Note: The use of physiologic doses (e.g., prednisone 10 mg) of corticosteroids may be
approved after consultation with the Sponsor.  Concomitant administration of higher
steroid doses with study medication is prohibited.
Note:  Systemic steroid therapy allowed for subjects in the GBM cohort as long as ≤
dexamethasone 4 mg, or its steroid equivalent (other exceptions may be considered
after sponsor consultation).
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (e.g. IV contrast
dye) is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
5.6 
Supportive Care Guidelines
5.6.1 
Subjects should receive appropriate supportive care measures as deemed necessary by the
treating investigator including but not limited to the items outlined below:
 Diarrhea: Subjects should be carefully monitored for signs and symptoms of
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or
without fever) and of bowel perforation (such as peritoneal signs and ileus).  In
 
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symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are
persistent and/or severe, endoscopic evaluation should be considered.
o All subjects who experience diarrhea 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.
 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and
consideration should be given in subsequent cycles to the administration of
prophylactic antiemetic therapy according to standard institutional practice.  Subjects
should be strongly encouraged to maintain liberal oral fluid intake.
 Anti-infectives: Subjects with a documented infectious complication should receive
oral or IV antibiotics or other anti-infective agents as considered appropriate by the
treating investigator for a given infectious condition, according to standard
institutional practice.
 Immune-related adverse events: Suggested supportive care measures for the
management of AEs with potential immunologic etiology are outlined along with
dose modification guidelines in Section 5.2.1.2, Table 3 and Section 5.6.1.1 below.
 Management of Infusion Reactions:  Pembrolizumab may cause severe or life
threatening infusion-reactions. Acute infusion reactions (which can include cytokine
release 
syndrome, 
angioedema, 
or 
anaphylaxis) 
are 
different 
from
allergic/hypersensitive reactions, although some of the manifestations are common to
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion
and generally resolve completely within 24 hours of completion of infusion.
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension;
Hypotension; Myalgia (muscle pain); Nausea; Pruritus/itching; Rash/desquamation;
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or
exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals);
Vomiting.  Dose modification and toxicity management guidelines on pembrolizumab
associated infusion reaction are provided in Table 5.
 
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Table 5  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 infusion interruption but 
responds promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated 
for ≤24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but 
is not limited to: 
 
IV fluids 
 
Antihistamines 
 
NSAIDs
 
Acetaminophen  
 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms resolve 
and the subject should be premedicated for the next
scheduled dose.
Subjects who develop Grade 2 toxicity despite
adequate premedication should be permanently
discontinued 
from 
further 
trial 
treatment
administration.
Subject may be
premedicated 1.5h (±
30 minutes) prior to
infusion of
pembrolizumab with:
Diphenhydramine
50 mg PO (or
equivalent dose of
antihistamine)
Acetaminophen 500-
1000 mg PO (or
equivalent dose of
analgesic)
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
 
Epinephrine
Increase monitoring of vital signs as medically indicated
until the subject is deemed medically stable in the
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used
immediately.
Subject is permanently discontinued from further
trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of
drug administration.
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at
http://ctep.cancer.gov
IV=intravenous; NSAIDs= non-steroidal anti-inflammatory drugs; PO=oral administration
 
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The treatment guidelines are intended to be applied when the Investigator determines the
events to be related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab,
the Investigator does not need to follow the treatment guidance.  Refer to Section 5.2.1.2,
Table 3 for guidelines regarding dose modification and supportive care.
It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or
skin photography as part of evaluation of the event.
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related
Adverse Events (irAEs)
Immune-related Adverse Events (irAE)
Adverse events (both non-serious and serious) associated with drug exposure and consistent
with an immune phenomenon may represent an immunologic etiology.  These irAEs may be
predicted based on the nature of the pembrolizumab compound, its mechanism of action, and
reported experience with immunotherapies that have a similar mechanism of action.  An irAE
can occur shortly after the first dose or several months after the last dose of treatment and
may affect more than on body system simultaneously.  Particular attention should be paid to
AEs that may be suggestive of potential irAEs as outlined in 7.2.3.2.  Based on existing
clinical trial data, most irAEs were reversible and could be managed with interruptions of
pembrolizumab, administration of corticosteroids and/or other supportive care.  For
suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. 
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and
administer corticosteroids.  Dose modification and toxicity management guidelines for irAEs
associated with pembrolizumab are provided in Section 5.2.1.2, Table 3.
Events of Clinical Interest (ECI)
Events of clinical interest (ECI) are non-serious and serious adverse events that may or may
not be irAEs. ECIs must be reported to Merck within 24 hours regardless of attribution to
study treatment. Information on how to identify and report ECIs can be referenced in
Section 7.2.3.2. 
Diet/Activity/Other Considerations
5.7 
Diet
5.7.1 
Subjects should maintain a normal diet unless modifications are required to manage an AE
such as diarrhea, nausea, or vomiting.
Contraception
5.7.2 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if
MK 3475 has transient adverse effects on the composition of sperm. 
 
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For this trial, male subjects will be considered to be of non-reproductive potential if they
have azoospermia (whether due to having had a vasectomy or due to an underlying medical
condition). 
Female subjects will be considered of non-reproductive potential if they meet 1 of the
following criteria:
 She is postmenopausal, defined as at least 12 months with no menses without an
alternative medical cause.  In women <45 years of age who are not using hormonal
contraception or hormonal replacement therapy, a high follicle-stimulating hormone
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal
state.  In the absence of 12 months of amenorrhea, a single FSH measurement is
insufficient.
 She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening.
 She has a congenital or an acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant
or impregnating a partner, respectively, while receiving trial drug and for 120 days after the
last dose of trial drug by complying with 1 of the following:
 Practice abstinence from heterosexual activity.
Abstinence (relative to heterosexual activity) can be used as the sole method of
contraception if it is consistently employed as the subject’s preferred and usual
lifestyle and if considered acceptable by local regulatory agencies and European
Research Councils (ERCs)/IRBs.  Periodic abstinence (eg, calendar, ovulation,
symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptable
methods of contraception.
 Use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡:
 Single method (1 of the following is acceptable):
o Intrauterine device (IUD)
o Vasectomy of a female subject’s male partner
o Contraceptive rod implanted into the skin
 Combination method (requires use of 2 of the following):
o Diaphragm with spermicide (cannot be used in conjunction with cervical
cap/spermicide)
o Cervical cap with spermicide (nulliparous women only) 
o Contraceptive sponge (nulliparous women only)
 
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o Male condom or female condom (cannot be used together)
o Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring,
or subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it
does not qualify as an acceptable method of contraception for subjects participating at sites in
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate
in the study they must adhere to the contraception requirement (described above) for the
duration of the study and during the follow-up period defined in Section 7.2.2 - Reporting of
Pregnancy and Lactation to the Sponsor.  If there is any question that a subject will not
reliably comply with the requirements for contraception, that subject should not be entered
into the study.
Use in Pregnancy
5.7.3 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the
subject will immediately discontinued from trial treatment.  The site will contact the subject
at least monthly and document the subject’s status until the pregnancy has been completed or
terminated.  The outcome of the pregnancy will be reported to the Sponsor without delay and
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion,
congenital anomaly, or other disabling or life-threatening complication to the mother or
newborn).  The study investigator will make every effort to obtain permission to follow the
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.  If
a male subject impregnates his female partner the study personnel at the site must be
informed immediately and the pregnancy reported to the Sponsor and followed as described
above and in Section 7.2.2.
Use in Nursing Women
5.7.4 
It is unknown whether pembrolizumab 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
5.8 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the
discretion of the investigator should any untoward effect occur.  In addition, a subject may be
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the
trial plan is violated, or for administrative and/or other safety reasons.  Specific details
regarding discontinuation or withdrawal procedures; including specific details regarding
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other
Procedures.
 
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A subject must be discontinued from the trial for any of the following reasons:
● The subject or legal representative (such as a parent or legal guardian) withdraws
consent.
Discontinuation of Treatment
5.8.1 
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  outlined in Section 7.1.2.5.1 (exception
if the Sponsor approves treatment continuation).
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2
Note: A subject may be granted an exception to continue on treatment with confirmed
radiographic progression if clinically stable or clinically improved, please see
Section 7.1.2.5.1
 Unacceptable adverse experiences as described in Section 5.2.1.2 and Section 7.2
 Any progression or recurrence of any malignancy, or any occurrence of another
malignancy that requires active treatment
 Intercurrent illness other than another malignancy as noted above that prevents
further administration of treatment
 Investigator’s decision to withdraw the subject
 A confirmed positive serum pregnancy test
 Noncompliance with trial treatment or procedure requirements
 Recurrent Grade 2 pneumonitis
 The subject is lost to follow-up
 Completed 24 months of treatment with pembrolizumab
Note: 24 months of study medication is calculated from the date of first dose.
Subjects who stop pembrolizumab after 24 months may be eligible for up to 1 year of
additional study treatment if they progress after stopping study treatment provided
they meet the requirements detailed in Section 7.1.5.2.1. 
 
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 Discontinuation of treatment may be considered for subjects who have attained a
confirmed CR that have been treated for at least at least 24 weeks, receiving at least 2
doses of pembrolizumab beyond the date when the initial CR was declared.  Subjects
who stop pembrolizumab with SD, PR, or CR, may be eligible for up to 1 year of
pembrolizumab if they experience disease progression after stopping pembrolizumab. 
This retreatment is termed the Second Course Phase (Retreatment) and is described in
detail in Section 7.1.5.2.1. 
 Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Protocol
Flow Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject
will be followed for 30 days for AE monitoring (serious adverse events will be collected for
90 days after the end of treatment 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 OS  until death, withdrawal of consent, or the end of the study,
whichever occurs first.
Subject Replacement Strategy
5.9 
Additional subjects may be enrolled in a given cohort to ensure that the required number of
evaluable subjects in each cohort is achieved.  A subject that discontinues the trial for
progressive disease or a drug-related AE will not be replaced and will be counted in the
evaluable population of subjects for the respective cohort.  Further details are provided in
Section 8.1.3.
Beginning and End of the Trial
5.10 
The study begins when the first subject signs the informed consent (either pre-screening
consent or main study consent).  The end of the study may be designated as the time point
when all subjects have discontinued the study or are a minimum of 6 months post initial
study medication administration.  If, by the end of the study, there remains at least 1 subject
still on study treatment for at least 6 months, the subject(s) may enter additional treatment
cycles.  At this point a database lock of the trial may occur to allow the analysis of the study
data.  Any remaining subjects may continue to receive study medication and be seen by the
investigator per usual standard of care for this subject population.  In addition, the
investigator will be expected to monitor for and report any serious adverse events, events of
clinical interest, and pregnancies, as detailed in Section 7.2.3 (Serious Adverse Experiences). 
The subject is considered on study until such time that he/she meets any of the
discontinuation criteria and written notification is given to the Sponsor.
Upon study completion, subjects are discontinued and enrolled in a pembrolizumab extension
study.
 
