Clinical trial NCT03099161
Conditions: Neoplasm
Keywords: Advanced Solid Tumor Programmed Cell Death Receptor 1 (PD-1) Programmed Cell Death Receptor Ligand 1 (PD-L1) PD1 PD-1 PDL1 PD-L1
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-06-27; Completion date: 2018-02-21
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety and preliminary efficacy of preladenant (MK-3814A) alone and in combination with pembrolizumab (MK-3475) (pembro) in participants with advanced solid tumors that have not responded to prior therapy. This study will be done in 2 parts. Part 1 will identify and confirm the recommended Phase 2 dose (RP2D) of preladenant when given alone or in combination with pembrolizumab. Part 2 of the study will determine the safety and efficacy of preladenant in combination with pembrolizumab at the RP2D in participants with select solid tumors .

Detailed description:

Arms: arm 1: During an initial dose evaluation phase, participants received 25 mg of preladenant orally twice a day (BID) on Days 1 through 21 of each 21-day cycle (for a maximum of 35 cycles) until the RP2D could be established. The RP2D was to be established based on the number of dose limiting toxicities (DLTs) at each dose level administered. Participants continued receiving 25 mg of preladenant BID on Days 1 through 21 of each infusion cycle until discontinuation or receiving a maximum of 35 cycles. arm 2: During an initial dose evaluation phase, participants received 50 mg of preladenant orally BID on Days 1 through 21 of each 21-day cycle (for a maximum of 35 cycles) until the RP2D could be established. The RP2D was established based on the number of DLTs at each dose level administered. Participants continued receiving 50 mg of preladenant BID on Days 1 through 21 of each infusion cycle until discontinuation or receiving a maximum of 35 cycles. arm 3: During an initial dose evaluation phase, participants received 25 mg of preladenant administered orally BID on Days 1 through 21 in combination with 200 mg pembrolizumab administered as an intravenous (IV) infusion on Day 1 of each 21-day cycle (for a maximum of 35 cycles). Participants continued receiving preladenant 25 mg BID in combination with 200 mg pembrolizumab for each infusion cycle until discontinuation or receiving a maximum of 35 cycles.
Interventions: intervention 1: preladenant intervention 2: pembrolizumab
Intervention descriptions: intervention 1: Administered as an oral capsule BID on Days 1 through 21 of each 21-day cycle intervention 2: Administered as IV infusion on Day 1 of each 21-day cycle

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03099161 
Document Date: 
30-Mar-2017
A Phase Ib/II Study to Evaluate the Safety and Tolerability of 
Preladenant as a Single Agent and in Combination with 
Pembrolizumab in Subjects with Advanced Malignancies


Product:  MK-3814A 
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Protocol/Amendment No.: 062-01 
MK-3814A-062-01 Final Protocol
30-Mar-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, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase Ib/II Study to Evaluate the Safety and Tolerability of Preladenant as a Single Agent 
and in Combination with Pembrolizumab in Subjects with Advanced Malignancies
IND NUMBER:  [133717]
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
2.1
Trial Diagram........................................................................................................ 18
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es) .............................................................. 18
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 19
3.2
Exploratory Objectives......................................................................................... 19
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
4.1
Pharmaceutical and Therapeutic Background .................................................... 19
4.1.1
Rationale for Preladenant in Monotherapy and in Combination with 
4.1.2
Pembrolizumab ................................................................................................... 21
Pre-clinical and Clinical Trials ........................................................................... 22
4.1.3
Preladenant................................................................................................... 22
4.1.3.1
Pembrolizumab ............................................................................................ 24
4.1.3.2
Ongoing Clinical Trials....................................................................................... 24
4.1.4
Preladenant................................................................................................... 24
4.1.4.1
Pembrolizumab ............................................................................................ 24
4.1.4.2
Rationale................................................................................................................ 25
4.2
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.1
Rationale for Dose Selection/Regimen............................................................... 25
4.2.2
Rationale for Starting Dose and Dose Escalation of Preladenant................ 25
4.2.2.1
Fixed Dose of Pembrolizumab..................................................................... 27
4.2.2.2
Starting Dose for This Trial ......................................................................... 28
4.2.2.3
Maximum Dose/Exposure for This Trial..................................................... 28
4.2.2.4
Rationale for Dose Interval and Trial Design .............................................. 28
4.2.2.5
Rationale for Endpoints ...................................................................................... 28
4.2.3
Safety Endpoints .......................................................................................... 28
4.2.3.1
 
 
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Efficacy Endpoints....................................................................................... 29
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 30
4.2.3.3
Anti-Drug Antibodies (ADA)...................................................................... 30
4.2.3.4
Planned Exploratory Biomarker Research (Tumor Biopsies and Blood 
4.2.3.5
samples) ....................................................................................................... 30
Future Biomedical Research........................................................................ 32
4.2.3.6
Benefit/Risk ........................................................................................................... 32
4.3
5.0
METHODOLOGY ................................................................................................... 32
Entry Criteria........................................................................................................ 32
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 32
5.1.1
Subject Inclusion Criteria.................................................................................... 33
5.1.2
Subject Exclusion Criteria .................................................................................. 35
5.1.3
Trial Treatment(s) ................................................................................................ 37
5.2
Dose Selection .................................................................................................... 38
5.2.1
Dose Selection (Preparation) ....................................................................... 38
5.2.1.1
Dose Escalation and Confirmation .............................................................. 38
5.2.1.2
Cohort Expansion......................................................................................... 41
5.2.1.3
Tolerability Evaluation Rules and Dose Escalation..................................... 41
5.2.1.4
Definition of Dose-Limiting Toxicities .............................................................. 42
5.2.2
Replacement of Subjects in DLT Period ..................................................... 44
5.2.2.1
Guideline for Dose Modification and Treatment Discontinuation ..................... 44
5.2.3
Preladenant Dose Modifications.................................................................. 44
5.2.3.1
Pembrolizumab Withholding....................................................................... 46
5.2.3.2
Timing of Dose Administration .......................................................................... 51
5.2.4
Trial Blinding...................................................................................................... 51
5.2.5
Randomization or Treatment Allocation............................................................ 52
5.3
Stratification.......................................................................................................... 52
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 52
5.5
Acceptable Concomitant Medications ................................................................ 52
5.5.1
Prohibited Concomitant Medications.................................................................. 53
5.5.2
Prohibited Concomitant Medications for Preladenant................................. 53
5.5.2.1
Prohibited Concomitant Medications for Pembrolizumab .......................... 56
5.5.2.2
 
 
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Rescue Medications & Supportive Care............................................................. 56
5.6
Supportive Care Guidelines for Preladenant....................................................... 56
5.6.1
Supportive Care Guidelines for Pembrolizumab ................................................ 57
5.6.2
Diet/Activity/Other Considerations..................................................................... 57
5.7
Diet...................................................................................................................... 57
5.7.1
Contraception...................................................................................................... 58
5.7.2
Pregnancy............................................................................................................ 59
5.7.3
Use in Nursing Women....................................................................................... 59
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 60
5.8
Discontinuation of Treatment ............................................................................. 60
5.8.1
Withdrawal from the Trial .................................................................................. 61
5.8.2
Subject Replacement Strategy............................................................................. 61
5.9
Beginning and End of the Trial ........................................................................... 62
5.10
Clinical Criteria for Early Trial Termination ................................................... 62
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 63
Flowchart............................................................................................................... 63
6.1
7.0
TRIAL PROCEDURES ........................................................................................... 73
Trial Procedures ................................................................................................... 73
7.1
Administrative Procedures.................................................................................. 73
7.1.1
Informed Consent......................................................................................... 73
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 73
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 74
Inclusion/Exclusion Criteria ........................................................................ 74
7.1.1.2
Subject Identification Card .......................................................................... 74
7.1.1.3
Medical History ........................................................................................... 74
7.1.1.4
Disease Details and Treatments................................................................... 74
7.1.1.5
7.1.1.5.1
Oncology Disease Details..................................................................... 74
7.1.1.5.2
Prior Oncology Treatment History ....................................................... 74
Prior and Concomitant Medications Review ............................................... 75
7.1.1.6
7.1.1.6.1
Prior Medications.................................................................................. 75
7.1.1.6.2
Concomitant Medications..................................................................... 75
 
 
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Assignment of Screening Number............................................................... 75
7.1.1.7
Assignment of Treatment/Randomization Number ..................................... 75
7.1.1.8
Trial Compliance (Medication).................................................................... 76
7.1.1.9
Clinical Procedures/Assessments........................................................................ 76
7.1.2
Adverse Event Monitoring........................................................................... 76
7.1.2.1
Physical Examination................................................................................... 76
7.1.2.2
7.1.2.2.1
Full Physical Examination.................................................................... 76
7.1.2.2.2
Directed Physical Examination............................................................. 77
Height, Weight, and Vital Signs .................................................................. 77
7.1.2.3
Electrocardiogram........................................................................................ 77
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 77
7.1.2.5
Tumor Imaging and Assessment of Disease................................................ 77
7.1.2.6
7.1.2.6.1
Initial Tumor Imaging........................................................................... 77
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 78
7.1.2.6.3
End of Treatment and Follow-up Treatment Imaging.......................... 78
7.1.2.6.4
RECIST 1.1 Assessment of Disease ..................................................... 79
7.1.2.6.5
irRECIST Assessment of Disease......................................................... 79
Laboratory Procedures/Assessments .................................................................. 81
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 82
7.1.3.1
Pregnancy Test............................................................................................. 83
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 83
7.1.3.3
7.1.3.3.1
Blood Collection for PK Assessment for Preladenant.......................... 83
7.1.3.3.2
Blood Collection for PK and ADA Assessment for 
Pembrolizumab ..................................................................................... 83
7.1.3.3.3
Blood Collection for RNA, Plasma and Serum Biomarker 
Analysis ................................................................................................ 83
Planned Genetic Analysis Sample Collection (On-Treatment Tumor 
7.1.3.4
Biopsy)......................................................................................................... 83
Future Biomedical Research Samples ......................................................... 84
7.1.3.5
Other Procedures................................................................................................. 84
7.1.4
Withdrawal/Discontinuation........................................................................ 84
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 84
7.1.4.1.2
Lost to Follow-up.................................................................................. 85
 
 
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Subject Blinding/Unblinding ....................................................................... 85
7.1.4.2
Domiciling ................................................................................................... 85
7.1.4.3
Calibration of Critical Equipment................................................................ 85
7.1.4.4
Visit Requirements.............................................................................................. 86
7.1.5
Screening Visit............................................................................................. 86
7.1.5.1
Treatment Period Visits ............................................................................... 87
7.1.5.2
Post-Treatment Visits................................................................................... 87
7.1.5.3
7.1.5.3.1
End of Treatment – Discontinuation Visit............................................ 87
7.1.5.3.2
Safety Follow-up Visit.......................................................................... 87
7.1.5.3.3
Imaging Follow-up Visits ..................................................................... 87
7.1.5.3.4
Survival Follow-up Visits..................................................................... 87
Assessing and Recording Adverse Events .......................................................... 88
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 89
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 89
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 90
7.2.3
Serious Adverse Events ............................................................................... 90
7.2.3.1
Events of Clinical Interest............................................................................ 91
7.2.3.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 91
7.2.3.3
Evaluating Adverse Events ................................................................................. 92
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 95
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 95
Statistical Analysis Plan Summary ..................................................................... 95
8.1
Responsibility for Analyses/In-House Blinding ................................................. 96
8.2
Hypotheses/Estimation ......................................................................................... 96
8.3
Analysis Endpoints ............................................................................................... 96
8.4
Efficacy/Immunogenicity/Pharmacokinetic Endpoints ...................................... 96
8.4.1
Safety Endpoints ................................................................................................. 96
8.4.2
Analysis Populations............................................................................................. 96
8.5
Safety Analysis Population ................................................................................. 96
8.5.1
Efficacy Analysis Populations ............................................................................ 97
8.5.2
Statistical Methods................................................................................................ 97
8.6
 