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Clinical Criteria for Early Trial Termination
5.11 
The clinical trial may be terminated early if the extent (incidence and/or severity) of
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial
site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems
or the number of discontinuations for administrative reasons is too high.
In the event of Sponsor decision to no longer supply study drug, ample notification will be
provided so that appropriate adjustments to subject treatment can be made.
 
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6.0 TRIAL FLOW CHART
Study Flow Chart
6.1 
Trial Period:
Screening
Phase
Treatment Cycles a 
End of
Treatment
Post-Treatment
Treatment Cycle/Title: 
Screening
(Visit 1) 
1 
2 
3 
4
To be repeated beyond 8
cycles a
Discon  
Safety
Follow-up
Follow Up
Visits b
Survival
Follow-Up
5 
6 
7 
8
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At time of
Discon
30 days
from last
dose
(± 3 days)
Every 12
weeks post
discon
(± 7 days)
Every 12
weeks
(± 4 weeks)
Administrative Procedures
Pre-screening Consent
X c
Informed Consent
X d
Informed Consent for Future Biomedical Research
(optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X f 
X 
X 
X 
X 
X 
X 
X 
X 
X
X f
Trial Treatment Administration
X 
X 
X 
X 
X 
X 
X 
X
Post-study Anticancer Therapy Status
X
X
Survival Status w
-----------------------------------------------------------------------------------------------------
X
Clinical Procedures/Assessments
Review Adverse Events
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g
X g
Full Physical Examination
X 
X h
Directed Physical Examination
X 
X 
X 
X
X u 
X u 
X u 
X
Vital Signs and Weight i
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
ECOG Performance Status
X 
X 
X 
X 
X 
X 
X v 
X v 
X v 
X
 
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Trial Period:
Screening
Phase
Treatment Cycles a 
End of
Treatment
Post-Treatment
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated beyond 8
cycles a 
Discon  
Safety
Follow-up
Follow Up
Visits b
Survival
Follow-Up
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
± 3 
± 3 
± 3 
± 3
± 3 
± 3 
± 3
At time of 
Discon  
30 days
from last
dose
(± 3 days)
Every 12
weeks post
discon
(± 7 days)
Every 12
weeks
(± 4 weeks)
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test –Urine or Serum β-human chorionic
gonadotropin (-HCG) k
X
PT/INR and aPTT  
X l
CBC with Differentialm
X l 
X 
X 
X 
X 
X 
X 
X 
X 
X n 
Comprehensive Chemistry Panelm
X l 
X 
X 
X 
X 
X 
X 
X 
X 
X n 
Urinalysis m 
X l
X h 
X n 
Total triiodothyronine (T3), free thyroxine (FT4) and
thyroid stimulating hormone (TSH) m
X l
X h
X n 
Tumor Marker Assessment (Optional) j 
X j
X j
X j 
X j
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Blood for Future Biomedical Research o 
X
Efficacy Measurements
Tumor Imaging a,p,q 
X 
X 
X r 
X b
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival or Newly Obtained Tissue Collection e
X s
Correlative Studies Blood Collection e
X t 
X t 
X t
 
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a. Treatment cycles are 2 weeks.  Imaging should be performed every 8 weeks initially (56 days ± 7 days) and after 6 months, imaging assessments should be
performed every 12 weeks regardless of any treatment delays (i.e. Screening visit, Cycle 5, Cycle 9, Cycle 13 and then every 6 cycles (12 weeks)).
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status
by radiologic imagingp every 8 weeks (± 7 days) in the first 6 months and every 12 weeks (± 7 days) after Month 6 until (1) the start of new anti-cancer
treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs first.
c. Pre-screening informed consent must be obtained prior to sending an archival sample to the vendor for characterization.  Subjects that do not have archival
tissue available must sign the main study consent prior to undergoing a newly obtained biopsy.
d. Written consent must be obtained prior to performing any protocol specific procedure.  Results of a test performed prior to the subject signing consent as part
of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first
dose of trial treatment).  Baseline number will be assigned when the study informed consent is signed. 
e. Leftover samples may be kept for Future Biomedical Research if the subject signs the Future Biomedical Research (FBR) consent.
f. Prior medications –Record all medications taken 28 days before the first dose of trial treatment.  Concomitant medications –Enter new medications started
during the trial and 30 days after last dose of trial treatment regardless of when the Safety Follow-up visit occurs. 
g. Record all AEs occurring within 30 days after the last dose of trial treatment regardless of when the Safety Follow-up visit occurs.  After 30 days, record all
SAEs (related and unrelated to trial treatment) / ECIs occurring up to 90 days after the last dose of trial treatment or the start of new anti-cancer treatment,
whichever comes first.  Afterwards, any drug related AE regardless of seriousness occurring outside of any reporting timeframes must be reported
h. To be repeated every 4 cycles after Cycle 5.
i. Height will be measured at visit 1 only. 
j. Tumor marker assessment is not an additional study-related laboratory evaluation.  The purpose is to collect information that may be a part of standard
clinical assessment for certain tumor types.  Data collection (if applicable and if available) should occur every 8 weeks initially (56 days ± 7 days) and after
6 months, assessments should be performed every 12 weeks regardless of any treatment delays (i.e. Screening visit, Cycle 5, Cycle 9, Cycle 13 and then
every 6 cycles (12 weeks) thereafter coinciding with imaging visits).  Upon discontinuation, tumor marker data collection will occur at the same time as
post-treatment imaging follow-up visits.  See Section 7.1.2.7 and Section 7.1.3.1 for additional details. 
k. 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.
l. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory
tests. 
m. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests. 
n. Unresolved abnormal labs that are drug related AEs should be followed until resolution. 
o. Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose,
on Day 1 (or with the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained.
p. The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment.  Scans performed as part of routine clinical management
are acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  On-study
imaging will be performed every 8 weeks (± 7 days) after the first dose of trial treatment (after 6 months, imaging assessments every 12 weeks) and should
follow calendar days and should not be adjusted for delays in cycle starts or withholding of pembrolizumab cycle frequencies.  The same imaging technique
should be used in a subject throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and
for subject management.  Tumor imaging and assessment per local standard of care should be performed for subject management, and may include
 
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additional imaging (e.g. bone scan for subjects with  prostate cancer) and appropriate tumor markers. Sponsor will collect radiological assessments for
retrospective analysis by a central vendor.  The processes for image collection and transmission to the central vendor are in the Site Imaging Manual (SIM).
q. Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be repeated at a minimum of 4
weeks later in order to confirm progressive disease as described in Section 4.2.3.1.
r. If a scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory.  In subjects who
discontinue study therapy without confirmed disease progression, a radiological evaluation should be repeated at the time of treatment discontinuation (i.e.
date of discontinuation ± 4 week window). 
s. Baseline tumor tissue for biomarker analysis from an archival tissue sample or newly obtained core or excisional biopsy (fine needle aspiration [FNA] not
adequate) of a tumor lesion not previously irradiated must be provided (tumors progressing in a prior site of radiation are allowed for PD-L1
characterization, other exceptions may be considered after Sponsor consultation) and received by the central vendor for characterization of PD-L1 status
prior to enrollment.  These samples are not required to be obtained within 28 days of enrollment. 
t. Blood for correlative studies should be collected prior to Cycle 1, at Cycle 5 and again at discontinuation (end of treatment). 
u. Directed physical exams are performed at Cycles 1, 2, 3, 4, 6, 7, 8 and 11.  After Cycle 11, directed physical exams should occur once every 4 cycles (Cycles
15, 19, etc.). 
v. Following Cycle 8, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam (Cycle
9, 11, 13, 15, 17, 19 and every 2 cycles thereafter.
w. After documented local site assessed disease progression or the start of new anticancer treatment; continuing subjects will be contacted approximately every
12 weeks by telephone. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all
subjects who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status
(excluding subjects that have a death event previously recorded).
 
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Second Course Phase (Retreatment ONLY)
6.2 
Trial Period: 
SECOND COURSE PHASE:  Treatment Cycles a
End of
Treatment
Post-Treatment
Treatment Cycle/Title: 
1 
2 
3 
4
To be repeated beyond 8 cycles a
Discon  
Safety 
Follow-up
Follow Up
Visits b
Survival Follow-
Up
5 
6 
7 
8
Scheduling Window (Days):
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3
At time of
discon
30 days from
last dose
(± 3 days)
Every
12weeks
post discon
(± 7 days)
Every 12 weeks
(± 4 weeks)
Administrative Procedures
Eligibility Criteria c
X
Concomitant Medication Review d
X 
X 
X 
X 
X 
X 
X 
X 
X
X
Trial Treatment Administration e
X 
X 
X 
X 
X 
X 
X 
X
Post-study Anticancer Therapy Status
X
X
Survival Statusr
----------------------------------------------------------------------------------------------------------------------
X
Clinical Procedures/Assessments
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X
X f 
X f
Full Physical Examination  
X 
X g 
Directed Physical Examination  
X 
X 
X 
X o 
X o 
X o 
X
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X
ECOG Performance Status 
X 
X 
X 
X 
X 
X p 
X p 
X p 
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test –Urine or Serum -HCG
h 
X
PT/INR and aPTT
X i
CBC with Differentialj
X i
X 
X 
X 
X 
X 
X 
X 
X 
X n
Comprehensive Chemistry Panelj
X i
X 
X 
X 
X 
X 
X 
X 
X
X n
T3, FT4 and TSH j
X i
X g
X n
Tumor Marker Assessment (Optional) q
X
X
X
X
Efficacy Measurements
Tumor Imaging a,k,l
X
X
X m
X b
 