 
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Statistical Methods for Efficacy Analyses .......................................................... 97
8.6.1
Statistical Methods for Safety Analyses ............................................................. 97
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 97
8.6.3
Interim Analyses ................................................................................................... 98
8.7
Multiplicity ............................................................................................................ 98
8.8
Sample Size and Power Calculations .................................................................. 98
8.9
Subgroup Analyses ............................................................................................... 98
8.10
Compliance (Medication Adherence).................................................................. 99
8.11
Extent of Exposure................................................................................................ 99
8.12
9.0
LABELING, 
PACKAGING, 
STORAGE 
AND 
RETURN 
OF 
CLINICAL SUPPLIES ............................................................................................ 99
Investigational Product ........................................................................................ 99
9.1
Packaging and Labeling Information ............................................................... 100
9.2
Clinical Supplies Disclosure............................................................................... 100
9.3
Storage and Handling Requirements................................................................ 100
9.4
Discard/Destruction/Returns and Reconciliation ............................................ 101
9.5
Standard Policies................................................................................................. 101
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 101
Confidentiality..................................................................................................... 101
10.1
Confidentiality of Data ..................................................................................... 101
10.1.1
Confidentiality of Subject Records ................................................................... 101
10.1.2
Confidentiality of Investigator Information...................................................... 102
10.1.3
Confidentiality of IRB/IEC Information........................................................... 102
10.1.4
Compliance with Financial Disclosure Requirements..................................... 102
10.2
Compliance with Law, Audit and Debarment ................................................. 103
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 105
10.4
Quality Management System............................................................................. 105
10.5
Data Management............................................................................................... 105
10.6
Publications ......................................................................................................... 105
10.7
11.0
LIST OF REFERENCES....................................................................................... 107
12.0
APPENDICES......................................................................................................... 109
 
 
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Merck Code of Conduct for Clinical Trials...................................................... 109
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 111
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 115
ECOG Performance Status................................................................................ 126
12.4
National Cancer Institute (NCI) Common Terminology Criteria for 
12.5
Adverse Events V4.0 (CTCAE) ......................................................................... 127
List of Abbreviations .......................................................................................... 128
12.6
13.0
SIGNATURES......................................................................................................... 131
Sponsor's Representative ................................................................................... 131
13.1
Investigator.......................................................................................................... 131
13.2
 
 
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LIST OF TABLES
Table 1
Summary on clinical trials where preladenant was administered at 25 
mg BID................................................................................................................ 26
Table 2
Adequate Organ Function Laboratory Values..................................................... 34
Table 3
Trial Treatment (21-Day Cycles) ........................................................................ 37
Table 4
Dose Escalation and Confirmation Rules Based on the Modified 
Toxicity Probability Interval Design (mTPI) ...................................................... 40
Table 5
Dose Levels for Preladenant Monotherapy (Part 1: Arm 1) ............................... 41
Table 6
Dose Levels for Preladenant and Pembrolizumab (Part 1: Arm 2)..................... 42
Table 7
Preladenant Dose Modification and Treatment Discontinuation 
Guidelines for Drug-Related Adverse Events..................................................... 45
Table 8
Dose Modification and Supportive Care Guidelines for Pembrolizumab 
for Drug-Related Adverse Events ....................................................................... 47
Table 9
Treatment Schedule for Preladenant Monotherapy in each Arm for each 
Treatment Cycle .................................................................................................. 51
Table 10
Treatment Schedule for Preladenant and Pembrolizumab in each Arm 
for each Treatment Cycle .................................................................................... 51
Table 11
Medications, Supplements, and Other Substances Prohibited During the 
Trial ..................................................................................................................... 55
Table 12
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease................................................................................................................. 81
Table 13
Laboratory Tests.................................................................................................. 82
Table 14
Evaluating Adverse Events ................................................................................. 93
Table 15
Estimate and 95% CI of ORR in Each Cohort.................................................... 98
Table 16
Product Descriptions ........................................................................................... 99
 
 
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LIST OF FIGURES
Figure 1
Study Design: Part 1: Dose Escalation and Confirmation of MK-3814 
as a Single Agent (Arm 1) and in Combination with Pembrolizumab 
(Arm 2); Part 2: Dose Expansion in 2 Select Solid Tumor Cohorts ................... 18
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
6.0
7.1.5.3.2
7.2
Trial Summary
Trial Design
Flow chart
Safety Follow-up Visit
Assessing 
and 
Recording 
Adverse Events
The protocol collection period for AEs 
was revised to 90 days after treatment 
discontinuation, 30 days if the subject 
initiates new anticancer therapy less
than 30 days after study treatment 
discontinuation, or
the day new 
anticancer therapy
is initiated if 
between 30 days and 90 days after 
study treatment discontinuation. 
This change was made at the 
request of the FDA to allow late 
toxicities that can be observed with 
immunomodulatory agents to be 
collected.
2.1
2.2
4.2.2
5.2 Trial Treatment(s)
Trial Design
Trial Diagram
Rationale 
for 
Dose 
Selection/Regimen
The starting dose has been changed 
from 10 mg BID to 25 mg BID. A 10 
mg BID (DL-1) dose is added as an 
alternative dose should 25 mg BID 
prove to be intolerable 
This change was made at the 
request of the FDA to ensure the 
dose escalation from DL1 to DL2 
does not exceed 2 fold. 
5.1.2
Subject Inclusion Criteria
Subjects to be enrolled to the study are 
defined as refractory to or intolerant of 
existing therapy(ies) known to provide 
clinical benefit for their condition.
This change was made at the 
request of the FDA to ensure 
patients to be enrolled in this trial 
are those who have exhausted all 
current 
approved 
therapeutic 
options. 
5.1.3
Subject Exclusion Criteria
Examples of A2a receptor antagonists
CPI-444, HTL1071, PBF-509
are 
added to exclusion criteria # 3. 
This change was made at the 
request of the FDA to clarify A2a 
receptor antagonists that preclude 
trial inclusion.
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.2.1
Replacement of Subjects in 
DLT period
The protocol was clarified to better 
describe the situation when patients 
are experiencing DLT but allowed to 
remain in the trial. Language is added 
to define “the subject is deriving
clinical benefit upon resolution of the 
DLT to a ≤ Grade 1 adverse event and 
after discussion with the sponsor.”
This change was made at the 
request of the FDA as an extra
safety precaution.
5.2.3
Guideline 
for 
Dose 
Modification and Treatment 
Discontinuation”
The protocol was clarified the section 
is applicable to both part 1 and part 2. 
This change was made at the
request 
of 
the 
FDA
for 
clarification. 
6.1
Flow Chart
Vital sign measurements were added 
to cycle 1 day 8 visit for both 
preladenant monotherapy arm and in 
combination 
with 
pembrolizumab 
arm. 
This change was made at the 
request of the FDA as an extra
safety precaution.
5.1.2
Subject 
Inclusion 
Criteria 
(Table 2)
The 
protocol 
was 
clarified 
in 
Coagulation section for INR and PT 
values 
when 
patients 
are 
using 
anticoagulant therapy. 
This change was made at the 
request of FDA for clarification.
5.2.3.2
Table 8
Delete 
language 
“Appropriate 
resuscitation equipment should be 
available in the room and a physician 
readily available during the period of 
drug administration.” Since it is no 
longer applicable in current study. 
The language is not applicable in 
this study. 
 
 
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Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.2
Definition of Dose-Limiting 
Toxicities
The duration of any Grade 3 or Grade 
4 non-hematologic laboratory value 
was changed from 1 week to 72 hours. 
This change was made at the 
request of the FDA as an extra
safety precaution.
5.2.2
Definition of Dose-Limiting 
Toxicities
Liver function test was eliminated 
from the exceptions for any Grade 3 or 
Grade 4 non-hematologic laboratory 
value.
This change was made at the 
request of the FDA as an extra
safety precaution.
5.2.2
Definition of Dose-Limiting 
Toxicities
Liver test abnormalities (Hy’s Law)
was added to the definition of DLT. 
This change was made at the 
request of the FDA as an extra
safety precaution.
5.5.2.2
Prohibited 
Concomitant 
Medications 
for 
Pembrolizumab
Protocol 
was 
clarified 
for 
glucocorticoids
dose 
limit 
and 
conditions 
for 
pembrolizumab  
prohibited medication. 
This change was made at the 
request of FDA for clarification.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
PhIb/II Study of Preladenant +/- Pembrolizumab in Subjects with Solid 
Tumor
Sponsor Product Identifiers
Preladenant (MK-3814) and pembrolizumab (MK-3475)
Trial Phase
Phase Ib/II
Clinical Indication
Treatment of Advanced Solid Tumors 
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral (preladenant) and intravenous  (pembrolizumab)
Trial Blinding
Unblinded Open-label
Treatment Groups
During Part 1 (dose escalation and confirmation phase) subjects will be 
allocated to one of two treatment arms:
Arm 1: preladenant in monotherapy
Arm 2: preladenant in combination with pembrolizumab
During Part 2 (expansion phase) subjects will be allocated to Arm 2
(preladenant in combination with pembrolizumab) in 2 select tumor 
cohorts.
Number of trial subjects
Approximately 100-120 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 42 months
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for up to 28 months from the time 
the subject signs the informed consent form (ICF) through the final 
protocol-specified contact.  
After a screening phase of up to 28 days, each subject will be receiving 
assigned treatment for up to 24 months. After treatment discontinuation, 
subjects will be monitored for adverse events (AEs) and serious adverse 
events (SAEs) for 90 days. Subjects who initiate new anticancer therapy 
less than 30 days after study treatment discontinuation will be monitored 
for AEs/SAEs for 30 days. Subjects who initiate new anticancer therapy 
between 30 days and 90 days after study treatment discontinuation will be 
monitored for AEs/SAEs until the day new anticancer therapy is initiated.
Subjects will be treated until progressive disease, unacceptable toxicity, 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw treatment, subject withdrawal of 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, subject completes treatment, or administrative 
reasons requiring cessation of treatment, at which point they will be 
discontinued from the study. Upon disease progression, subjects in the 
monotherapy arm will be able to cross-over to the combination regimen.
A list of abbreviations used in this document can be found in Section 12.6. 
Preladenant will be used throughout the protocol to refer to MK-3814 as supplied by the 
Sponsor. 
Pembrolizumab will be used throughout the protocol to refer to KEYTRUDA®or MK-3475 
as supplied by the Sponsor.
Randomization Ratio
N/A
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a multicenter, worldwide, open label, non-randomized, Phase Ib/II study of 
preladenant in monotherapy and in combination with pembrolizumab in subjects with a 
histologically or cytologically confirmed diagnosis of advanced solid tumor that has not 
responded to conventional therapy. 
This study will evaluate the safety, tolerability and preliminary efficacy of preladenant
administered in monotherapy (Arm 1), and in combination with pembrolizumab (Arm 2). 
There are two parts in this study, dose escalation and confirmation (Part 1) (Section 5.2.1.2) 
and cohort expansion (Part 2) which will include two select tumor cohorts (Section 5.2.1.3).
Subjects will be allocated to receive preladenant in monotherapy (Arm 1) or preladenant in 
combination with pembrolizumab (Arm 2) using an interactive voice response 
system/integrated web response system (IVRS/IWRS). In Arm 1 and Arm 2, preladenant 
will be administered orally (p.o.) twice a day (BID) every day of each 21-day cycle. In Arm 
2, pembrolizumab will be administered intravenously (IV) every 3 weeks, on Day 1 of each 
cycle. Archived tumor-specimen (or fresh tumor biopsy) are required prior to enrollment on 
the study. The subject must also agree to undergo an on-treatment tumor biopsy, assuming 
this is considered acceptable from a safety perspective by the subject’s physician.
In Part 1 of the study, a modified Toxicity Probability Interval (mTPI) design [1] will be used 
to identify and confirm the recommended Phase II dose (RP2D) of preladenant in Arm 1 
(preladenant as a single agent), and in Arm 2 (preladenant in combination with 
pembrolizumab). Four pre-determined dose levels (DL1 to DL4) of preladenant will be 
evaluated independently in each arm: 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg
BID. A 10 mg BID de-escalation dose (DL-1) will be used as an alternative dose level should 
25 mg BID prove to be intolerable. Lower and/or higher doses of preladenant may be 
explored depending on the combined safety, pharmacokinetic (PK), and pharmacodynamics 
(PD) data available at each dose level. The dose of pembrolizumab in Arm 2 will remain 
constant at 200 mg every 3 weeks.
Subjects who received at least one and up to five prior lines of therapy will be initially 
enrolled to receive preladenant at 25 mg twice a day in monotherapy (Arm 1).  Treatment 
allocation will be accomplished by non-random assignment. Enrollment in Arm 1 
(preladenant in monotherapy) at DL2 (Dose Level 2) will begin once all subjects complete 
Cycle 1 at DL1 (Dose Level 1) of Arm 1 and a dose escalation decision has been made.  
Enrollment in Arm 2 (preladenant in combination with pembrolizumab) at DL1 will also 
begin once all subjects complete Cycle 1 at DL1 of Arm 1 and a dose escalation decision has 
been made. Thus, the starting dose of preladenant in the combination arm will generally be 
one level below the dose level being tested concurrently in the preladenant monotherapy arm. 
Barring dose limiting toxicities (DLTs) during Cycle 1, additional subjects will be enrolled 
and dose-finding will proceed according to an algorithm based on the mTPI method, 
targeting a preladenant dose with a 30% DLT rate for each arm to determine the respective 
RP2D (see Section 5.2.1.2). 
 
 
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In Part 2, two expansion cohorts targeting a specific tumor type will enroll approximately 30 
subjects each. Subjects with select advanced solid tumors who received at least one and up to 
five prior lines of therapy will be enrolled to further evaluate safety and efficacy of 
preladenant in combination with pembrolizumab at the RP2D defined in Part 1 Arm 2 (See 
Section 5.2.1.3). 
Additional lower and/or higher doses of preladenant in combination with pembrolizumab
may also be explored in Part 2, if they were previously assessed in Part 1, and were deemed 
generally safe and tolerable. The final RP2D for future studies will be confirmed using all 
available safety information (including early and late toxicities from Parts 1 and 2), as well as 
PK and PD data, and preliminary efficacy assessments.
Preliminary efficacy will be evaluated using overall response rate (ORR) assessed by the 
investigator based on the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 
1.1) as a secondary objective.  The duration of response (DOR), disease control rate (DCR) 
and progression-free survival (PFS) based on RECIST 1.1 as assessed by the investigator, as 
well as overall survival (OS) will be evaluated as exploratory objectives. ORR and PFS will 
be also assessed by immune-related RECIST (irRECIST) (see Section 4.2.3.2). In Part 2, a 
futility check will be performed in each of the select solid tumor cohorts (see Section 8.7).
Subjects will be monitored carefully for the development of adverse events (AEs), and for 
clinical and/or radiographic evidence of disease progression according to RECIST 1.1.  
However, irRECIST could be used by the investigator for treatment decision.  In subjects 
who have initial evidence of radiological progressive disease by RECIST 1.1, it will be at the 
discretion of the investigator whether to continue a subject on study treatment until repeat 
imaging is obtained (see Section 4.2.3.2).  
Adverse events (AEs) will be evaluated by the investigator, according to criteria outlined in 
the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0, to establish the safety and tolerability of preladenant when administered in 
monotherapy and in combination with pembrolizumab as per the primary objective of this 
study. 
There will be no intra-subject dose escalation for subjects enrolled in this study.  The 
definition of DLTs and criteria for dose modification of preladenant are outlined in Sections 
5.2.2 and 5.2.3.1.  Pembrolizumab will be administered at a fixed dose of 200 mg every 
3 weeks, which will not be modified.  
Subjects may receive study treatment (preladenant in monotherapy in Arm 1 or in 
combination with pembrolizumab in Arm 2, or pembrolizumab alone in Arm 2 if only 
preladenant was discontinued) for up to 35 cycles (24 months) (see Section 5.2.1.4).  
Subjects who discontinue preladenant in monotherapy (Arm 1) due to progressive disease 
may, at the investigator’s discretion and after consultation with the Sponsor, cross-over to the 
combination treatment (Arm 2) (see Sections 4.2.3.1 and 4.2.3.2). It will be at the discretion 
of the investigator whether to continue a subject on study treatment until repeat imaging is 
obtained.  Once they discontinue from any part of the study, subjects will be treated at the 
discretion of the physician.
 
 
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After treatment discontinuation, subjects will be monitored for AEs and SAEs for 90 days. 
Subjects who initiate new anticancer therapy less than 30 days after study treatment 
discontinuation will be monitored for AEs/SAEs for 30 days. Subjects who initiate new 
anticancer therapy between 30 days and 90 days after study treatment discontinuation will 
bemonitored for AEs/SAEs until the day new anticancer therapy is initiated. 
Subjects with an ongoing AE of Grade >1 at the time of treatment discontinuation will be 
followed until resolution of the AE to Grade 0-1, until considered stable by the treating 
physician, or until beginning a new anti-cancer therapy, whichever occurs first.  
Subjects who discontinue treatment for reasons other than confirmed progressive disease will 
have post-treatment follow-up for disease status (including imaging) until progressive 
disease, initiating a new anti-cancer therapy, discontinuing from the study participation, or 
becoming lost to follow-up. 
After confirmed progressive disease each subject will be contacted by telephone every 12
weeks (84±7 days) for survival until subject discontinues from the study, becoming lost to 
follow-up, death, or end of the study, whichever occurs first.
The trial will be conducted in conformance with Good Clinical Practices (GCP).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
 
 
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Trial Diagram
2.2
The study design is presented in Figure 1.
1. DL-1: De-escalating dose 
2. DL1: Starting dose
Note: Subjects who discontinue preladenant in monotherapy (Arm 1) due to progressive disease may, at the 
investigator’s discretion and after consultation with the Sponsor, cross-over to combination treatment (Arm 2)
Figure 1
Study Design: Part 1: Dose Escalation and Confirmation of MK-3814 as a Single 
Agent (Arm 1) and in Combination with Pembrolizumab (Arm 2); Part 2: Dose 
Expansion in 2 Select Solid Tumor Cohorts
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In male/female subjects with advanced or metastatic solid tumors in Part 1 (Phase Ib) and 
with select advanced or metastatic solid tumors in Part 2 (Phase II):
Primary Objective(s) & Hypothesis(es)
3.1
(1) To evaluate the safety and tolerability of dose level-specific preladenant in monotherapy 
(Part 1) and in combination with pembrolizumab (Parts 1 and 2)
 
 
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Secondary Objective(s) & Hypothesis(es)
3.2
(1) In Part 1, to determine a Recommended Phase 2 Dose (RP2D) of preladenant in 
monotherapy and in combination with pembrolizumab
(2) To evaluate ORR based on RECIST 1.1 as assessed by the investigator for dose level-
specific preladenant in monotherapy (Part 1) and in combination with pembrolizumab
(Parts 1 and 2)
Exploratory Objectives
3.3
(1) To assess the PK profile for dose level-specific preladenant in monotherapy (Part 1) and 
in combination with pembrolizumab (Parts 1 and 2)
(2) To evaluate the DOR, DCR and PFS based on RECIST 1.1 as assessed by the 
investigator, and OS, for dose level-specific preladenant in monotherapy (Part 1) and in 
combination with pembrolizumab (Parts 1 and 2)
(3) To evaluate ORR and PFS based on irRECIST as assessed by the investigator for dose 
level-specific preladenant in monotherapy (Part 1) and in combination with 
pembrolizumab (Parts 1 and 2)
(4) To evaluate the correlation between PD-L1 expression levels and tumor response for 
dose level-specific preladenant in monotherapy (Part 1) and in combination with 
pembrolizumab (Parts 1 and 2)
(5) To identify molecular (genomic, metabolic and/or proteomic) biomarkers that may be 
indicative of clinical response/resistance, safety, pharmacodynamic activity, and/or the 
mechanism of action for dose level-specific preladenant in monotherapy (Part 1) and in 
combination with pembrolizumab (Parts 1 and 2)
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the respective investigator brochures (IBs) for detailed background information on 
preladenant or pembrolizumab.
Pharmaceutical and Therapeutic Background
4.1.1
Preladenant
Preladenant is a potent and selective competitive antagonist of the human adenosine Type 2a 
(A2a) receptor, with an inhibition constant (Ki) of 1.1 nM and > 1000-fold selectivity over 
the other three adenosine receptor subtypes (A1, A2b, and A3) and a variety of other 
receptors and ion channels. 
 
 
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Safety pharmacology and toxicology studies demonstrated a favorable safety profile for 
preladenant. In addition, genetic toxicology studies and carcinogenicity studies indicate no 
evidence of mutagenic or carcinogenic potential (See IB).
Preladenant was originally developed for Parkinson’s disease and tested in clinical trials up 
to Phase III. While a generally acceptable safety and tolerability profile and good 
pharmacology properties were demonstrated, preladenant development for the Parkinson’ 
disease indication was halted in Phase III due to lack of clinical efficacy.
One of signature features of the solid tumor microenvironment is hypoxia which is a state of 
cellular oxygen deprivation. It has been shown that hypoxia induces vascular endothelial 
growth factor (VEGF) production, angiogenesis and diverse epigenetic changes in tumor 
cells [2]. In addition, hypoxia causes an accumulation of extracellular adenosine, which 
exerts its biological function through a set of four G protein coupled receptors: A1, A2a, A2b 
and A3. Adenosine receptor (A2a) is expressed on CD-8+ tumor-infiltrating T lymphocytes
(TILs), natural killer cells (NK), regulatory T cells (Tregs) and myeloid derived suppressor 
cells (MDSCs) and plays important roles in modulating the immune response in the context 
of inflammation within the tumor microenvironment. 
Under normal physiologic conditions extracellular release of adenosine is balanced by rapid 
cellular uptake. In contrast, inflamed environments and tumors produce high levels of 
extracellular ATP and adenosine. As tissues are subjected to immune attack, increased 
cellular turnover and hypoxia trigger release of ATP and adenosine. Levels of extracellular 
adenosine are also increased by the catabolism of extracellular ATP and ADP by the tandem 
activity of the ectonucleotidases CD-39 and CD-73. In response to hypoxia-induced HIF-1 
generation in tumors and inflamed tissues, CD-39 and CD-73 are up regulated on endothelial, 
stromal and some solid tumor cells, and on several subsets of immune cells, including T regs, 
CD-8+ T cells, and B cells [3]. Adenosine/A2aR signaling on endothelial cells upregulates 
VEGF production and leads to angiogenesis which directly promotes cancer cell proliferation 
and tumor metastasis. More importantly, adenosine/A2aR signaling on T cells leads to 
intracellular cAMP level increase and inhibition of AKT activity transmitted from CD-28 co-
receptor and TCR activation. 
Therefore, adenosine/A2aR represents a non-overlapping inhibitory pathway distinct from 
that of PD-1/PD-L1 and CTLA-4. Antagonism of A2aR is anticipated to demonstrate 
synergy with other immune checkpoint inhibitors in T cell activation. Pharmacologic 
blockade of A2a receptors on effector T cells, Tregs, NK cells, dendritic cells (DCs), MDSCs 
and tumor-associated macrophages (TAMs) may counteract the immunosuppressive effect of 
adenosine in tumor microenvironment and enhance multiple phases of the immune response. 
Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  
 
 
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Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is 
in clinical development as an 
i.v
immunotherapy for advanced malignancies.  
KEYTRUDA™ (pembrolizumab) is indicated in several countries for the treatment of 
patients with melanomas, non-small cell lung cancer (NSCLC), and head and neck squamous 
cell cancer (HNSCC) (See KEYTRUDA™Package Circular).
The importance of intact immune surveillance function in controlling outgrowth of neoplastic
transformations has been known for decades [4].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD-8+ T-cells and the ratio of CD-8+ effector T 
cells/FoxP3+ regulatory T-cells (Tregs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma [5] [6].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD-28 and CTLA-4 that 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 its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV type) domain responsible 
for ligand binding and a cytoplasmic tail 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.  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD-3 zeta (CD-3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD-3 
T-cell signaling cascade [8] [10] [11] [12].  The mechanism by which PD-1 down-modulates 
T cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins [13] [14].  As a consequence, the PD-1/PD-
L1 pathway is an attractive target for therapeutic intervention in multiple solid tumors.
Rationale for Preladenant
in Monotherapy and in Combination with 
4.1.2
Pembrolizumab
As described before, the adenosine/A2aR pathway, active in the tumor microenvironment, is 
another checkpoint pathway with a distinct mechanism from that of PD-1 and CTLA-4. 
Adenosine signaling (triggered by hypoxia and high cell turnover) in the inflammatory 
setting dampen the immunologic response and protect tissues from associated injury. 
 