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a. Treatment cycles are 2 weeks.  Imaging should be performed every 8 weeks initially (56 days ± 7 days) and after 6 months, imaging assessments should be performed every 12
weeks regardless of any treatment delays (i.e. Screening visit, Cycle 5, Cycle 9, Cycle 13and then every 6 cycles (12 weeks)).
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic
imagingevery 12 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs
first.
c. Subjects who either a) attain a CR and discontinue treatment or b) discontinue treatment after 24 months on pembrolizumab 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. 
d. Concomitant medications –Enter new medications started during the trial and 30 days after last dose of trial treatment regardless of when the Safety Follow-up visit occurs. 
e. Subjects who restart treatment should resume at the same dose and cycle interval which they were receiving prior to discontinuation.
f. Record all AEs occurring within 30 days after the last dose of trial treatment regardless of when the Safety Follow-up visit occurs.  After 30 days record all SAEs (related and
unrelated to trial treatment) / 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,
any drug related AE regardless of seriousness occurring outside of any reporting timeframes must be reported.
g. To be repeated every 4 cycles after Cycle 5.
h. For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to first dose of retreatment.  If urine pregnancy results cannot be
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if
required by local guidelines.
i. Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose of pembrolizumab.  See Section 7.1.3 for
details regarding laboratory tests.
j. After the first dose, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.
k. A scan must be performed within 28 days prior to restarting treatment with pembrolizumab.  Imaging should continue to be performed every 12 weeks (84 ± 7 days) from the
first dose of trial treatment or more frequently if clinically indicated.  Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or
withholding of pembrolizumab cycle frequencies.  The same imaging technique should be used in a subject throughout the trial.  Local reading (investigator assessment with
site radiology reading) will be used to determine eligibility and for subject management.  Tumor imaging and assessment per local standard of care should be performed for
subject management, and may include additional imaging (e.g. bone scan for subjects with  prostate cancer) and appropriate tumor markers. The Sponsor will collect
radiological assessments for retrospective analysis by a central vendor.  The processes for image collection and transmission to the central vendor are in the SIM.
l. Per the modified RECIST 1.1 used in this protocol, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later in order
to confirm progressive disease as described in Section 4.2.3.1.
m. If a scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory.  In subjects who discontinue study therapy
without confirmed disease progression, a radiological evaluation should be performed at the time of treatment discontinuation (i.e. date of discontinuation ± 4 week window). 
If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory.
n. Unresolved labs that are drug related AEs should be followed until resolution. 
o. Directed physical exams are performed at Cycles 2, 3, 4, 6, 7, 8 and 11.  After Cycle 11, directed physical exams should occur once every 4 cycles (Cycles 15, 19, etc.). 
p. Following Cycle 8, the ECOG performance status should be determined only in conjunction with a protocol-specified full or directed physical exam (Cycle 9, 11, 13, 15, 17,
19 and every 2 cycles thereafter.
q. Tumor marker assessment is not an additional study-related laboratory evaluation.  The purpose is to collect information that may be a part of standard clinical assessment for
certain tumor types.  Data collection (if applicable and if available) should occur every 8 weeks initially (56 days ± 7 days) and after 6 months, assessments should be
performed every 12 weeks regardless of any treatment delays (i.e. Screening visit, Cycle 5, Cycle 9, Cycle 13 and then every 6 cycles (12 weeks) thereafter coinciding with
imaging visits).   Upon discontinuation, tumor marker data collection will occur at the same time as post-treatment imaging follow-up visits.  See Section 7.1.2.7 and Section
7.1.3.1 for additional details. 
r.   After documented local site assessed disease progression, or the start of new anticancer treatment; continuing subjects will be contacted approximately every 12 weeks by
telephone. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not
have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for their survival status (excluding subjects that have a death event
previously recorded).
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each
visit.  Individual trial procedures are described in detail below.  It may be necessary to
perform these procedures at unscheduled time points if deemed clinically necessary by the
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations
may require that additional informed consent be obtained from the subject.  In these cases,
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1 
7.1.1.1 Informed Consent
The investigator or qualified designee must obtain documented consent from each potential
subject or each subject’s legally acceptable representative prior to participating in a clinical
trialor 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.
7.1.1.4 Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history
will include all active conditions, and any condition diagnosed within the prior 10 years that
are considered to be clinically significant by the Investigator.  Details regarding the disease
for which the subject has enrolled in this study will be recorded separately and not listed as
medical history.
7.1.1.5 Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any
protocol-specified washout requirement, and record prior medication taken by the subject
within 28 days before starting the trial.  Treatment for the disease for which the subject has
enrolled in the study will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject
during the trial through the Safety Follow-up visit.  In addition, new medications started
during the Second Course Phase through the Second Course Safety Follow-up visit should be
recorded. 
All medications related to reportable SAEs and ECIs should be recorded as defined in
Section 7.2.
 
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7.1.1.6 Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease
status. 
7.1.1.6.2 Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including
systemic treatments, radiation and surgeries.
7.1.1.6.3 Subsequent Anti-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. 
7.1.1.7 Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify
the subject for all procedures that occur prior to randomization or allocation.  Each subject
will be assigned only one screening number.  Screening numbers must not be re-used for
different subjects. 
Any subject who is screened multiple times will retain the original screening number
assigned at the initial screening visit.
7.1.1.8 Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a
randomization number.  The randomization number identifies the subject for all procedures
occurring after treatment allocation.  This unique number is termed a randomization number
throughout the protocol for operational purposes. Once a randomization number is assigned
to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
7.1.1.9 Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between
pembrolizumab doses due to toxicity require consultation between the investigator and the
Sponsor and written documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff. 
The total volume of trial treatment infused will be compared to the total volume prepared to
determine compliance with each dose administered. 
 
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The instructions for preparing and administering pembrolizumab will be provided in the
Pharmacy Manual. 
Clinical Procedures/Assessments
7.1.2 
7.1.2.1 Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new
or worsening AEs as specified in the Trial Flow Chart (Section 6.0) and more frequently if
clinically indicated.  Adverse events will be graded and recorded throughout the study and
during the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). 
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading,
and action taken with regard to trial treatment.
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated
to determine if it is possibly an ECI of a potentially immunologic etiology (irAE) (See
Section 5.6.1.1). 
Please refer to Section 7.2 for detailed information regarding the assessment and recording of
AEs. 
7.1.2.2 Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the
screening period.  Clinically significant abnormal findings should be recorded as medical
history.  A full physical exam should be performed during Screening, at Cycle 5 and every 4
cycles thereafter (Cycle 9, 13, 17, etc.) per the Trial Flow Chart (Section 6.0).  After the first
dose of trial treatment new clinically significant abnormal findings should be recorded as
AEs.
7.1.2.2.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart (Section 6.0), the
investigator or qualified designee will perform a directed physical exam as clinically
indicated prior to the administration of the trial treatment (Cycles 1, 2, 3, 4, 6, 7, 8 and 11). 
After Cycle 11 directed physical exams should occur once every 4 cycles thereafter (Cycles
15, 19, etc.).  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 (Section 6.0).  Vital signs should include temperature, pulse, respiratory
rate, weight and blood pressure.  Height will be measured at screening only.
 
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7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) at
screening, prior to the administration of each dose of trial treatment and discontinuation of
trial treatment as specified in the Trial Flow Chart.  After Cycle 8 assessment of ECOG
status will be performed every other cycle in conjunction with the directed or full physical
exam.
7.1.2.5 Tumor Imaging and Assessment of Disease
Processes for image collection and transmission to the central vendor can be found in the Site
Imaging Manual (SIM).  Tumor imaging is strongly preferred to be acquired by computed
tomography (CT). Magnetic resonance imaging (MRI) should be used only when CT is
contraindicated or for imaging of the brain. The same imaging technique regarding modality
and the use of contrast should be used in a subject throughout the trial to optimize the
visualization of existing and new tumor burden.  Please refer to the SIM for guidance on
imaging parameters, required anatomic regions and modality options.
7.1.2.5.1 Assessment of Disease
RECIST 1.1 will be applied by the site as the primary measure for assessment of tumor
response and as a basis for all protocol guidelines related to disease status (e.g.,
discontinuation of study therapy). 
RECIST 1.1 will be adapted as follows to account for the unique tumor response seen in this
class of therapeutics. 
If imaging shows PD, tumor assessment should be repeated ≥4 weeks later in order to
confirm PD with the option of continuing treatment for clinically stable subjects as discussed
below in Table 6.
Clinically stable is defined by the following criteria: 
 Absence of signs and symptoms indicating disease progression
 No decline in ECOG performance status
 Absence of rapid progression of disease
 Absence of progressive tumor at critical anatomical sites (e.g., cord compression)
requiring urgent alternative medical intervention
 
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Table 6  Imaging and Treatment after 1st Radiologic Evidence of PD
Clinically Stable 
Clinically Unstable
Imaging 
Treatment 
Imaging 
Treatment
1 st radiologic 
evidence of PD  
Repeat imaging 
at 4 weeks to 
confirm PD  
May continue 
study treatment 
at the 
Investigator’s 
discretion while
awaiting
confirmatory
scan
Repeat imaging 
at 4 weeks to 
confirm PD if
possible
Discontinue
treatment
Repeat scan 
confirms PD  
No additional 
imaging required 
Discontinue 
treatment 
(exception noted
in Section
7.1.2.5.1)
No additional 
imaging required
N/A
Repeat scan 
shows SD, PR 
or CR  
Continue 
regularly 
scheduled 
imaging 
assessments 
every 8 weeks 
(after 6 months 
every 12 weeks) 
Continue study 
treatment at the 
Investigator’s 
discretion  
Continue 
regularly 
scheduled 
imaging 
assessments 
every 8 weeks 
(after 6 months 
every 12 weeks)
May restart study
treatment if
condition has
improved and/or
clinically stable
per Investigator’s
discretion
CR=completed response; N/A=not applicable; SD=stable disease; PD=progressive disease; PR=partial response
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).  Subjects that are deemed clinically unstable are not required to have repeat
imaging for confirmation. If radiologic progression is confirmed, then the subject will be
discontinued from trial treatment.  If radiologic progression is not confirmed, then the subject
should resume/continue trial treatment and have their next scan according to the every 8 or
12 weeks (56 or 84 ±7 days) schedule based on their on-treatment imaging frequency. 
NOTE:  If a subject with confirmed radiographic progression (i.e., 2 scans at least 28 days
apart demonstrating progressive disease) is clinically stable or clinically improved, and there
is no further increase in the tumor dimensions at the confirmatory scan, an exception may be
considered to continue treatment upon consultation with the Sponsor.  Clinically stable
subjects should also have at the confirmatory scan no further increase in the target lesions, no
unequivocal increase in non-target lesions, and no additional new lesions develop (non-
worsening PD) to continue study treatment.
Subjects who discontinue trial treatment in the First Course Phase, for reasons other than
disease progression, should continue tumor imaging using the same imaging schedule used
while on treatment (every 8 weeks (±7 days) in the first 6 months, and every 12 weeks
(±7 days) after Month 6) until the subject experiences confirmed disease progression or starts
a new anti-cancer therapy.  In the Second Course phase imagining assessments should be
 
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performed every 12 weeks (±7 days) until the subject experiences confirmed disease
progression or starts a new anti-cancer therapy. 
Local reading (investigator assessment with site radiology reading) based on RECIST 1.1
will be used to determine subject eligibility and for subject management.  Tumor imaging
and assessment per local standard of care should be performed for subject management, and
may include additional imaging (e.g. bone scan for subjects with  prostate cancer) and
appropriate tumor markers.  The Sponsor will also receive radiologic images for a
retrospective analysis of subject eligibility and treatment response to be performed by a
central vendor, which may include RECIST 1.1, RANO, PCWG2 tumor response.
7.1.2.5.2 Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the first dose of
trial treatment.  The site trial team must review screening images to confirm the subject has
measurable disease per RECIST 1.1.  The screening imaging scan must be submitted to the
central imaging vendor for a possible retrospective analysis of this eligibility criterion.
Scans performed as part of routine clinical management are acceptable for use as the
screening scan if they are of diagnostic quality and performed within 28 days prior to the first
dose of trial treatment.  The same imaging technique should be used in a subject throughout
the study. 
7.1.2.5.3 Tumor Imaging During Trial
Tumor imaging may be performed by CT or magnetic resonance imaging (MRI), but the
same imaging technique should be used in a subject throughout the trial.  Imaging should be
performed every 8 weeks (56 days ± 7 days) from the first dose of trial treatment or more
frequently if clinically indicated. After 6 months, imaging should be performed every
12 weeks (84 ± 7 days).  Imaging timing should follow calendar days and should not be
delayed for delays in cycle starts or withholding of pembrolizumab cycle intervals. 
Per RECIST 1.1, PR and CR  response should be confirmed by a repeat radiographic
assessment not less than 4 weeks from the date the response was first documented.  The
tumor imaging performed for confirmation of response may be performed at the earliest
4 weeks after the first indication of response, or at the next scheduled scan, whichever is
clinically indicated. 
Imaging should continue to be performed until documented disease progression, the start of
new anti-cancer treatment, withdrawal of consent, death, or the end of the study, whichever
occurs first.  Disease progression should be confirmed at least 4 weeks after the first scan
indicating progressive disease in clinically stable subjects.  Subjects who have unconfirmed
disease progression may continue on treatment until progression is confirmed provided they
have met the conditions detailed in Section 7.1.2.5.1.
 