 
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A2aR deletion or blockade has been shown to slow or eliminate tumor growth and activate 
tumor-infiltrating lymphocytes (TILs). Selective deletion of A2aRs on myeloid cells was also 
found to inhibit solid tumor growth and lung colonization by tumor cells and markedly 
reduce IL-10 production by TAMs, DCs, and MDSCs, while directly increasing antigen-
specific CD-8+ T-cells and natural killer (NK) cell activation [15].  Thus, preladenant in 
monotherapy is expected to demonstrate clinical activity in a variety of solid tumors where 
adenosine is secreted in the tumor microenvironment. Emerging data from a Phase 1 clinical 
study with A2aR inhibitor CPI-444 (see below) suggest clinical activity for A2aR inhibitors 
as single agents in different tumor types (e.g. 1 partial response (PR) and 3 stable disease
(SD) out of 5 subjects with advanced renal cell carcinoma).
Previously, the effectiveness of combining adenosinergic signaling blockade in the context of 
cytotoxic chemotherapy [3] has been demonstrated, by combining CD-73 blockade with 
doxorubicin chemotherapy in a murine breast cancer model [16]. The enhanced anti-tumor 
response, with increased survival in mice with established metastatic breast cancer compared 
with either agent in monotherapy, was also observed when a specific A2aR compound was 
used in combination with doxorubicin [3].
The independence of the adenosine/A2aR pathway in regards to other established checkpoint 
pathways has the potential ability to produce additive effects and to dramatically increase 
response rates.
Preclinical efficacy studies of preladenant in monotherapy have shown 
partial inhibition of tumor growth in several murine models such as CT-26 or MC-38, with a 
titration study in MC-38 model showing a dose-dependent response (see IB for preladenant).
Due to the pleotropic effects of the adenosine pathway and its potential to synergize with
other immune checkpoint inhibitors, a number of A2aR antagonists and adenosine 
metabolism key enzymes inhibitors have been pursued in the clinic for cancer
immunotherapy. These include: 1) CPI-444, a small molecule A2aR antagonist in Phase 1
(Corvus); AZD4635 (AstraZeneca) and HTL-1071 (Heptares) in Phase 1; Redox, an A2aR
inhibitor planned for Phase 1 in combination with CAR-T cells (JUNO); 2) anti-CD-73 
antibodies: MEDI-9447 in Phase 1 (MedImmune) and BMS anti-CD-73 antibody; both has 
been in Phase 1 since June 2016. In addition, a number of small molecules and antibodies 
against CD-73 and CD-39 are in pre-clinical development.
It is hypothesized that the non-redundant effect of the adenosine/A2aR pathway blockade 
with PD-1/PDL-1 inhibition will have additive effect in the clinic by disrupting the immune 
suppressive tumor microenvironment and enhancing TCR-mediated T-cell activity.
Pre-clinical and Clinical Trials
4.1.3
Preladenant
4.1.3.1
Safety pharmacology and toxicology studies have demonstrated a generally favorable safety 
profile for preladenant (see the IB for further details).
In dogs, hepatic changes and increases in heart rate (28% to 45% in first 8 hours after dosing) 
and blood pressure (BP; 10% to 12% in the first 8 hours after dosing) support the continued 
and careful monitoring of these parameters during clinical investigations. 
 
 
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Results of a definitive embryo-fetal development study in rabbits indicate a non-dose-related 
low incidence of increases in cardiac malformations at all doses of preladenant. However, in 
a second rabbit embryo-fetal developmental toxicity study at the same doses, the results of 
the first study were not confirmed. Consequently, the reasons for the cardiac findings in the 
first study are unknown but may be due to genetic variability. Nevertheless, potential 
embryo/fetal exposure in women should be avoided.
In addition, genetic toxicology studies and carcinogenicity studies indicate no evidence of 
mutagenic or carcinogenic potential. In animals and humans, preladenant metabolism 
includes O-demethylation to an alcohol (SCH 434748) and subsequent oxidation to a 
carboxylic acid (SCH 446637), as well as N-dealkylation and alterations to the furan ring. 
Both SCH 434748 and SCH 446637 are also selective, high-affinity A2a receptor 
antagonists.
A total of 38 clinical trials were conducted with preladenant (see the IB for further details). 
In Phase 1, 24 clinical studies in healthy volunteers have been completed. In Phase 2, 8 
clinical studies have been completed in subjects with drug-induced movement disorders and 
subjects with idiopathic Parkinson’s disease. Four Phase 3 trials in subjects with Parkinson’s
disease have been also completed.
Approximately 3300 subjects have received preladenant in the Parkinson’s disease clinical 
program. Doses have ranged from 2 to 200 mg/day and have been administered as a single 
dose or BID for up to 1 year.  In general, preladenant was generally well tolerated in these 
trials (see IB for preladenant). 
Adverse events reported by ≥5% of the healthy volunteers in Phase 1 multiple-dose trials 
include (preladenant vs. placebo): insomnia (24% vs. 3%), headache (15% vs. 3%), dizziness 
(9% vs. 5%), nausea (9% vs. 1%), abdominal pain (6% vs. 3%), and energy increased (6% 
vs. 0%). The most common AEs reported in subjects with Parkinson’s disease who received 
preladenant in the double-blind Phase 2 dose-finding trial P04501 were Parkinson’s disease
(11%), somnolence (9%), dyskinesia (7%), nausea (7%), constipation (7%), headache (7%), 
and dizziness (6%). Adverse events reported by subjects with Parkinson’s disease in Phase 1 
trials (n=52) were generally similar to AEs reported in Phase 2 trials.
In later phases of the preladenant clinical program, the following AEs have been noted as 
risks for preladenant:  increases in liver function enzymes and transient increases in blood 
pressure (BP). 
Two Phase 2 trials (P02541 and P03376) were terminated early by the sponsor because of 
asymptomatic elevated liver enzymes in P02541. In P02541, 3 of 29 subjects had liver 
function test (LFT) elevations that reached protocol-specified criteria for discontinuation 
(alanine aminotransferase [ALT] > 3 x upper limit of normal [ULN]).  Overall, in 7 of the 8 
Phase 2 studies (the 8th being accounted below with the Phase 3 studies), the number of 
subjects / frequency of ALT or AST elevations ≥ 3x ULN was 7/429 (1.6%) for all doses of 
preladenant vs 4/145 (2.8%) in the placebo group. These increases were higher in the 25, 50 
and 100 mg daily dose than that in the lower dose groups (see preladenant IB).
In the unblinded Phase 2 (P6402) and four Phase 3 trials (P06402, P04938, P07037, P06153,
P05664) there were a total of 52 subjects (37 on preladenant at doses ) meeting the protocol 
threshold for adjudication of ≥3x ULN, out of 2699 treated, for an incidence rate of 
 
 
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approximately 2% for ALT increased. Of the 37 preladenant cases, 29 were assessed as drug-
related by the investigator. Subjects with increased ALT or AST received 2mg BID, 5mg 
BID or 10mg BID of preladenant and these elevations were not dose dependent. Although 
there were other liver enzyme elevations of unknown significance, none of the individuals 
with ALT elevations had concurrent elevations of any other liver function test to a clinically 
meaningful degree. Two subjects experienced mild bilirubin concentration fluctuations, but 
none of the variations exceeded 2 x ULN. None of the subjects enrolled on preladenant 
clinical trials fulfilled Hy’s Law criteria (see preladenant IB).
Adenosine is known to be a vasodilator, and antagonism of the A2a receptor may lead to 
elevations in BP. Small, non-dose-dependent elevations in BP have been observed in all 
preladenant treatment groups relative to placebo following the first dose of study medication.
These transient mild increases in blood pressure occurred within a few hours after 
preladenant administration; blood pressure changes were neither cumulative nor dose-related 
nor associated with clinical sequelae.
Pembrolizumab
4.1.3.2
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD-8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD-8+ 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 [17] [5] [6] [18] [8] [7]. Experiments have 
confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination 
with chemotherapy in syngeneic mouse tumor models (see the IB for further details). 
Clinical trials have demonstrated efficacy in subjects with advanced melanoma, non-small 
cell lung cancer, head and neck cancer, bladder cancer, Hodgkin’s lymphoma, triple-negative 
breast cancer, and gastric adenocarcinoma.
Ongoing Clinical Trials
4.1.4
Preladenant
4.1.4.1
There is no current ongoing clinical trial conducted with preladenant.
Pembrolizumab
4.1.4.2
Clinical trials investigating pembrolizumab are on-going in advanced melanoma, non-small 
cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck, bladder cancer, 
hematologic malignancies, and in a number of other advanced solid tumor indications. For 
study details, and safety and efficacy summaries, please refer to the IB.
 
 
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Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Preladenant is an adenosine A(2a) receptor antagonist with a high affinity and very high 
selectivity for adenosine A(2a) receptors, that has demonstrated enhanced tumor inhibition in 
combination with PD-1 in CD-73-expressing tumors [19], in preclinical cancer cell lines, and
in xenograft animal models. 
In Part 1 of the current study, preladenant will be evaluated as a single agent and in 
combination with pembrolizumab in subjects with advanced solid tumors.
In Part 2, subjects with select advanced tumors will be enrolled in two separate cohorts (~30 
subjects per cohort) and will be treated at the RP2D of preladenant in combination with 
pembrolizumab established in Part 1 (Arm 2).   
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB for preladenant and pembrolizumab, respectively, and 
Informed Consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Rationale for Dose Selection/Regimen
4.2.2
Rationale for Starting Dose and Dose Escalation of Preladenant
4.2.2.1
A total of 38 clinical trials have been conducted with preladenant in the Parkinson’s disease
indication. Overall, ~3300 subjects have received preladenant in the neurology clinical 
development program. Doses have ranged from 2 to 200mg/day and have been administered 
as a single dose or BID for up to one year. Preladenant was generally well tolerated in these 
trials (see the IB for further details). 
Preclinically, a dose of 25 mpk BID of preladenant has demonstrated efficacy in the CT -26 
murine syngeneic tumor model. In combination, the same 25 mpk BID dose of preladenant 
with a murine anti-PD1 antibody produced additional tumor reduction over monotherapy 
treatments.  Subsequent dose ranging experiments in the same model have indicated that a 
lower dose of 12.5 mpk may also produce additional efficacy over monotherapy (potentially 
higher than that observed at 25 mpk).  In the RENCA murine syngeneic model, 6.25 and 12.5 
mpk combinations have shown added efficacy over monotherapy (while a 25 mpk dose 
showed little benefit). This indicates a U-shaped dose response curve, which may in part be 
explained by inhibition of T cell proliferation at high concentration or increased upregulation 
of PDL-1.
In contrast to these high doses used in preclinical cancer models, preladenant doses of 0.03-3 
mpk showed efficacy in rodent models of Parkinson's disease. Thus, while the shape of dose 
responses in murine cancer models has not always shown monotonic trends, these 
experiments have indicated that in general higher doses of preladenant may be required for 
cancer treatment in comparison to Parkinson's disease.
 
 
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In the Parkinson's disease clinical development program, doses ranging from 2-10 mg BID 
were tested in Phase 3 studies (based in part on evidence of evidence of Brain RO measured 
by PET, and preliminary evidence of PD activity at these doses in Phase 2). Consistent with 
our preclinical observations, it is expected that doses greater than those showing activity in 
Parkinson's (>10mg) to be required to be effective in oncology program.
The 25 mg dose of preladenant was extensively studied in the Parkinsons program, and was 
deemed to be a safe starting dose, that would achieve exposures greater than those targeted in 
the Parkinson’s disease Phase 3 trials. A Summary of subjects with 25 mg BID preladenant 
exposure in prior trials is shown in Table 1.  
Table 1
Summary on clinical trials where preladenant was administered at 25 mg BID
Trial ID
Phase
Dosing Regimen
Subject 
Exposure
Trial Population
Treatment 
Duration
P03286
1
25 mg BID
25
Healthy Volunteer
5 days
P03291
1
25 mg BID
19
Mild/moderate 
Parkinson’s disease
2 days
P03792
1
25 mg BID
13
Mild/moderate/severe 
Parkinson’s disease
3 days
P04628
2
25 mg BID
9
Schizophrenia with 
DIMD
14 days
P05145
2
25 mg BID
27
Acute psychosis or 
akathisias
14 days
P05174
2
25 mg BID
21
Healthy volunteers
3 days
Preliminary projections using preladenant PK and in vitro measurement of Ki and fraction 
unbound suggest that a starting dose of 25 mg is likely to result in approximately 80% A2a 
receptor occupancy at trough. While the A2a receptor occupancy levels required for optimum 
efficacy are unclear, this starting dose minimizes the possibility of treating oncology patients 
at potentially ineffective doses. Since sporadic LFT elevations and blood pressure increases 
were noted in the Parkinson’s disease program, dose escalation will proceed cautiously based 
on safety, PK and PD data from previous dose level cohorts. 100 mg of preladenant BID will 
achieve greater than 92% A2a receptor occupancy (RO). Assuming linear increases in PK 
from 100 to 200 mg BID, greater than 96% A2a receptor occupancy is expected after 200 mg 
BID dosing. Higher doses beyond 200 mg BID may be explored based on data collected at 
previous dose levels, as noted in Section 5.2.1.2. 
In summary, the starting dose for this clinical study is 25 mg BID based on: (i) previous 
experience with preladenant at 25 mg BID in the Phase 1 and 2 clinical trials for the 
Parkinson’s disease indication, which showed a generally well tolerated safety profile at this 
dose (see Table 1, and IB for preladenant); (ii) the opportunity to administer a dose that is 
more likely to be efficacious in oncology patients than lower starting doses; (iii) the fact that 
monotherapy cohorts (Arm 1) for each dose level will be started before each combination 
cohorts (Arm 2) will ensure that a dose is generally well tolerated prior to evaluating that 
dose in combination with pembrolizumab.  
 
 
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Fixed Dose of Pembrolizumab 
4.2.2.2
An open-label Phase I trial (KEYNOTE 001) has been conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475).   The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 
2 weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no DLTs were observed.  This first in human study of pembrolizumab 
(MK-3475) showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1mg/kg, 3mg/kg and 10mg/kg Q2W).  No MTD has been 
identified.  
In KEYNOTE 001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab (MK-3475) at a dose of 2mg/kg versus 10mg/kg Q3W had been completed, 
and one randomized cohort evaluating of 10mg/kg Q3W versus 10mg/kg Q2W had also been 
completed.  The clinical efficacy and safety data demonstrated a lack of clinically important 
differences in efficacy response or safety profile at these doses.  For example, in Cohort B2, 
advanced melanoma subjects who had received prior ipilimumab therapy were randomized to 
receive pembrolizumab (MK-3475) at 2mg/kg versus 10mg/kg Q3W.   The ORR was 26% 
(21/81) in the 2 mg/kg group and 32% (25/79) in the 10mg/kg group (FAS).   The proportion 
of subjects with drug-related AE, grade 3-5 drug-related AE, serious drug-related AE, death 
or discontinuation due to an AE was comparable between groups or lower in the 10mg/kg 
group.  In Cohort B3, advanced melanoma subjects (irrespective of prior ipilimumab therapy) 
were randomized to receive pembrolizumab (MK-3475) at 10mg/kg Q2W versus 10mg/kg 
Q3W.   The ORR was 30.9% (38/123) in the 10mg/kg Q2W group and 24.8% (30/121) in the 
10 mg/kg Q3W group (APaT).   The proportion of subjects with drug-related AE, grade 3-5 
drug-related AE, serious drug-related AE, death or discontinuation due to an AE was 
comparable between groups.  
Pharmacokinetic data analysis of pembrolizumab (MK-3475) administered Q2W and Q3W 
showed slow systemic clearance, limited volume of distribution, and a long half-life (refer to 
IB).  Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21days).   This early PK/PD data provides scientific rationale for testing a Q3W 
dosing schedule.   Because Q3W dosing is more convenient for subjects, Q3W dosing will be 
further studied.  
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
(MK-3475) in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab 
(MK-3475) when dosed at either 2 mg/kg or 10mg/kg Q3W in melanoma subjects, 2) the flat 
exposure-response relationships of pembrolizumab (MK-3475) for both efficacy and safety 
in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden 
or indication on distribution behavior of pembrolizumab (MK-3475) (as assessed by the 
population PK model) and 4) the assumption that the dynamics of pembrolizumab 
(MK-3475) target engagement will not vary meaningfully with tumor type.  
The choice of the 200mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab (MK-3475) 
showing that the fixed dose of 200mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
 
 
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associated with maximal efficacy response and 3) will maintain individual subjects exposure 
in the exposure range established in melanoma that are well tolerated and safe.   
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  
Additionally, recently approved supplemental Biologics License Applications such as that for 
subjects with advanced HNSCC, mandate the administration of pembrolizumab at the fixed 
dose of 200mg Q3W.
Therefore, preladenant will be evaluated in combination with pembrolizumab at the fixed 
dose of 200mg Q3W.  Modifications to the dose or dosing regimen of pembrolizumab will 
not be allowed in this study.   Details are provided in Section 5.2.3.2.
Starting Dose for This Trial
4.2.2.3
The starting dose for preladenant in monotherapy (Arm 1) and in combination with 
pembrolizumab (Arm 2) is 25 mg BID (See Section 4.2.2.1).
Maximum Dose/Exposure for This Trial
4.2.2.4
The maximum pre-planned dose of preladenant for this trial will be 200 mg administered 
orally twice a day. However, based on safety evaluation and PK and PD data, dose escalation 
may continue to a MTD (with constant safety monitoring). 
The maximum pre-planned dose of preladenant is based on the single agent doses tested in
healthy volunteer studies and in Phase 1 studies of the preladenant development program in 
Parkinson Disease (See Section 4.2.2.1).
Rationale for Dose Interval and Trial Design
4.2.2.5
In healthy volunteer studies and in Phase 1 to 3 clinical studies of the preladenant clinical
program in subjects with Parkinson’s disease, preladenant was evaluated in monotherapy 
with doses ranging from 2mg/day to 200mg/day.  Doses up to 200mg/day (QD or 100 mg 
BID) were found to be generally safe and well tolerated in Phase 2 clinical studies.
Pembrolizumab will be evaluated in the combination therapy (Arm 2) at its full single-agent 
dose (200mg intravenously every 3weeks), and will not be escalated or de-escalated during 
this trial (See Section 5.2.3.2).   This dose was shown to be efficacious as a single-agent and 
in combination, with an acceptable AE profile.   
Rationale for Endpoints
4.2.3
Safety Endpoints 
4.2.3.1
The primary objective of this trial is to characterize the safety and tolerability of preladenant
in monotherapy and in combination with pembrolizumab in subjects with advanced solid 
tumors.  The primary safety analysis will be based on subjects who experience toxicities as 
defined by CTCAE Version 4.0 criteria.  The primary safety endpoint is the rate of DLTs 
(see definition in Section 5.2.2). Safety will be assessed by quantifying the toxicities and 
 
 
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grades of toxicities experienced by subjects who received preladenant in monotherapy or in 
combination with pembrolizumab.
For adverse events, attribution to drug, time-of-onset, duration of the event, its resolution, 
and any concomitant medications administered will be recorded.  AEs that will be analyzed 
include, but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
Safety data for subjects in Arm 1 who cross-over to combination treatment (Arm 2) due to 
disease progression will be analyzed separately than that of the subjects enrolled in Arm 1 or 
Arm 2 from the time they cross-over (Section 8.5.1).
Efficacy Endpoints
4.2.3.2
Objective response rate (ORR) will be used as a secondary endpoint as assessed by the site 
investigator/local radiology review based on RECIST 1.1, to evaluate efficacy of preladenant
in monotherapy or in combination with pembrolizumab in subjects with advanced solid 
tumors (Part 1) and in subjects with select advanced solid tumors (Part 2).
Exploratory endpoints include OS, and DCR, DOR and PFS as assessed by the 
investigator/local radiology review based on RECIST 1.1. In addition, ORR and PFS based 
on irRECIST will be also assessed by the investigator/local radiology review (see Section 
7.1.2.6.5).
Secondary and exploratory efficacy endpoints will also be summarized according to tumor 
types, in Part 1 and in Part 2.
Efficacy data for subjects in Arm 1 who cross-over to combination treatment (Arm 2) due to 
disease progression will be analyzed separately than that of the subjects enrolled in Arm 1 or 
Arm 2 from the time they cross over (Section 8.5.2).
Radiological images (e.g.  CT, MRI) will be collected for possible review and analysis by 
blinded, independent central imaging laboratory. The Site Imaging Manual (SIM) contains 
specific instructions for the acquisition and submission of radiologic images to the central 
imaging vendor for this study.
The assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1.  However, the Sponsor has implemented an adaptation related to 
new lesions, non-target lesions and tumor burden assessment in order to confirm 
radiographic progression. In this study, irRECIST will be used by site investigators/local 
radiology review to assess tumor response and progression and to make treatment decisions
for subjects with advanced solid tumors. This clinical judgment decision should be based on 
the subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may continue to receive study treatment until tumor assessment is 
repeated ≥4 weeks later in order to confirm progressive disease by irRECIST per site 
assessment.
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described by Nishino, et al.
[20]. 
Immunotherapeutic agents 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
 
 
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participants can manifest a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions.  
Based on an analysis of patients with melanoma enrolled in Keynote-001, 7% of evaluable 
patients experienced delayed or early tumor pseudoprogression.  Of note, patients who had 
progressive disease by RECIST 1.1 but not by immune related Response Criteria had longer 
OS than patients with progressive disease by both criteria.  Additionally, the data suggest that 
RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
patients.  These findings support the need to apply a modification to RECIST 1.1 that takes 
into account the unique patterns of atypical response in immunotherapy and enable treatment 
beyond initial radiographic progression. 
Pharmacokinetic Endpoints
4.2.3.3
An exploratory objective of this study is to characterize (i) the pharmacokinetic (PK) profile 
of preladenant administered as a single agent (Arm 1), and when administered in 
combination with pembrolizumab (Arm 2), and (ii) to characterize the pharmacokinetic 
profile of pembrolizumab when administered in combination with preladenant (Arm 2). The 
serum concentrations of these agents will serve as the primary read-out for the PK, and these 
data will be used to derive PK parameters of the agents when administered alone and in 
combination. Furthermore, the results of these analyses will be used in conjunction with the 
pharmacodynamics, and safety and exploratory endpoint data to help assess future dosing 
strategies for preladenant.
Anti-Drug Antibodies (ADA)
4.2.3.4
Formation of ADAs can potentially confound drug exposures at therapeutic doses, and prime 
for subsequent infusion-related toxicity.  In Arm 2, anti-drug antibody response to 
pembrolizumab at the beginning of each cycle will be determined to understand drug 
metabolism, exposure, and safety.
Planned Exploratory Biomarker Research
(Tumor Biopsies and Blood 
4.2.3.5
samples)
Cancer immunotherapies represent an important and novel class of antitumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients.  Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy, as well as determinants of 
AEs in the course of our clinical trials.  These efforts will identify novel predictive/PD 
biomarkers and generate information that will better guide single-agent and combination 
therapy with immuno-oncology drugs.  
To identify novel biomarkers, biospecimens (ie, blood components, tumor material from 
archived tumor samples or new biopsy during screening, and new biopsy during study 
treatment) will be collected to support analyses of cellular components (e.g., protein, DNA, 
RNA, metabolites) and other circulating molecules (see Section 6.0 for timing of collection).  
 