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7.1.2.5.4 End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time
of treatment discontinuation (±4 week window).  If a previous scan was obtained within
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory.  In subjects who discontinue trial treatment due to documented disease
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every
effort should be made to continue monitoring their disease status by tumor imaging using the
same imaging schedule used while on treatment (every 8 weeks (±7 days) in  the first
6 months, and every 12 weeks (±7 days) after Month 6) until the start of a new anticancer
treatment, disease progression, death, or the end of the trial, whichever occurs first.
7.1.2.5.5 Second Course (Retreatment) Tumor Imaging
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab. 
Local reading (Investigator assessment with site radiology reading) will be used to determine
eligibility  and subject management.  Imaging should be submitted to the central imaging
vendor for retrospective review.
The first on-trial imaging assessment should be performed at 12 weeks (84  days ±7 days)
after the restart of treatment.  Subsequent tumor imaging should be performed every
12 weeks (84 days ±7 days), or more frequently if clinically indicated.
Per the modified RECIST 1.1 used in this protocol (Section 7.1.2.5.1), if tumor imaging
shows initial PD, tumor assessment should be repeated ≥4 weeks later in order to confirm PD
with the option of continuing treatment while awaiting radiologic confirmation of
progression.  Subjects who obtain a confirmation scan do not need to undergo scheduled
tumor imaging if it is 4 weeks later and may wait until the next scheduled imaging time point
if clinically stable.
Imaging should continue to be performed until disease progression, the start of a new
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever
occurs first.  Disease progression may be confirmed at least 4 weeks after the first tumor
imaging indicating PD in clinically stable subjects.
In subjects who discontinue trial treatment, tumor imaging should be performed at the time
of treatment discontinuation (±4 week window).  If a previous scan was obtained within
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not
mandatory.  In subjects who discontinue trial treatment due to documented disease
progression, this is the final required tumor imaging.
In subjects who discontinue trial treatment without documented disease progression, every
effort should be made to continue monitoring their disease status by radiologic imaging every
12 weeks (±7 days) until either the start of a new anticancer treatment, disease progression,
death, or the end of the trial, whichever occurs first.
 
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7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling
Enrollment in this study is limited to those subjects with tumors that are characterized as PD-
L1 positive by IHC.  Archived FFPE tumor sample or newly obtained core or excisional
biopsy (FNA not adequate) must be submitted for characterization at a central lab to
determine subject eligibility.  These samples are not required to be obtained within 28 days
of enrollment, however, a biopsy for screening purposes cannot be performed until the main
consent is signed.
Blood for correlative biomarker studies should be collected prior to Cycle 1, at Cycle 5 and
upon Discontinuation / End of Treatment.
Detailed instructions for tissue collection, process and shipment are provided in the
Procedures Manual.
7.1.2.7 Tumor Marker Assessment (Optional)
Tumor marker assessment is not an additional study-related laboratory evaluation.  The
purpose is to collect information that may be a part of standard clinical assessment for certain
tumor types.  Data collection (if applicable and if available) should occur every 8 weeks
(± 7 days) initially and after 6 months, assessments should be performed every 12 weeks
(± 7 days) regardless of any treatment delays (i.e., Screening visit, Cycle 5, Cycle 9, Cycle 13
and then every 6 cycles [12 weeks] thereafter coinciding with imaging visits).  Upon
discontinuation, tumor marker data collection will occur at the same time as post-treatment
imaging follow-up visits.
Table 7 shows tumor types that are commonly evaluated using markers.
Table 7  Tumor Markers and Associated Tumor Type
Tumor Type
Tumor Marker
ER Positive HER2 Negative
Breast Cancer
Cancer Antigen 15-3 (CA 15-3)
Cancer Antigen 27-29 (CA 27-29)
Carcinoid Tumors
Chromogranin A (CgA)
5-Hydroxyindoleacetic acid (5-HIAA) (24 hours in urine)
Colon or Rectal Adenocarcinoma 
Carcinoembryonic Antigen (CEA)
Neuroendocrine Carcinoma
Chromogranin A (CgA)
5-Hydroxyindoleacetic acid (5-HIAA) (24 hours in urine)
Ovarian 
Epithelial, 
Fallopian
Tube 
or 
Primary 
Peritoneal
Carcinoma 
Cancer Antigen 125 (CA-125)
Pancreas Adenocarcinoma 
Carbohydrate Antigen 19-9 (CA 19-9)
Prostate Adenocarcinoma 
Prostate-Specific Antigen (PSA)
Thyroid Cancer 
Thyroglobulin (Tg)
 
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Laboratory Procedures/Assessments
7.1.3 
Details regarding specific laboratory procedures/assessments to be performed in this trial are
provided below. The total amount of blood/tissue to be drawn/collected over the course of
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes
drawn/collected by visit and by sample type per subject can be found in the Procedures
Manual.  Refer to the Trial Flow Chart (Section 6.0) for the timing of laboratory assessments.
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 8.
 
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Table 8  Laboratory Tests
Hematology  
Chemistry  
Urinalysis 
Other
Hematocrit 
Albumin  
Blood 
Serum β-human Chorionic Gonadotropin a 
Hemoglobin  
Alkaline Phosphatase 
Glucose 
  (β-hCG) a 
Platelet Count 
Alanine Aminotransferase (ALT) 
Protein  
PT (INR)
White Blood Cell 
(Total and 
Differential)
Aspartate Aminotransferase (AST) 
Specific Gravity 
aPTT
Red Blood Cell Count 
Lactate Dehydrogenase (LDH) 
Microscopic Exam  
Total Triiodothyronine (T3) e 
Absolute Neutrophil Count 
Carbon Dioxide b
  (If abnormal results are noted) c 
Free Thyroxine (FT4)
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine Pregnancy Test a 
Thyroid Stimulating Hormone (TSH)
Uric Acid 
Blood for FBR
Calcium  
Blood for Correlative Studies
Chloride 
Cancer Antigen 15-3 (CA 15-3) d 
Glucose 
Carbohydrate Antigen 19-9 (CA 19-9) d 
Phosphorus 
Cancer Antigen 27-29 (CA 27-29) d 
Potassium  
Cancer Antigen 125 (CA-125) d 
Sodium  
Carcinoembryonic Antigen (CEA) d 
Magnesium  
Chromogranin A (CgA) d 
Total Bilirubin  
Prostate-Specific Antigen (PSA) d 
Direct Bilirubin (If total bilirubin is elevated 
above the upper limit of normal) 
Thyroglobulin (Tg) d 
5-Hydroxyindoleacetic acid (5-HIAA) d 
Total protein  
(24 hours in urine)
Blood Urea Nitrogen
Creatinine f
a. Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.  Pregnancy tests
(serum and/or urine) should be repeated if required by local guidance.
b.  If considered standard of care in your region.
c.   Institutional standards are acceptable.
d.  Tumor marker assessment is not an additional study-related laboratory evaluation.  The purpose is to collect information that may be a part of standard clinical assessment for
certain tumor types. 
e.   Free T3 may be performed in place of Total T3 per local standards
f.   GFR (measured or calculated) or CrClcan be used in place of creatinine.
Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 days prior to the first dose of
treatment.  After Cycle 1, in both the Initial Treatment Phase and the Second Course Phase, pre-dose laboratory procedures can be
conducted up to 72 hours prior to dosing unless otherwise noted on the flow charts. 
Laboratory results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of trial
treatment.
 
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7.1.3.2 Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically
sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to first dose
of trial treatment or retreatment.  Pregnancy tests (serum and/or urine tests) should be
repeated if required by local guidelines.  If a urine test is positive or not evaluable, a serum
test will be required.  Subjects must be excluded/discontinued from the trial in the event of a
positive or borderline-positive test result.
7.1.3.3 Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:
 Blood for genomics use
 Leftover archival tumor tissue or leftover newly obtained biopsy sample
 Leftover correlative blood samples
Other Procedures
7.1.4 
7.1.4.1 Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities
scheduled for the final trial visit should be performed at the time of discontinuation.  Any
adverse events which are present at the time of discontinuation/withdrawal should be
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and
Recording Adverse Events. Subjects who a) attain a CR or b) complete 24 months of
treatment with pembrolizumab 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 therapy, these subjects should return
to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to
the Follow-Up Period of the study (described in Section 7.1.5.4).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by
contacting the principal investigator for the main trial.  If medical records for the main trial
are still available, the investigator will contact the Sponsor using the designated mailbox
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to
obtain appropriate information to complete specimen withdrawal.  Subsequently, the
subject's specimens will be removed from the biorepository and be destroyed.  A letter will
be sent from the Sponsor to the investigator confirming the destruction. It is the
responsibility of the investigator to inform the subject of completion of destruction.  Any
analyses in progress at the time of request for destruction or already performed prior to the
request being received by the Sponsor will continue to be used as part of the overall research
trial data and results.   No new analyses would be generated after the request is received.
 
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In the event that the medical records for the main trial are no longer available (e.g., if the
investigator is no longer required by regulatory authorities to retain the main trial records) or
the specimens have been completely anonymized, there will no longer be a link between the
subject’s personal information and their specimens.  In this situation, the request for
specimen destruction 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 with the study
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:
• Laboratory equipment –as required for inclusion labs and trial assessments
• Imaging equipment –as required for study objectives
See protocol-specific Administrative Binder, Procedures Manual, Pharmacy Manual, and
SIM.
Visit Requirements
7.1.5 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1 Screening Period
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine
that they fulfill the entry requirements as set forth in Section 5.1.  Visit requirements are
outlined in Section 6.0 –Trial Flow Chart. 
Subjects that have an archival tumor biopsy sample may sign a prescreening consent for
characterization of PD-L1 status.  After providing prescreening consent, subjects will be
assigned a screening number. Subjects characterized with a PD-L1 positive tumor must
subsequently provide written consent for the main study prior to performing any protocol
specific procedure.  As noted in Section 7.2, AEs will NOT be collected for subjects during
this pre-screening period (for determination of archival tissue status) as long as that subject
has not undergone any protocol-specified procedure or intervention  beyond archive sample
collection for PD-L1 characterization. 
 
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Subjects that do not have an archival tumor biopsy sample available must provide written
consent for the main study before the newly obtained tumor biopsy or any other protocol-
specified procedures can occur.  After providing main study consent, subjects not already
provided a screening number will be assigned a screening number. 
Results of a test performed prior to the subject signing consent as part of routine clinical
management are acceptable in lieu of a screening test if performed within the specified time
frame.  Screening procedures are to be completed within 28 days prior to the first dose of
trial treatment except for the following:
 Laboratory tests are to be performed within 10 days prior to the first dose of trial
treatment
 For women ofreproductive 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)
 Tumor collection and PD-L1 characterization are not required to be completed within
28 days prior to the first dose of trial treatment
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu
of a repeat screening test if performed within the specified time frame and the
inclusion/exclusion criteria is met.
7.1.5.2 Treatment Period Visit
Visit requirements are outlined in the Trial Flow Chart (Section 6.0).  Specific procedure-
related details are provided in Section 7.1.
7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab with SD or better may be eligible for up to an additional
1 year ofpembrolizumab therapy if they progress after stopping MK-3745.  This retreatment
is termed the Second Course Phase of this study and is only available if the study remains
open and the subject meets the following conditions:
 Either
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and
 Was treated for at least 24 weeks with pembrolizumab before
discontinuing therapy, and
 Received at least 2 treatments with pembrolizumab beyond the date
when the initial CR was declared
 
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OR
o Subject had SD, PR or CR and stopped pembrolizumab treatment after
24 months of study therapy for reasons other than disease progression or
intolerability
AND
 Experienced an investigator-determined confirmed radiographic disease progression
by RECIST 1.1 after stopping their initial treatment with pembrolizumab, and
 No new anticancer treatment was administered after the last dose of trial treatment,
and
 The subject meets all of the safety parameters listed in the inclusion criteria and none
of the safety parameters listed in the exclusion criteria, and
 The trial is ongoing
Subjects who restart treatment will be retreated at the same dose frequency as when they last
received pembrolizumab.  Treatment will be administered for up to 1 additional year.
Visit requirements are outlined in Section 6.0 –Trial Flow Chart.
An objective response or disease progression that occurs during the Second Course Phase for
a subject will not be counted as an event for the primary analysis of either endpoint in this
trial.
7.1.5.3 Post-Treatment Visits
7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days
(±3 days) after the last dose of trial treatment or before the initiation of a new anti-cancer
treatment, whichever comes first.
All AEs and concomitant medications within 30 days of last dose of trial treatment,
regardless of when the Safety Follow-Up visit occurs should be recorded.  After day 30, all
SAEs and ECIs continue to be captured until 90 days after last dose of trial treatment or
before initiation of a new anti-cancer treatment, whichever comes first. 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.
Subjects who are eligible for retreatment with pembrolizumab (as described in Section
7.1.5.2.1) may have up to 2 safety follow-up visits, 1 after the Treatment Period and 1 after
the Second Course Phase.
 
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7.1.5.4 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression in the
First Course Phase will move into the Follow-Up Phase and should be assessed every
8 weeks (56 ±7 days) in the first 6 months, and every 12 weeks (±7 days) after Month 6, by
radiologic imaging to monitor disease status.  In the Second Course phase Follow-up
assessments should be performed every 12 weeks (±7 days).  Every effort should be made to
collect information regarding disease status until the start of new anti-cancer therapy, disease
progression, death, end of the study or if the subject begins retreatment with pembrolizumab
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 according to the criteria
in Section 7.1.5.2.1 will move from the follow-up phase to the Second Course Phase when
they experience disease progression.  Details are provided in Section 6.2 –Trial Flow Chart
for Retreatment. 
7.1.5.4.1 Survival Status
Once a subject experiences confirmed disease progression or starts a new anti-cancer
therapy, the subject moves into the Survival Follow-Up Phase and should be contacted by
telephone every 12 weeks (± 4 weeks) to assess for survival status until death, withdrawal of
consent, or the end of the study, whichever occurs first.
To ensure current and complete survival data is available at the time of database locks,
updated survival status may be requested during the course of the study by the Sponsor.  For
example, updated survival status may be requested prior to but not limited to an external Data
Monitoring Committee review, interim and/or final analysis. Upon Sponsor notification, all
subjects who do not/will not have a scheduled study visit or study contact during the Sponsor
defined time period will be contacted for their survival status (excluding subjects that have a
previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
7.2 
An adverse event is defined as any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and which does not necessarily
have to have a causal relationship with this treatment. An adverse event can therefore be any
unfavourable and unintended sign (including an abnormal laboratory finding, for example),
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in
frequency and/or intensity) of a preexisting condition that is temporally associated with the
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in
frequency or severity from expected levels are not to be considered adverse events. 
 
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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 the course of the use of the Sponsor's product in clinical
trials or within the follow-up period specified by the protocol, or prescribed in clinical
practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.
Adverse events may also occur in screened subjects during any pre-allocation baseline period
as a result of a protocol-specified intervention, including washout or discontinuation of usual
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event unless it is
considered to be drug related by the investigator.
All adverse events will be recorded from the time the consent form is signed through 30 days
following cessation of treatment and at each examination on the Adverse Event case report
forms/worksheets.  The reporting timeframe for adverse events meeting any serious criteria is
described in section 7.2.3.1.
Adverse events will not be collected for subjects during the pre-screening period (for
determination of archival tissue status) as long as that subject has not undergone any
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the
7.2.1 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed
dose for pembrolizumab by 20% over the prescribed dose. No specific information is
available on the treatment of overdose of pembrolizumab. In the event of overdose,
pembrolizumab should be discontinued and the subject should be observed closely for signs
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken
without any associated clinical symptoms or abnormal laboratory results, the overdose is
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental
or intentional overdose without adverse effect.”
 
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All reports of overdose with and without an adverse event must be reported within 24 hours
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of
investigators or their designees to report any pregnancy or lactation in a subject
(spontaneously reported to them) that occurs during the trial or within 120 days of
completing the trial, or 30 days following cessation of treatment if the subject initiates new
anticancer therapy, whichever is earlier.  All subjects who become pregnant must be
followed to the completion/termination of the pregnancy.  Pregnancy outcomes of
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal
death, intrauterine death, miscarriage and stillbirth must be reported as serious events
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or
equivalent).
Immediate Reporting ofAdverse Events to the Sponsor
7.2.3 
7.2.3.1 Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose;
●
Is an other important medical event
Refer to Table 9 for additional details regarding each of the above criteria.
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 from the time the consent is signed through 90
days following cessation of treatment, or 30 days following cessation of treatment if the
subject initiates new anticancer therapy, whichever is earlier, whether or not related to the
Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic
media or paper.  Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
 
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Additionally, any serious adverse event, considered by an investigator who is a qualified
physician to be related to the Sponsor's product that is brought to the attention of the
investigator at any time outside of the time period specified in the previous paragraph also
must be reported immediately to the Sponsor. 
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 recorded as such on the Adverse Event case report forms/worksheets and
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).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with
clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require
an additional evaluation for an underlying etiology.  The trial site guidance for
assessment and follow up of these criteria can be found in the Investigator Trial File
Binder (or equivalent).
3. Additional adverse events:
irAEs as defined in Section 5.2.1.2. 
ECIs (both non-serious and serious adverse events) 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
 
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symptoms indicate a possible irECI, 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, unless there is
evidence suggesting a causal relationship between the drug and the event.  Any such event
will be submitted to the Sponsor within 24 hours either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is
not progression of the cancer under study will be forwarded to global safety as a SAE within
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
7.2.4 
An investigator who is a qualified physician will evaluate all adverse events according to the
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event
which changes CTCAE grade over the course of a given episode will have each change of
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
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Table 9  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 subject’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) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 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 
test drug 
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 there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in
accordance with all applicable global laws and regulations.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after
the study has begun, changes are made to primary and/or key secondary hypotheses, or the
statistical methods related to those hypotheses, then the protocol will be amended (consistent
with International Conference on Harmonisation  (ICH) Guideline E-9).  Changes to
exploratory or other non-confirmatory analyses made after the protocol has been finalized,
along with an explanation as to when and why they occurred, will be listed in the Clinical
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in
the CSR.  No separate Statistical Analysis Plan (SAP) for the primary, secondary and
exploratory endpoints will be issued for this study, however, a separate molecular profiling
analysis plan will be developed to explicitly address exploratory biomarker objectives.
Statistical Analysis Plan Summary
8.1 
This section contains a brief summary of the statistical analyses for this trial. Full detail is in
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analyses
8.1.1 
The primary and key secondary endpoints, primary analysis population, and statistical
methods that will be employed for the efficacy analyses are presented in Table 10 below  .
The primary hypothesis will be evaluated separately in each disease indication by evaluating
best ORR by RECIST 1.1.  A sequential monitoring approach will be used following the time
that a minimum of 6 subjects have had at least 1 post-baseline scan in each indication.
The Type-I error rate over the multiple evaluations within an indication will be controlled by
the truncated sequential probability ratio test procedure at 0.08 (1-sided) [32]. 
 