 
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Investigations may include but are not limited to:  

Germline (blood) genetic analyses (e.g., SNP analyses, whole exome sequencing, 
whole genome sequencing):   This research will evaluate whether genetic variation 
within a clinical trial population correlates with response to the treatment(s) under 
evaluation.  If genetic variation is found to predict efficacy or AEs, the data might 
inform optimal use of therapies in the patient population.  Furthermore, it is important 
to evaluate germline DNA variation across the genome in order to interpret tumor-
specific DNA mutations.    

Genetic (DNA) analyses from tumor:  The application of new technologies, such as 
next generation sequencing, has provided scientists the opportunity to identify tumor-
specific DNA changes (i.e., mutations, methylation status, microsatellite instability 
etc.).  Key molecular changes of interest to immune-oncology drug development 
include (for example) the mutational burden of tumors and the clonality of T-cells in 
the tumor microenvironment.   Increased mutational burden (sometimes referred to as 
a ‘hyper-mutated’ state) may generate neo-antigen presentation in the tumor 
microenvironment.   To conduct this type of research, it is important to identify 
tumor-specific mutations that occur across all genes in the tumor genome.   Thus, 
genome wide approaches may be used for this effort.  Note that in order to understand 
tumor-specific mutations; it is necessary to compare the tumor genome with the 
germline genome.       

Tumor and blood RNA analyses: Both genome-wide and targeted messenger RNA 
(mRNA) expression profiling and sequencing in tumor tissue and in blood may be 
performed to define gene signatures that correlate to clinical response to treatment 
with pembrolizumab or other immunotherapies.   Pembrolizumab induces a response 
in tumors that likely reflects an inflamed/ immune phenotype.   Specific immune-
related gene sets (such as those capturing interferon-gamma transcriptional pathways) 
may be evaluated and new signatures may be identified.    Individual genes related to 
the immune system may also be evaluated (e.g., IL-10).   MicroRNA profiling may 
also be pursued.  

Proteomics and immunohistochemistry (IHC) using blood or tumor: Tumor and blood 
samples from this study may undergo proteomic analyses (e.g., PD-L1 IHC).  PD-L1 
protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in subjects with NSCLC, and an InVitro Diagnostic 
(IVD) device has been developed for use with pembrolizumab in NSCLC. 
Preliminary data indicate that this association may also be true in additional cancer 
types (i.e., triple-negative breast cancer, head and neck cancer, and gastric cancer).  
Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab.  Tumor tissue may, therefore, be subjected to proteomic analyses 
using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry.  This approach could identify novel 
protein biomarkers that could aid in patient selection for pembrolizumab therapy.
 
 
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
Other blood derived biomarkers: In addition to expression on tumor tissue, PD-L1 
and other tumor derived proteins can be shed from tumors and released into the 
blood.  Assays such as enzyme-linked immunoassay measure such proteins in serum.  
Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from 
today’s reliance on assessing tumor biomarkers.  This research would serve to 
develop such assays for future clinical use.
Future Biomedical Research
4.2.3.6
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
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/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. 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.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying preladenant and pembrolizumab 
Investigators Brochure (IB) and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with advanced or metastatic solid tumors in Part 1 and Male/Female 
subjects with select advanced or metastatic solid tumors in Part 2 will be enrolled in this 
trial.
 
 
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Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1.
Be ≥ 18 years of age on day of signing the informed consent.
2.
Be willing and able to provide written informed consent for the trial.   The subject may 
also provide consent for Future Biomedical Research.   However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
3.
Part 1 and Part 2: Have a histologically- or pathologically-documented, locally-
advanced or metastatic solid tumor for which standard therapy, either does not exist or 
has been proven ineffective, intolerable or refused by the subject. Each subject must 
have received at least one and up to five prior lines of cancer treatment regimens, 
excluding neo-adjuvant, adjuvant, maintenance treatment and surgery.
4.
Have provided archival tumor tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded 
(FFPE) tissue blocks are preferred to slides.  Newly obtained biopsies are preferred to 
archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut (details pertaining to 
tumor tissue submission can be found in the Procedures Manual).
5.
Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology.  Target lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions.
6.
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
7.
Be able to swallow and retain oral medication and must not have any clinically 
significant gastrointestinal abnormalities that may alter absorption.
8.
Demonstrate adequate organ function as defined by the following table (Table 2):
 
 
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Table 2
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/La
Renal
Serum creatinine
OR Measured or calculatedb
creatinine 
clearance
(CrCl)
or
Glomerular Filtration Rate (GFR) in 
place of CrCl
≤1.5 X upper limit of normal (ULN) OR
60 mL/min for subject with creatinine levels >1.5x 
institutional ULN
Hepatic
Serum total bilirubin
OR Direct bilirubin
≤  1.5 X ULN OR
Direct bilirubin 1≤ ULN for subjects with total bilirubin 
levels > 1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN 
If subject is receiving anticoagulant therapy only PT is 
required to be within therapeutic range of intended use 
of anticoagulants.
≤1.5 X ULN 
If subject is receiving anticoagulant therapy only aPTT 
is required to be within therapeutic range of intended 
use of anticoagulants 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR = glomerular filtration rate; ULN = upper limit of normal.
a    Criteria must be met without packed red blood cell (pRBC) transfusion within last 2 weeks.  Subjects can 
be on stable dose of erythropoietin (≥ approximately 3 months).
b   Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment;
laboratory value requirements should be adapted according to local regulations and guidelines for
the administration of specific chemotherapies.
9. If a female subject of childbearing potential (see Section 5.7.2) have a negative urine or 
serum pregnancy test within 72 hours prior to receiving the first dose of study treatment.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  The serum pregnancy test must be negative for the subject to be 
eligible.
10. If a female of childbearing potential (Section 5.7.2), be willing to use an adequate method 
of contraception, as outlined in Section 5.7.2 - Contraception, for the course of the study 
through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle preferred contraception for 
the subject.
 
 
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11.
If a male subject with a female partner(s) of child-bearing potential, 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. Males with pregnant partners must agree to use a condom; no additional 
method of contraception is required for the pregnant partner (if partner pregnancy is 
collected, males must also agree to not give/donate sperm).
Note: Abstinence is acceptable if this is the usual lifestyle preferred contraception for 
the subject.
12.
Concomitant treatment such as bisphosphonate or denosumab therapy is allowed as 
long as it is begun at least 2 weeks prior to treatment allocation.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1.
Has disease that is suitable for local treatment administered with curative intent.
2.
Has received previous treatment with an immunomodulatory agent (e.g. anti-PD-1/PD-
L1 or anti-CTLA-4) and was discontinued from that treatment due to a Grade 3 or 
higher irAE.
3.
Has received previous treatment with an A2a receptor antagonist (e.g. CPI-444;
HTL1071; PBF-509).
4.
Has had chemotherapy, definitive radiation, or biological cancer therapy within 4weeks 
(2 weeks for palliative radiation) prior to the first dose of study therapy, or has not 
recovered to CTCAE grade 1 or better from any adverse events that were due to cancer 
therapeutics administered more than 4 weeks earlier (this includes subjects with 
previous immunomodulatory therapy with residual immune-related adverse events).  
Subjects receiving ongoing replacement hormone therapy for endocrine immune-
related adverse events will not be excluded from participation in this study.
5.
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and has received study therapy or has used an investigational 
device within 28 days of administration of study therapy.
Note:  Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
6. Has taken during the 14 days prior to start of study treatment, or is currently taking drugs 
or grapefruit and star fruit in diet that interferes with CYP3A4 or CYP2C8 as listed in 
Table 11.
7. Has taken during the 5 days prior to start of study treatment, or is currently taking Proton 
Pump Inhibitors (PPI).
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(exceeding 10 mg dose daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of trial drug.
 
 
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9. Is expected to require any other form of systemic or localized antineoplastic therapy 
while in study.
10. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 5 years.
Note:  The time requirement does not apply to subjects who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or 
in situ cervical cancer, or other in-situ cancers.
11.
Has clinically active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain or meningeal metastases may 
participate and be eligible for treatment provided they are stable and asymptomatic 
(without evidence of progression by MRI scan of the brain separated by at least 4 
weeks after treatment), have no evidence of new or enlarging brain metastases, are 
evaluated within 4 weeks prior to first study drug administration, and are off 
immunosuppressive doses of systemic steroids at least 2 weeks from enrollment.
12.
Has had a severe hypersensitivity reaction to treatment with the monoclonal 
antibody/components of the study drug.
13.
Has an active infection requiring therapy.
14.
Has a history of interstitial lung disease. 
15.
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
16.
Has a known history of active tuberculosis.
17.
Has an active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs) except vitiligo or resolved childhood asthma/atopy.  Replacement therapy, such 
as thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed.  
Use of non-systemic steroids is permitted (see Section 5.5.2.2).
18.
Has received a live-virus vaccine within 30 days of planned treatment start.  Seasonal 
flu vaccines that do not contain live virus are permitted.
19.
Has known Human Immunodeficiency Virus (HIV) (HIV 1 or 2 antibodies) and/or 
known active and acute Hepatitis B or C infections (e.g., positive for HBsAg/HBV 
DNA or HCV RNA).
20.
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, make administration of the study drugs hazardous or 
make it difficult to monitor adverse effects such that it is not in the best interest of the 
subject to participate, in the opinion of the treating Investigator.
21.
Has known psychiatric or substance abuse disorders that would interfere with the 
subject’s ability to cooperate with the requirements of the trial.
 