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Table 10  Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Timepoint)
Statistical Method
Analysis
Population
Missing Data
Approach
Primary Hypothesis #1:
Best ORR by RECIST 1.1 in each
disease indication
Truncated sequential
probability  ratio test
[32]
Full Analysis Set
(FAS)
Missing
observation
counted as non-
responder
Secondary Objectives –Within Indication
PFS
Summary 
statistics
using 
Kaplan-Meier
method 
FAS
Censored at last
assessment
OS
Kaplan-Meier method 
FAS
Censored at last
assessment
DOR
Summary 
statistics
using 
Kaplan-Meier
method 
All responders
Non-responders
are excluded in
analysis
Safety Analyses
8.1.2 
The All-Subjects-as-Treated population will be employed for safety analyses.  Immune
related adverse experiences are prespecified as events of interest. 
Power and Sample Size
8.1.3 
Within each indication, the study will enroll a minimum of 6 subjects.  Following the time
that at least 6 subjects have had at least 1 post-baseline response assessment, a sequential
monitoring procedure will be used to evaluate for efficacy and futility simultaneously based
on the number of subjects with a confirmed or unconfirmed response according to the rules
outlined in Figure 2, Table 11, and Table 12. 
Depending on the enrollment rate, it is possible that more than 6 subjects may be enrolled
prior to the first evaluation of efficacy or futility.  Enrollment is expected to be continuous
and will not be held within an indication. 
Once at least 6 subjects are evaluable for confirmed or unconfirmed response, subsequent
rules for pausing enrollment and future evaluations will be based on the boundaries identified
by the sequential monitoring procedure.  Approximately 22 subjects will be enrolled in each
indication.  The total sample size is approximately 440 subjects. Further details are provided
in Section 8.2.7. 
With 22 subjects per indication, this study provides 80% power to demonstrate that the best
ORR induced by pembrolizumab exceeds 10% at an overall one-sided 8% alpha-level, if the
true best ORR within an indication is 35%.  The underlying treatment effect is regarded as
clinically important in each of the indications studied. The calculation is based on the
 
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binomialSPRT function in the gsDesign package and is carried out using R. The minimum
criterion for success is that the lower bound of the repeated CI > 10%  [33]. Given the
underlying true rate, this may occur when at least 6/22 subjects develop a response.  Further
details are provided in Section 8.2.7.
Figure 2  Sequential Monitoring Rules for Efficacy and Futility
 
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Table 11 Decision Rules Based on Efficacy Bounds
Monitoring Point (# Subjects)
Minimum # Responders to Start Future
Study Planning
6-7
3
8-12
4
13-17
5
18-22*
6
23-26
7
27-30
8
Design assumes overall Type I error of 8% (1-sided) and 80% power.
*Success at the final analysis requires ≥6/22 subjects with a response.
Table 12  Decision Rules Based on Futility Bounds
Monitoring Point (# Subjects)
Maximum # Subjects with Response to
Declare Futility
6-9
0
10-14
1
15-19
2
20-24*
3
25-28
4
29-30
5
Design assumes overall Type I error of 8% (1-sided) and 80% power.
*Success at the final analysis requires ≥6/22 subjects with a response.
Interim Analysis
8.1.4 
Multiple interim analyses may be performed in this study due to the sequential design of the
trial.  Results will be reviewed by the study team.  The endpoint(s), timing, and purpose of
the interim analysis are summarized in the Table 13.  The decision rule and other statistical
details are further described in Section 8.2.9.
 
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Table 13  Summary of Interim Analysis Strategy
Key Endpoints for
Interim Analysis
Timing of
Interim Analysis
Purpose of
Interim Analysis
Objective response rate
(confirmed or
unconfirmed)
Sequential monitoring
approach
 Stop for futility
 Go to future study
planning
Statistical Analysis Plan
8.2 
Responsibility for Analyses/In-House Blinding
8.2.1 
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
This trial is being conducted as an open-label study, i.e., subjects, investigators, and Sponsor
personnel will be aware of subject treatment assignments after each subject is enrolled and
treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study
treatment assignment.  Allocation will be implemented in an interactive voice response
system (IVRS).
Hypotheses/Estimation
8.2.2 
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.2.3 
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment
differences are listed below, followed by the descriptions of the derivations of selected
endpoints.
8.2.3.1 Efficacy Endpoints
Efficacy endpoints that will be evaluated for are listed below, followed by the descriptions of
the derivations of selected endpoints.
The primary efficacy endpoint is best ORR, defined as the proportion of subjects in the
analysis population who have CR or PR  based on assessments by the investigator, and
confirmed per RECIST 1.1 at any time during the study.  Response for the primary analysis
will be determined by the investigator assessment, and a confirmation assessment is required
per RECIST 1.1. 
Secondary efficacy endpoints include: (1) DOR, defined as time from first RECIST 1.1
response to disease progression in subjects who achieve a PR or better based on assessments
by the investigator, and confirmed per RECIST 1.1; (2) PFS, defined as the time from
allocation to the first documented disease progression based on assessments by the
 
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investigator, and confirmed per RECIST 1.1 or death due to any cause, whichever occurs
first; and (3) OS, defined as the time from first dose of trial medication to the time of death
due to any cause. 
Additional supportive analyses of best ORR, DOR, and PFS will be conducted using
modified RECIST 1.1 criteria, in which a confirmation assessment of disease progression
must be obtained at least 4 weeks after the initial disease assessment indicating progressive
disease. 
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 pembrolizumab, including SAEs and ECIs. Immune related adverse experiences
(irAEs) are prespecified as events of interest.  Other safety endpoints include laboratory
safety assessments, ECOG performance status, vital signs and physical examinations.
Analysis Populations
8.2.4 
8.2.4.1 Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of efficacy data in
this study.  The FAS population consists of all subjects within each indication who:
 Receive at least 1 dose of study treatment, and
 Have a baseline scan with measurable disease per RECIST 1.1
Subjects will be included in the treatment group to which they are allocated for the analysis
of efficacy data.  Details on the approach to handling missing data are provided in Section
8.2.5, Statistical Methods.
8.2.4.2 Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in
this study.  The ASaT  population consists of all allocated subjects who received at least 1
dose of study treatment.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of
study treatment is required for inclusion in the analysis of each specific parameter.  To assess
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section
8.2.5, Statistical Methods.
 
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Statistical Methods
8.2.5 
Statistical testing and inference for safety analyses are described in 8.2.5.2. Efficacy results
that will be considered to be statistically significant after consideration of the strategy for
controlling the Type I error are described in Section 8.2.6, Multiplicity. Nominal p-values
may be computed for other efficacy analyses as a measure of strength of association between
the endpoint and the treatment effect rather than formal tests of hypotheses.  Unless
otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level.
8.2.5.1 Statistical Methods for Efficacy Analyses
Efficacy will be evaluated separately in each cohort.  For the primary efficacy endpoint
investigator assessed RECIST 1.1 best ORR, the point estimate, repeated confidence interval,
and adjusted p-value for testing the RECIST 1.1 response rate is greater than 10% for each
disease indication will be provided using a truncated sequential probability ratio test [32],
which is a specific instance of an exact binomial group sequential design for a single arm
trial with a binary outcome. Subjects in the primary analysis population (FAS) without
response data will be counted as non-responder.  Interim decisions may be made based on
confirmed or unconfirmed response assessments (see Sections 8.2.7 and 8.2.9). However, the
final analysis (if enrollment in a given indication expands to 22 subjects) will require a
confirmation assessment for all subjects who develop a CR or PR.
For PFS endpoint, Kaplan-Meier (KM) curves and median estimates from the KM curves
will be provided as appropriate. Subjects without efficacy evaluation data or without survival
data will be censored at Day 1.
 
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Table 14 summarizes the key efficacy analyses.
Table 14  Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Primary vs.
Supportive
Approach  
†
Statistical Method 
Analysis
Population
Missing Data
Approach
Primary Hypothesis #1 –Within Indication
Best ORR using RECIST 1.1
by site radiology assessment
(each disease indication
evaluated separately)
P
Truncated sequential
probability test
FAS
Subjects with
missing data are
considered non-
responders
Best ORR using modified
RECIST 1.1  by site radiology
assessment (each disease
indication evaluated
separately)
S
Truncated sequential
probability test 
FAS
Subjects with
missing data are
considered non-
responders
Secondary Endpoints/Objectives–Within Indication
PFS using RECIST 1.1 criteria
by site assessment
P 
Summary statistics
using Kaplan-Meier
method 
FAS
Censored at last
assessment
PFS using modified RECIST
1.1 criteria by site assessment 
S
Summary statistics
using Kaplan-Meier
method 
FAS
Censored at last
assessment
OS  
P 
Kaplan-Meier method 
FAS
Censored at last
assessment
DOR by site assessment 
P
Summary statistics
using Kaplan-Meier
method 
All
responders
Non-responders
are excluded in
analysis
Duration of modified RECIST
1.1 response (DOR) by site
assessment 
S
Summary statistics 
using Kaplan-Meier 
method 
All modified
RECIST 1.1
responders
Non-responders
are excluded in
analysis
  † P=Primary approach; S=Secondary approach.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints is
described in Section 8.2.6, Multiplicity and Section 8.2.9, Interim Analyses.
8.2.5.2 Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, laboratory tests, and vital signs.  Safety summaries will be pooled across all indications.
Immune related adverse experiences are prespecified as events of interest.  These events will
be summarized in separate tables from other AEs by toxicity grade and will include the
counts, percentage, and 95% CI.  Any AE of unknown etiology associated with
pembrolizumab exposure will be evaluated to determine if it is possibly an ECI of a
potentially immunologic etiology (irECI). Other ECIs listed in Section 7.2.3.2 will also be
summarized in the same manner as irAEs.
 
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Adverse experiences (specific terms as well as system organ class terms) and predefined
limits of change in laboratory, and vital sign parameters that are not pre-specified as events
of interest will be summarized with descriptive statistics (counts, percentage, mean, standard
deviation, etc.).
Continuous measures such as changes from baseline in laboratory, and vital signs parameters
that are not pre-specified as events of interest will be summarized using descriptive statistics
(mean, standard deviation, etc.) for baseline, on-treatment, and change from baseline values. 
8.2.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.3.1 Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs for each
indication.  No statistical hypothesis tests will be performed on these characteristics.  The
number and percentage of subjects screened, allocated, the primary reasons for screening
failure, and the primary reason for discontinuation will be displayed.  Demographic variables
(e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and
concomitant therapies will be summarized by treatment either by descriptive statistics or
categorical tables.
Multiplicity
8.2.6 
The false positive rate for testing the primary efficacy endpoint in each disease indication is
controlled at 0.08 (1-sided) for each cohort.  No additional multiplicity adjustment is required
because each disease indication will be evaluated independently.
Sample Size and Power Calculations
8.2.7 
Efficacy
Within each indication, the study will enroll a minimum of 6 subjects.  Following the time
that at least 6 subjects have had at least 1 post-baseline response assessment, a sequential
monitoring procedure will be used to evaluate for efficacy and futility simultaneously based
on the number of subjects with a confirmed or unconfirmed response according to the rules
outlined in Figure 2, Table 11, and Table 12. 
Enrollment will not be suspended at 6 subjects for the initial evaluation of efficacy.
Once at least 6 subjects are evaluable for confirmed or unconfirmed response, subsequent
rules for pausing enrollment and future evaluations will be based on the boundaries identified
by the sequential monitoring procedure.  If 0 out of the first 6 subjects with a post-baseline
evaluation have a confirmed or unconfirmed response following the first post-baseline
assessment, then enrollment will be paused in that indication.  The first 6 subjects and any
additional subjects enrolled up to the time that the first 6 subjects are evaluated will continue
to be followed for response.  If the required number of subjects subsequently  develop a
confirmed or unconfirmed response to continue enrollment according to Figure 2, Table 11,
and Table 12, then enrollment may resume in that indication.  If ≥1 of the first 6 subjects
with a post-baseline evaluation have a confirmed or unconfirmed response, then enrollment
 
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will continue.  Depending on the enrollment rate, additional monitoring may be performed
according to the boundaries defined in Figure 2, Table 11, and Table 12 until approximately
22 subjects is enrolled within an indication.
If at any time during the trial, the efficacy boundary is crossed for a given indication,
enrollment will continue to 22 subjects and subsequent trial planning may be initiated.
If enrollment within an indication is so rapid that 22 subjects are assigned a screening slot for
potential enrollment at the time that the first 6 subjects are evaluable for response, then no
sequential monitoring will be performed.  If enrollment within an indication is so slow that a
cohort is unlikely to complete within a reasonable amount of time, a cohort may be closed
(e.g. low prevalence of PD-L1 such that fewer than 3 PD-L1 positive subjects are enrolled
within a cohort after approximately 6 months of screening activity from all sites).
With an approximate maximum of 22 subjects enrolled within each indication, the study
provides 80% power to demonstrate that the best ORR induced by pembrolizumab exceeds
10% at an overall one-sided 8% alpha-level, if the true best ORR  is 35%.  The null
hypothesis of 10% is based on the assumption that the population for each indication is
expected to consist of subjects with incurable solid tumors that have failed multiple lines of
standard therapy.  The best ORR for the limited treatment options available in these subject
populations is generally <10%.  The alternative best ORR is determined to be a clinically
meaningful improvement over other standard treatment options within each studied
indication. The calculation is based on the binomialSPRT function in the gsDesign package
and is carried out using R assuming a null best ORR of 10%, an alternative best ORR of
35%, type I error of 0.08 and type II error of 0.2 (binomialSPRT  (p0=0.1, p1=0.35,
alpha=0.08, beta=0.2, minn=6, maxn=22)).
For the final analysis, the response assessment will be based on confirmed best ORR. The
adjusted p-value and repeated confidence interval will be computed using sequential methods
outlined by Jennison and Turnbull (2000) [33].  The minimum criterion for success is that the
lower bound of the adjusted CI > 10%. Given the underlying true rate, this may occur when
at least 6/22 subjects develop a confirmed PR or CR.  Table 15 summarizes the power under
various assumptions.
If the optional exploratory efficacy objective of best ORR per RECIST 1.1 based on central
radiology review, best ORR per RANO criteria (GBM cohort), or best ORR per PCWG2
(prostate cancer cohort) is evaluated in an indication, and if fewer than 22 subjects in the
respective indication have centrally confirmed measurable disease at baseline in that
indication, then additional subjects may be enrolled to ensure that at least 22 subjects with
centrally confirmed measurable disease are evaluable for the applicable central radiologist
response assessment.
 
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Table 15  Operating Characteristics of the Sequential Monitoring Approach
True Response Rate
(RR)
Probability of
Stopping for Futility
Probability of Go
at end of Study
Average Sample
Size
10%
0.92
0.05
9.9
15%
0.76
0.15
12.6
20%
0.57
0.31
15.2
25%
0.39
0.50
17.3
30%
0.25
0.67
18.9
35%
0.14
0.80
20.1
40%
0.08
0.89
20.9
45%
0.04
0.95
21.4
50%
0.02
0.97
21.7
Because the sample size within each indication is 22 subjects (assuming no additional
subjects needed for the optional exploratory objective evaluation) the sample size for the
entire study is approximately 440 subjects. 
Safety
The probability of observing at least 10 subjects with a Grade 3-5 immune related in this
study depends on the number of subjects treated and the underlying percentage of subjects
with irAEs in the study population. If the underlying incidence of Grade 3-5 irAE is 10%,
there is a 77% chance of observing at least 10 subjects with irAEs among the minimum 120
subjects enrolled in the study across all indications, whereas if the underlying incidence is
5% there is a 7.8% chance of observing at 10 occurrences or irAEs. Table 16 provides the
point estimate and 95% CI for the underlying percentage of subjects with irAEs given
various hypothetical numbers of subjects with irAEs and sample size across indications.
 
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Table 16  Point Estimate and 95% CI for Hypothetical Number of Subjects with a
Grade 3-5 irAE
Number of Subjects 
with Grade 3-5 irAE 
Number of
Subjects 
Point Estimate 
95% CI†
10 
120 
8.3%  
(4.1%, 14.8%)
15 
120 
12.5% 
(7.2%, 19.8%)
20 
120 
16.7%  
(10.5%, 24.6%)
10 
220 
4.5%  
(2.2%, 8.2%)
15 
220 
6.8%  
(3.9%, 11.0%)
20 
220 
9.1%  
(5.6%, 13.7%)
10 
320 
3.1%  
(1.5%, 5.7%)
15 
320 
4.7%  
(2.6%, 7.6%)
20 
320 
6.3%  
(3.9%, 9.5%)
10 
440 
2.3%  
(1.1%, 4.1%)
15 
440 
3.4%  
(1.9%, 5.6%)
20 
440 
4.5%  
(2.8%, 6.9%)
† Based on the 2-tailed exact confidence interval of a binomial proportion
(Clopper and Pearson, 1934) [34].
Subgroup Analyses and Effect of Baseline Factors
8.2.8 
No subgroup analysis is planned.
Interim Analyses
8.2.9 
Multiple interim analyses may be performed in this study due to the sequential design of the
trial.  Results will be reviewed by the study team.  The primary best ORR endpoint will be
used for all interim decision-making with or without a confirmation assessment; however, a
confirmation assessment is required for the final best ORR analyses after 22 subjects are
enrolled in a cohort. For purpose of interim monitoring, subjects who are still on study but
without a post baseline scan will be excluded from the analyses specified in Table 14. The
decision rule and other statistical details are further described in Section 8.2.7.
Compliance (Medication Adherence)
8.2.10 
A day within the study will be considered an On-Therapy day if the subject receives the
study medication infusion. The number of Days Should be on Therapy is the total number of
days from the first day of study medication to the date of the last dose of study medication.
For each subject, percent compliance will then be calculated using the following formula:
x 100
Summary statistics will be provided on percent compliance by treatment group for the FAS
population.
Therapy
on 
be
  
Should
  
Days
of
Number 
Therapy
on 
Days
of
Number 
  
Compliance 
Percent  

 
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Extent of Exposure
8.2.11  
Extent of Exposure for a subject is defined as number of cycles in which the subject receives
the study medication infusion. Summary statistics will be provided on Extent of Exposure for
ASaT population.
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL
SUPPLIES
Investigational Product
9.1 
The investigator shall take responsibility for and shall take all steps to maintain appropriate
records and ensure appropriate supply, storage, handling, distribution and usage of
investigational product in accordance with the protocol and any applicable laws and
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 17.
Table 17 Product Descriptions
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/4 mL
Solution for Infusion
Packaging and Labeling Information
9.2 
Clinical supplies will be affixed with a clinical label in accordance with regulatory
requirements.
Vials will be provided in an open label fashion for subject dosing.
Clinical Supplies Disclosure
9.3 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or
designee are not blinded. Treatment (name, strength or potency) is included in the label text;
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4 
Clinical supplies must be stored in a secure, limited-access location under the storage
conditions specified on the label. 
Receipt and dispensing of trial medication must be recorded by an authorized person at the
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
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Returns and Reconciliation
9.5 
The investigator is responsible for keeping accurate records of the clinical supplies received
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the
amount remaining at the conclusion of the trial.
For all trial sites, the local country Sponsor personnel or designee will provide appropriate
documentation that must be completed for drug accountability and return.
Standard Policies
9.6 
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
10.1 
Confidentiality of Data
10.1.1 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to
the investigator by the Sponsor will be maintained in confidence, and such information will
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar
or expert committee; affiliated institution and employees, only under an appropriate
understanding of confidentiality with such board or committee, affiliated institution and
employees.  Data generated by this trial will be considered confidential by the investigator,
except to the extent that it is included in a publication as provided in the Publications section
of this protocol.
Confidentiality of Subject Records
10.1.2 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative),
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in
order to verify worksheet/case report form data.  By signing the consent form, the subject
agrees to this process.  If trial documents will be photocopied during the process of verifying
worksheet/case report form information, the subject will be identified by unique code only;
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in
connection with this trial in accordance with all applicable privacy laws, rules and
regulations.
 
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Confidentiality of Investigator Information
10.1.3 
By signing this protocol, the investigator recognizes that certain personal identifying
information with respect to the investigator, and all subinvestigators and trial site personnel,
may be used and disclosed for trial management purposes, as part of a regulatory
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other
countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included
when reporting certain serious adverse events to regulatory authorities or to other
investigators.  By signing this protocol, the investigator expressly consents to these uses and
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor
may share an investigator’s name and contact information with other participating
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4 
The Sponsor is required to record the name and address of each IRB/IEC member that
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC
meets regulatory and ICH GCP requirements by requesting and maintaining records of the
names and qualifications of the IRB/IEC members and to make these records available for
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2 
Financial Disclosure requirements are outlined in the US Food and Drug Administration
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the
Sponsor's responsibility to determine, based on these regulations, whether a request for
Financial Disclosure information is required.  It is the investigator's/subinvestigator's
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by
 
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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
10.3 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and
diligent manner and in conformance with this protocol; generally accepted standards of Good
Clinical Practice (e.g., International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice:
Consolidated Guideline and other generally accepted standards of good clinical practice); and
all applicable federal, state and local laws, rules and regulations relating to the conduct of the
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory
authority inspection of trial-related documents and procedures and provide for direct access
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or
from government programs for procedures included as part of the trial reimbursed to the
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in
compliance with Good Clinical Practice standards and applicable federal, state and local
laws, rules and regulations; and, for each subject participating in the trial, provide all data,
and, upon completion or termination of the clinical trial, submit any other reports to the
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator
upon request and also shall be made available at the trial site upon request for inspection,
copying, review and audit at reasonable times by representatives of the Sponsor or any
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This
documentation includes, but is not limited to, the protocol, worksheets/case report forms,
advertising for subject participation, adverse event reports, subject source data,
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s
 
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curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or
quality control procedures and laboratory director curriculum vitae.  By signing this protocol,
the investigator agrees that documentation shall be retained until at least 2 years after the last
approval of a marketing application in an ICH region or until there are no pending or
contemplated marketing applications in an ICH region or until at least 2 years have elapsed
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is
anticipated that the retention period can be up to 15 years or longer after protocol database
lock. The Sponsor will determine the minimum retention period and notify the investigator
when documents may be destroyed.  The sponsor also recognizes that documents may need
to be retained for a longer period if required by local regulatory requirements. All trial
documents shall be made available if required by relevant regulatory authorities. The
investigator must consult with and obtain written approval by the Sponsor prior to discarding
trial and/or subject files. 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s
primary physician about the subject’s participation in the trial if the subject has a primary
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator
will immediately disclose in writing to the Sponsor if any person who is involved in
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating
investigator for a multi-center trial (including multinational).  When more than one trial site
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national
principal coordinator (Protocol CI), responsible for coordinating the work of the principal
investigators at the different trial sites in that Member State, according to national
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In
addition, the Sponsor must designate a principal or coordinating investigator to review the
trial report that summarizes the trial results and confirm that, to the best of his/her
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the
anticipated review process, thorough understanding of clinical trial methods, appropriate
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must
be a participating trial investigator.
 