 
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22.
Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
23.
Has not fully recovered from any effects of major surgery without significant detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study drug administration.  Surgery requiring regional/epidural anesthesia 
must be completed at least 72 hours before first study drug administration and subjects 
should be recovered.
Trial Treatment(s)
5.2
In Part 1 (dose escalation and confirmation phase), an mTPI design with a target DLT rate of
approximately 30% will be applied to identify the RP2D of preladenant independently in 
each treatment arm (preladenant monotherapy [Arm 1] and preladenant in combination with
pembrolizumab [Arm 2]). 
The starting dose of preladenant will be 25 mg BID and may proceed, based on DLT 
assessment to a dose of 200 mg BID. Doses lower or higher than the pre-determined doses
may be explored based on safety, PK/PD assessment at the pre-determined dose levels.
Table 3
Trial Treatment (21-Day Cycles)
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Arm 1 and 
Arm 2: 
Preladenant
DL-1  10 mg
DL1  25 mg
DL2   50 mg
DL3   100 mg
DL4   200 mg
Twice a day 
Oral 
Days 1 to 21 
of each cycle 
Experimental
Arm 2: 
Pembrolizumab 
200 mg 
Every 
three 
week 
Intravenous 
infusion 
Day 
1 
of 
each cycle 
Experimental 
Part 2: Preladenant will be administered at the RP2D identified in Part 1 of the study, in 
combination with pembrolizumab at a fixed dose of 200 mg (same fixed dose as in Part 1). 
Additional lower and/or higher doses of preladenant in combination with pembrolizumab 
may be explored in Part 2.
Throughout the study (Part 1 and Part 2), the first intake of preladenant will occur at the trial 
site on Day 1 of each cycle for Arm 1 and Arm 2. 
Following the first dose, preladenant will be administered every 12 hours unsupervised at 
home (e.g. dose 2 on the evening of first dose and then twice daily at approximately the same 
time each day), until Day 1 of the next cycle.
In combination treatment cohorts (Part 1 Arm 2 and Part 2), the first dose of each cycle will 
be preladenant followed by pembrolizumab infusion.  Pembrolizumab will be administered 
through an intravenous infusion as described in the Pharmacy Manual.  Subsequent dosing of 
preladenant will be performed in the evening of the same day (Day 1), and then twice daily 
 
 
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by the subject (i.e., unsupervised at his/her home) at approximately the same time each day, 
until Day 1 of the next cycle.
All supplies indicated above 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
5.2.1
Dose Selection (Preparation)
5.2.1.1
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.  Concomitant immunotherapeutic agents will be prepared and administered as per 
the approved product label(s).
Dose Escalation and Confirmation
5.2.1.2
In Part 1 of the study, an mTPI design [1] with a target DLT rate of approximately 30% will 
be applied for dose escalation and confirmation to determine a RP2D in each treatment arm 
(preladenant monotherapy [Arm 1] and preladenant in combination with pembrolizumab 
[Arm 2]). The final number of subjects enrolled in Part 1 will depend on the empirical safety 
observations (DLT occurrence), and what dose is ultimately identified as the RP2D using the 
mTPI design. 
Four pre-determined dose levels of preladenant in each arm will be explored independently
in Part 1: 25 mg BID, 50 mg BID, 100 mg BID, and 200 mg BID. A 10 mg BID de-
escalation dose (DL-1) will be used as an alternative dose level should 25 mg BID prove to 
be intolerable. Lower and/or higher doses of preladenant may be explored depending on the 
combined safety, PK/PD data available at each dose level. All dose escalation and de-
escalation decisions will be based on the occurrence of DLTs at a given dose and will be 
made jointly by the investigators and the Sponsor. In Arm 2, the dose of pembrolizumab will 
remain constant at 200 mg every 3 weeks in Part 1 and Part 2 of the study.
Treatment allocation will be accomplished by non-random assignment. Enrollment in Arm 1 
(preladenant in monotherapy) at DL2 will begin once all subjects complete Cycle 1 at DL1 of 
Arm 1 and a dose escalation decision has been made.  Enrollment in Arm 2 (preladenant in 
combination with pembrolizumab) at DL1 will also begin once all subjects complete Cycle 1 
at DL1 of Arm 1 and a dose escalation decision has been made. Thus, the starting dose of 
preladenant in the combination arm will generally be 1 dose level below the dose being 
tested concurrently in the preladenant monotherapy arm. 
When both treatment arms are open for enrollment, IVRS/IWRS will alternate subject 
assignment between Arm 1 and Arm 2 starting with Arm 1. For example, once the 50 mg 
BID dose cohort of Arm 1 (preladenant monotherapy) and the 25 mg BID dose cohort of 
Arm 2 (preladenant in combination with pembrolizumab) are open for enrollment, the first 
subject will be allocated to Arm 1, the second subject will be allocated to Arm 2, the third 
subject will be allocated to Arm 1, etc. Each new dose cohort will open for enrollment 
 
 
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without delay once the 21 day DLT observation period of the previous dose cohort is 
completed and a dose escalation decision is made.
In Table 4, the number of subjects treated is indicated in the columns and the number of 
subjects who experienced a DLT is indicated in the rows.  Dosing decisions include escalate 
to the next higher dose (E), stay at the current dose (S), de-escalate to the next lower dose 
(D), and de-escalate to a lower dose and never test this dose again (i.e., unacceptably toxic 
dose; DU).  
During dose escalation, a minimum of three subjects are required at each dose. Depending on 
accrual rate, 3, 4, 5 or 6 subjects may be enrolled at each new dose until the last of those 
subjects completes the 21-day DLT assessment period.  For example, the dose escalation 
rules will proceed as follows if 3 subjects are enrolled: if 0 out of the first three subjects at a 
given dose level develops a DLT, then the dose can be escalated to the next level without 
further expansion.  If 1 out of the first three subjects at a given dose level develops a DLT, no 
more than an additional three subjects should be enrolled at this dose level until additional 
DLT data are available since this dose would be considered unacceptably toxic if all three of 
the additional subjects experience a DLT (i.e., 4 out of 6 subjects).  If two out of the first 3
subjects at a given dose level develop a DLT, the dose will be de-escalated to the next lower 
level.  If 3 out of the first three subjects at a given dose level develop a DLT, this dose will 
be considered unacceptably toxic, i.e., the dose will be de-escalated and never re-escalated to 
that dose again. The same principle will be applied whether 3, 4, 5 or 6 subjects are enrolled 
in the same dose cohort according to Table 4.
The number of subjects who are enrolled at each dose is capped to minimize the exposure to
a dose that may be unacceptably toxic (denoted as DU in Table 4). To determine how many 
more subjects can be enrolled at a dose level, one can count steps in a diagonal direction 
(down and to the right) from the current cell to the first cell marked DU. In total, three to 14 
subjects may be enrolled at a given dose level.
For example, if 1/3 subjects have experienced a DLT at a given dose level, no more than an 
additional three subjects should be enrolled at this dose level until additional DLT data are 
available. This is because this dose level would be considered unacceptably toxic if all three 
of the additional subjects experience a DLT (i.e., 4/6 subjects with DLTs as in Table 4).   
The dose of preladenant in the combination arm (Arm 2) may not be escalated to a dose that 
is higher than the preladenant dose in the preladenant monotherapy arm (Arm 1); however, 
once dose escalation of preladenant in Arm 1 is stopped, the dose of preladenant in Arm 2 
may be escalated up to that dose.
Dose escalation and confirmation in Arm 1 and Arm 2 will end after 14 subjects have been 
treated at any of the selected doses (which may include the optional doses). The pool-
adjacent-violators algorithm [1] will be used to estimate the DLT rates across doses in each 
treatment arm under the assumption of monotonicity between DLT rates and dose levels. The 
dose with an estimated DLT rate closest to 30% may be treated as a preliminary RP2D. The 
totality of the data will be considered before deciding on the dose(s) to carry forward to Part 
2 and the escalation schedule may be adjusted based on PK, and safety data emerging 
throughout the study to determine the RP2D. The RP2D of preladenant in the combination 
arm (Arm 2) will not exceed, but may equal, the RP2D in the preladenant monotherapy arm 
(Arm 1).
 
 
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Note that while 30% was the target toxicity rate used to generate the guidelines in Table 4, 
the observed rates of subjects with DLTs at the MTD may be slightly above or below 30%.
While during this study there will not be any hypothesis testing, an interim look at the data 
may be conducted to enable future trial planning and dosing decisions after undergoing first 
imaging follow-up (see Section 8.7). 
Table 4
Dose Escalation and Confirmation Rules Based on the Modified Toxicity 
Probability Interval Design (mTPI)
Number of subjects treated at current dose
Number of subjects 
with at least one DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 30%
Flat non-informative prior Beta (1,1) is used as a prior and ε1=ε2=0.03[1].
 
 
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Cohort Expansion 
5.2.1.3
In Part 2 of the trial, approximately 30 additional subjects will be treated in each of two
cohorts of subjects with select advanced tumors. Subjects in these two cohorts will be treated 
at the RP2D identified using the mTPI design in Arm 2 of Part 1 (preladenant in combination 
with pembrolizumab). The dose of pembrolizumab in Arm 2 will remain fixed at 200 mg
every 3 weeks. 
Each of the select advanced solid tumor cohorts will focus on a specific type of tumor (e.g., 
Cohort 1: Triple Negative Breast Cancer (TNBC) and Cohort 2: Pancreatic Cancer). The 
determination of which tumor type chosen will be made at a later time, based on
accumulating data from the field. The Sponsor will issue a memo and indicate in the 
supplemental Statistical Analysis Plan (sSAP) the specific tumor types, based on emerging 
data in the field.
Part 2 will begin once an RP2D for Arm 2 has been identified. When Part 2 is open for 
enrollment, IVRS/IWRS will assign subjects to one of two cohorts by tumor type.
In Part 2, a futility check will be performed after the first ~15 evaluable subjects in each of 
the select solid tumor cohorts.  If no responses are observed in a given cohort, enrollment in 
this cohort may be stopped early (see Section 8.7).
Tolerability Evaluation Rules and Dose Escalation 
5.2.1.4
Four dose levels of preladenant are planned in Part 1 (Table 5 and Table 6) 
The starting dose (DL1) of preladenant is 25 mg BID  Dose escalation will continue as 
outlined above (Section 5.2.1.2) according to mTPI dose finding rules.   
Table 5
Dose Levels for Preladenant Monotherapy (Part 1: Arm 1)
Arm 1
Preladenant (BID)
Dose Levels
mg per dose
mg per day
DL-1
10
20
DL1
25
50
DL2
50
100
DL3
100
200
DL4
200
400
 
 
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Table 6
Dose Levels for Preladenant and Pembrolizumab (Part 1: Arm 2)
Arm 2
Preladenant (BID)
Pembrolizumab (Q3W)
Dose Levels
mg per dose
mg per day
IV Infusion (mg per dose)
DL-1
10
20
200
DL1
25
50
200
DL2
50
100
200
DL3
100
200
200
DL4
200
400
200
Each individual subject will be assigned to a single dose level of study therapy.  Intra-subject 
dose escalation is not allowed.   Individual patient dose interruptions and/or dose decreases 
for preladenant may be implemented based on toxicity as described in Section 5.2.3.1.  
However, dose adjustments should not be made during the DLT observation period without 
discussion with the Sponsor.  In Arm 2, pembrolizumab administration can be delayed or 
interrupted but will not be de-escalated see Section 5.2.3.2.
The decision to enroll subjects in the next dose level will be made by the sponsor in 
consultation with the participating investigators after reviewing the safety and any available 
PK data of the previous dose level(s).
Subjects may continue on treatment until disease progression, unacceptable toxicity, 
investigator’s decision to withdraw the subject, withdrawal of consent, development of an 
inter-current condition precluding further administration of study treatment, pregnancy of the 
subject, failure to comply with dosing evaluations or other study requirements, or 
administrative reasons requiring cessation of treatment, at which point they will be 
discontinued from the study.
Definition of Dose-Limiting Toxicities 
5.2.2
All toxicities will be graded using NCI CTCAE Version 4.0 based on Investigator assessment 
(Appendix 12.5).  
The DLT window of observation will be during Cycle 1 (Day 1 to Day 21).
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the Investigator to be possibly, probably or definitely related to study drug 
administration:
1) Grade 4 non-hematologic toxicity (not laboratory).
2) Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
a) Grade 4 thrombocytopenia of any duration
b) Grade 3 thrombocytopenia associated with bleeding
3) Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care.
 
 
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4) Any Grade 3 or Grade 4 non-hematologic laboratory value if:

Medical intervention is required to treat the subject, or

The abnormality leads to hospitalization, or

The abnormality persists for >72 hours. 

Exceptions:
o
Clinically non-significant, treatable, or reversible laboratory abnormalities 
including uric acid, etc.
5) Any of the following liver test abnormalities are observed (Hy’s Law)

ALT or AST > 3X ULN with TBL > 2X ULN with no elevation in alkaline 
phosphatase (AP < 2X ULN) 

No other reasons can be found to explain the combination of increased AT and TBL, 
such as viral hepatitis, A,B or C, preexisting or acute liver diseases, or another drug 
capable of causing the observed injury
6) Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees 
C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than one hour

Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 degrees 
C (101 degrees F) or a sustained temperature of ≥38 degrees C (100.4 degrees F) for 
more than one hour, with life-threatening consequences and urgent intervention 
indicated.
7) Prolonged delay (>2 weeks) in initiating cycle 2 due to treatment-related toxicity.
8) Any treatment-related toxicity which causes the subject to discontinue treatment during 
Cycle 1.
9) Missing >25% of Preladenant doses as a result of drug-related AE(s) during the first 
cycle.
10) Grade 5 toxicity.
 