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Compliance with Trial Registration and Results Posting Requirements
10.4 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely
responsible for determining whether the trial and its results are subject to the requirements
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials.
Information posted will allow subjects to identify potentially appropriate trials for their
disease conditions and pursue participation by calling a central contact number for further
information on appropriate trial locations and trial site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5 
By signing this protocol, the Sponsor agrees to be responsible for implementing and
maintaining a quality management system with written development procedures and
functional area standard operating procedures (SOPs) to ensure that trials are conducted and
data are generated, documented, and reported in compliance with the protocol, accepted
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and
regulations relating to the conduct of the clinical trial.
Data Management
10.6 
The investigator or qualified designee is responsible for recording and verifying the accuracy
of subject data.  By signing this protocol, the investigator acknowledges that his/her
electronic signature is the legally binding equivalent of a written signature.  By entering
his/her electronic signature, the investigator confirms that all recorded data have been
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be
provided separately.
Publications
10.7 
This trial is intended for publication, even if terminated prematurely. Publication may include
any or all of the following: posting of a synopsis online, abstract and/or presentation at a
scientific conference, or publication of a full manuscript.  The Sponsor will work with the
authors to submit a manuscript describing trial results within 12 months after the last data
become available, which may take up to several months after the last subject visit in some
cases such as vaccine trials.  However, manuscript submission timelines may be extended on
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees
to delay publication of the trial results until the Sponsor notifies the investigator that all
relevant regulatory authority decisions on the trial drug have been made with regard to
 
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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
the trial and writing, as discussed above. The first author is responsible for defending the
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or
presentations regarding this trial 45 days prior to submission for publication/presentation.
Any information identified by the Sponsor as confidential must be deleted prior to
submission; this confidentiality does not include efficacy and safety results. Sponsor review
can be expedited to meet publication timelines.
 
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11.0 LIST OF REFERENCES
[1] 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[2] 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune
evasion. Nat Med 2002;8(8):793-800.
[3] 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol
2002;2(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(3):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 is expressed by tumor-infiltrating immune cells and is associated with poor outcome
for patients with renal cell carcinoma. Clin Cancer 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(3-4):373-400.
[8] 
Usubütün A, Ayhan A, Uygur MC, Özen 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 lymphocyte 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(1B):689-94.
[12] 
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al.
Type, density, and location of immune cells within human colorectal tumors predict
clinical outcome. Science 2006;313(5795):1960-4.
[13] 
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular
biology. Int J Clin Oncol 2010;15(6):544-51.
 
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[14] 
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case.
Tumori 2008;94(3):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 Oncol.
2009 Sep;10(9):840-1.
[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(1):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(3):449-59.
[20] 
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of
positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar
6;191(5):891-8.
[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 Int 2011;107(9):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(3):318-24.
[23] 
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al.
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting
chemotherapy for the treatment of patients with refractory metastatic melanoma. J
Clin Oncol 2005;23(10):2346-57.
[24] 
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J
Med 2008;358(25):2698-703.
 
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[25] 
Pölcher 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(6):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. Proc Natl Acad Sci U S A
2001;98(24):13866-71.
[27] 
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol
2005;23:515-48.
[28] 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al.
Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J
Med. "in press" 2012.
[29] 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
Eur J Cancer 2009;45(2):228-47.
[30] 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E., et
al. Updated response assessment criteria for high-grade gliomas: Response assessment
in neuro-oncology working group. J Clin Oncol 2010;28(11):1963-72.
[31] 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger
MA, et al. Design and end points of clinical trials for patients with progressive
prostate cancer and castrate levels of testosterone: Recommendations of the prostate
Cancer clinical trials working group. J Clin Oncol 2008;26(7):1148-59.
[32] 
Romeu, JL. Understanding Binomial Sequential Testing. Statistical Confidence,
Reliability Information Analysis Center (RIAC START). Department of Defense
United States of America, 2013.
[33] 
Jennison C, Turnbull BW. Analysis following a sequential test. In: Group Sequential
Methods with Application to Clinical Trials. Boca Raton, FL: Chapman & Hall/CRC,
2000:171-81.
[34] 
Clopper CJ, Pearson ES. The use of confidence or Fiducial limits illustrated in the
case of the binomial. Biometrika 1934;26(4):404-13.
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1 
Merck*
Code of Conduct for Clinical Trials
I. Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine
subject preferences, etc. 
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud,
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary,
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and
data disclosed accordingly.
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial,
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to
defend the trialresults and conclusions.  Merck funding of a trialwill 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, trialparticipation. 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 trialprotocol, and in signing
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
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Collection and Management of Specimens for Future Biomedical Research
12.2 
1. Definitions
a.Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a
sign of a normal or abnormal process or of a condition or disease.  A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics
as related to drug/vaccine response.2
c. Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e. RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA and blood 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 blood 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
12.3 
IRBs/IECs and Investigational Site Staff
 
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ECOG Performance Status
12.4 
Grade 
Description
0
Normal activity. Fully active, able to carry on all pre-disease
performance without restriction.
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity,
but ambulatory and able to carry out work of a light or sedentary nature
(e.g., light housework, office work).
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but
unable to carry out any work activities. Up and about more than 50% of
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair.
5
Dead.
*As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group,
Robert Comis M.D., Group Chair.
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.5 
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.
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For
12.6 
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:
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al.  New
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1).
Eur J Cancer 2009;45(2):228-47.
 
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Updated Response Assessment Criteria for High-Grade Gliomas: Response
12.7 
Assessment in Neuro-Oncology Working Group
RANO criteria* will be used in this study to retrospectively confirm RECIST 1.1
response activity in GBM subjects using central review.  While either CT or MRI may
be utilized, as per RANO criteria, MRI is the preferred imaging technique for this
cohort.
*As published in the Journal of Clinical Oncology:
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E., et al.
Updated response assessment criteria for high-grade gliomas: Response assessment in
neuro-oncology working group. J Clin Oncol 2010;28(11):1963-72.
 
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Design and End Points of Clinical Trials for Patients With Progressive Prostate
12.8 
Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate
Cancer Clinical Trials Working Group
PCWG2 criteria* will be used in this study to retrospectively confirm RECIST 1.1
response activity in prostate cancer subjects using central review.  The primary
imaging modality for this cohort is CT for tumor assessment, with a bone scan to be
considered at screening if consistent with local standard of care practices. Bone scans
may be performed at subsequent time points when clinically indicated such as in the
presence of new bone pain.
* As published in the Journal of Clinical Oncology:
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger
MA, et al. Design and end points of clinical trials for patients with progressive prostate
Cancer and castrate levels of testosterone: Recommendations of the prostate Cancer
clinical trials working group. J Clin Oncol 2008;26(7):1148-59.
 
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12.9 List of Abbreviations
Abbreviation/Term  Definition
-HCG  
Serum β-human Chorionic Gonadotropin
5-HIAA 
5-Hydroxyindoleacetic acid
AE 
Adverse Event
ALT  
Alanine Aminotransferase
ANC  
Absolute Neutrophil Count
aPTT  
Activated Partial Thromboplastin Time
ASaT  
All Subjects as Treated
AST  
Aspartate Aminotransferase
BCG  
Bacillus Calmette–Guérin
ß-HCG  
Beta Human Chorionic Gonadotropin
CA 15-3 
Cancer Antigen 15-3
CA 19-9 
Carbohydrate Antigen 19-9
A 27-29 
Cancer Antigen 27-29
CA-125 
Cancer Antigen 125
CBC  
Complete Blood Count
CD28 
clusters of differentiation 28
CEA  
Carcinoembryonic Antigen
CgA  
Chromogranin A
CNS  
Central Nervous System
CR  
Complete Response
CrCl 
Creatinine Clearance
CSR  
Clinical Study Report
CT  
Computed Tomography
CTCAE 
Common Toxicity Criteria for Adverse Events
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Antigen-4
DNA  
Deoxyribonucleic acid
DOR  
Duration of Response
ECI 
Events of Clinical Interest
ECOG  
Eastern Cooperative Oncology Group
eCRF  
Electronic case report form
ER  
Estrogen Receptor
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
FNA  
Fine needle aspiration
FSH  
Follicle-stimulating hormone
FT4 
Free Thyroxine
 
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Abbreviation/Term  Definition
GBM  
Glioblastoma Multiforme
GCP  
Good Clinical Practice
GFR  
Glomerular Filtration Rate
HBsAg 
hepatitis B surface antigen
HCV  
Hepatitis C virus
HER2 
Human Epidermal Growth Factor Receptor-2
HIV  
Human Immunodeficiency Virus
ICF  
Informed Consent Form
ICH  
International Conference on Harmonization
Ig 
Immunoglobulin
IgC  
Immunoglobulin constant domain
IgV  
Immunoglobulin variable domain
IHC  
Immunohistochemistry
INR  
International Normalized Ratio
irAEs 
Immune-related Adverse Events
irECI 
Immune-related Events of Clinical Interest
IRB  
Institutional Review Board
ITSM  
Immunoreceptor Tyrosine-based Switch Motif
IUD  
Intrauterine device
IV  
Intravenous
Kg 
kilogram
KM  
Kaplan-Meier
LDH  
Lactate Dehydrogenase
LHRH  
Luteinizing-Hormone-Releasing Hormone
mAb 
Monoclonal Antibody
mcL 
microliter
MEL 
Melanoma
mg 
milligram
mg/kg 
milligram per kilogram
mL 
milliliter
MRI 
Magnetic Resonance Imaging
mRNA  
Messenger ribonucleic acid
MSD  
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD  
Maximum tolerated dose
N/A  
Not Applicable
NCI 
National Cancer Institute
NSAID  
Non-Steroidal Anti-inflammatory Drug
ORR  
Overall Response Rate
OS  
Overall Survival
OTC  
Over-the-counter
PCWG2 
Prostate Cancer Clinical Trials Working Group 2
PD  
Progressive Disease
 
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Abbreviation/Term  Definition
PDCD1 
Programmed cell death 1
PD-L1 
Programmed Death - Ligand 1
PFS  
Progression Free Survival
PGt 
Pharmacogenetic
PK  
Pharmacokinetic
PKPD  
Pharmacokinetic-Pharmacodynamic
PO  
Oral Administration
PR  
Partial Response
PT  
Prothrombin Time
PSA  
Prostate Specific Antigen
RANO  
Response Assessment in Neuro-Oncology
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
SGOT  
Serum Glutamic Oxaloacetic Transaminase
SGPT  
Serum Glutamic Pyruvic Transaminase
SIM  
Site Imaging Manual
SOP  
Standard Operating Procedures
T1DM  
Type 1 diabetes mellitus
T3 
Total Triiodothyronine
Tg 
Thyroglobulin
TIL 
Tumor-Infiltrating Lymphocytes
TSH  
Thyroid Stimulating Hormone
ULN  
Upper Limit of Normal
ZAP70 
Zeta-chain-associated protein kinase
 
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13.0 SIGNATURES
Sponsor's Representative
13.1 
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2 
I agree to conduct this clinical trial in accordance with the design outlined in this protocol
and to abide by all provisions of this protocol (including other manuals and documents
referenced from this protocol).  I agree to conduct the trial in accordance with generally
accepted standards of Good Clinical Practice.  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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