 
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Replacement of Subjects in DLT Period 
5.2.2.1
In order to fully evaluate the safety of the combination therapy in this study, all subjects 
enrolled must meet the criteria for evaluability for Cycle 1. Subjects are considered non -
evaluable and will be replaced if:

They are enrolled but not treated,

They discontinue from the trial prior to completing all safety evaluations due to reasons 
other than drug-related AEs,

They received <90% of the total pembrolizumab infusion in Cycle 1 (e.g., because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a 
drug-related event, 

They received ≤75% of preladenant doses intended for the trial during Cycle 1 and did 
not experience a drug-related AE,

They must take a prohibited concomitant medication during Cycle 1, unless this 
medication is used to treat a study drug-related AE,

They must undergo medical / surgical procedures or have logistical issues not related to 
study therapy (e.g., elective surgery, unrelated medical events) during Cycle 1.
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation.  
Subjects who experience a DLT in Cycle 1 should be discontinued from treatment.  
However, if in the opinion of the Investigator, the subject is deriving clinical benefit from the 
study treatment, the subject may be allowed to continue on the study upon resolution of the 
DLT to a ≤ Grade 1 adverse event and after discussion with the sponsor.  
Guideline for Dose Modification and Treatment Discontinuation
5.2.3
For individual subjects, dose delays and modifications of trial treatment will be based on 
treatment-related toxicity, laboratory test results prior to treatment administration, and 
clinical assessments during the previous cycle and on the day of treatment.  Guidelines for 
dose delay and dose modification for Parts 1 and 2 are described below and are applicable to 
the start of each cycle as well as during the cycle if treatment-related toxicities occur.
Preladenant Dose Modifications
5.2.3.1
Adverse events (both non-serious and serious) associated with preladenant and 
pembrolizumab exposure may represent an immunologic etiology.  These adverse events 
may occur shortly after the first dose or several months after the last dose of treatment. 
The Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events.  The investigator may attribute each toxicity 
event to preladenant alone, or to the combination of preladenant and pembrolizumab, and 
modify the dose according to Table 7 and Table 8 (pembro dose mod table added to Section 
5.2.3.2). If a dose modification for toxicity occurs with preladenant, the dose may not be re-
escalated to the dose which preceded the dose modification.  Dose modifications are always 
based on the previous cycle.
 
 
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Reduction or holding of one agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to one of the study drugs.  For example, in the 
combination arm (Arm 2), if preladenant is held due to an adverse event attributed to that 
drug, then pembrolizumab may continue to be administered.  Appropriate documentation is 
required regarding which drug the investigator is attributing the adverse event to. If, in the 
opinion of the investigator, the toxicity is related to the combination of two agents, then both 
drugs should be held according to recommended dose modifications. 
Subjects may have up to 2 dose modifications of preladenant throughout the course of the 
study, as described in Table 7.  If further toxicity occurs or the criteria for resuming treatment 
are not met, the subject must be discontinued from the agent.  If a subject experiences several 
toxicities and there are conflicting recommendations, follow the most conservative dose 
adjustment recommended (dose reduction appropriate to the most severe toxicity).
Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
Table 7
Preladenant Dose Modification and Treatment Discontinuation Guidelines for 
Drug-Related Adverse Events
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation after 
Consultation with 
Sponsor
Hematological toxicities:
Any Grade 1 
hematological toxicity
No
N/A
N/A
N/A
Any Grade 2 
hematological toxicity, or 
Grade 3 toxicity that 
persists for ≤ 5 days
Per medical 
assessment 
of the 
Investigator
If treatment held, 
may be restarted 
when AE resolves 
back to baseline 
or to Grade 1.
Per medical assessment of the 
investigator:  may decrease 
dose by one dose level.  
If AE persists for 
12 weeks without 
resolution following 
reduction in dose.
Any Grade 3 hematologic 
toxicity that persists for > 
5 days,  or Grade 4  
hematological toxicity
Febrile neutropenia
Grade 3 
thrombocytopenia of any 
durations if associated 
with bleeding
Yes
Treatment may be 
restarted when 
AE resolves back 
to baseline or to 
Grade 1.
Decrease dose by one dose 
level. 
If AE persists for 
12 weeks without 
resolution following 
reduction in dosing 
schedule.
Permanent 
discontinuation should 
be considered for any 
severe or life-
threatening event
Non-hematological toxicities:
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for Restarting 
Treatment
Criteria for 
Discontinuation after 
Consultation with 
Sponsor
Any Grade 1 non-
hematological toxicity 
Grade 2 alopecia
Grade 2 fatigue
No 
N/A
N/A
N/A
Any Grade 2 non-
hematological toxicity 
except Grade 2 alopecia 
and Grade 2 fatigue
Per medical 
assessment 
of the 
investigator
If treatment held, 
may be restarted 
when AE resolves 
back to baseline 
or to Grade 1.
Per medical assessment of the 
Investigator:  may decrease 
dose by one dose level.  
If AE persists for 
12 weeks without 
resolution following 
reduction in dose.
 
 
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Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation after 
Consultation with 
Sponsor
Any Grade 3 or 4 non-
hematological toxicity 
(not including laboratory, 
unless clinically 
significant medical 
intervention is required to 
treat the subject, or the 
abnormality leads to 
hospitalization, or the 
abnormality persists for 
>1 week)
Yes
Treatment may be 
restarted when 
AE resolves back 
to baseline or to 
Grade 1.
Decrease dose by one dose 
level. 
If AE persists for 
12 weeks without 
resolution following 
reduction in dose.
Permanent 
discontinuation should 
be considered for any 
severe or life-
threatening event
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last treatment, 
preladenant should be discontinued after consultation with the Sponsor. 
With Investigator and Sponsor agreement, subjects with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and 
controlled.
After any Grade 4 drug-related adverse event, subjects should not restart study treatment 
without consultation with the Sponsor.  (Toxicity must have resolved to 0-1 or baseline prior 
to restarting).
Dose reductions are not permitted during Cycle 1.
Pembrolizumab Withholding
5.2.3.2
AEs (both non-serious and serious) associated with pembrolizumab exposure may represent 
an immunologic etiology.  These AEs may occur shortly after the first dose or several months 
after the last dose of treatment.  Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per Table 8. Pembrolizumab dose reductions are not 
permitted during the trial.
In addition, subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures, as described in 
Section 5.6.2, are also included in (Table 8).
Dosing interruptions are permitted after Cycle 1 in the case of 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 3 
weeks of the scheduled interruption, unless otherwise discussed with the Sponsor.  The 
reason for interruption should be documented in the subject's trial record.
 
 
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Table 8
Dose Modification and Supportive Care Guidelines for Pembrolizumab for Drug-
Related Adverse Events 
Dose Modification Guidelines
Supportive Care Guidelines
Toxicity
Hold 
Treatment 
for Grade
Timing for 
Restarting 
Treatment
Treatment 
Discontinuation
CTCAE 
v4.0 
Grade
Action / Supportive Care Guidelines
Diarrhea/Co
litis
General Considerations across all Grades: Subjects should be carefully monitored 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).
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids.  If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.
2-3
Toxicity resolves to 
Grade 0-1
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose or inability 
to reduce corticosteroid 
to 10 mg or less of 
prednisone or equivalent 
per day within 12 weeks
2
Monitor for enterocolitis and bowel 
perforation. Consider GI consultation 
and endoscopy.
Administer oral corticosteroids.
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks.
4
Permanently 
discontinue
Permanently discontinue
3-4
Monitor for enterocolitis and bowel 
perforation.  Consider GI consultation 
and endoscopy.
Treat with IV steroids followed by 
high-dose oral steroids.
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks.  
AST, ALT 
or Increased 
Bilirubin
2
Toxicity resolves to 
Grade 0-1
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose
2
Monitor liver function tests more 
frequently until returned to baseline 
values (consider weekly).
Treat with IV or oral corticosteroids.
≥3
Permanently 
discontinue
(see exception below)a
Permanently discontinue
3-4
Treat with IV corticosteroids for 24 to 
48 hours.
When symptoms improve to Grade 1 
or less, a steroid taper should be 
started and continued over no less 
than 4 weeks. 
 
 
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Dose Modification Guidelines
Supportive Care Guidelines
Toxicity
Hold 
Treatment 
for Grade
Timing for 
Restarting 
Treatment
Treatment 
Discontinuation
CTCAE 
v4.0 
Grade
Action / Supportive Care Guidelines
Type 
1 
diabetes 
mellitus (if 
new onset) 
including 
diabetic 
ketoacidosis 
(DKA)
or 
Hyperglyce
mia 
(≥Grade 3) 
if associated 
with ketosis 
(ketonuria) 
or 
metabolic 
acidosis 
(DKA)
T1DM or 
3-4 hyper-
glycemia
Hold pembrolizumab 
for new onset Type 1 
diabetes mellitus or 
Grade 
3-4 
hyperglycemia 
associated 
with 
evidence of beta cell 
failure
Resume pembrolizumab 
when 
subjects 
are 
clinically 
and 
metabolically stable
T1DM or
3-4 hyper-
glycemia
Insulin replacement therapy is 
recommended for T1DM and for 
Grade 3-4 hyperglycemia associated 
with metabolic acidosis or ketonuria.
Evaluate subjects with serum glucose 
and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-
peptide.
Hypophysiti
s
2-4
Toxicity resolves to 
Grade 0-1. Therapy 
with 
pembrolizumab 
can be continued while 
endocrine replacement 
therapy is instituted
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose or inability 
to reduce corticosteroid 
to 10 mg or less of 
prednisone or equivalent 
per day within 12 weeks
2
Treat with corticosteroids. 
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks.  Replacement of appropriate 
hormones may be required as the 
steroid dose is tapered. 
3-4
Treat with an initial dose of IV 
corticosteroids 
followed 
by 
oral 
corticosteroids.
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks. Replacement of appropriate 
hormones may be required as the 
steroid dose is tapered.
Hyperthyroi
dism 
General Considerations across all Grades: Thyroid disorders can occur at any time during treatment.  Monitor subjects for 
changes in thyroid function (at start of treatment, periodically during treatment and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders.
2
In hyperthyroidism, non-selective 
beta-blockers (e.g. propranolol) are 
suggested as initial therapy.
3
Toxicity resolves to 
Grade 0-1
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose or inability 
to reduce corticosteroid 
to 10 mg or less of 
prednisone or equivalent 
per day within 12 weeks
3-4
Treat with an initial dose of IV 
corticosteroid 
followed 
by 
oral 
corticosteroids. 
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks. Replacement of appropriate 
hormones may be required as the 
steroid dose is tapered.
4
Permanently 
discontinue
Permanently discontinue
Hypothyroi
dism
Therapy 
with 
pembrolizumab can be 
continued 
while 
thyroid 
replacement 
therapy is instituted
Therapy 
with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted
2-4
Treat with thyroid hormone 
replacement therapy (levothyroxine or 
liothyroinine), as indicated per 
standard of care.
 
 
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Dose Modification Guidelines
Supportive Care Guidelines
Toxicity
Hold 
Treatment 
for Grade
Timing for 
Restarting 
Treatment
Treatment 
Discontinuation
CTCAE 
v4.0 
Grade
Action / Supportive Care Guidelines
Infusion 
Reaction
General Considerations across all Grades: Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.
1d:
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
opinion of the investigator.
No premedication at subsequent 
dosing.
2b
Toxicity resolves to 
Grade 0-1
2e
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.
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 
antipyretic).
3-4
Permanently 
discontinue
Permanently discontinue
3f or 4g
Stop Infusion.
Additional 
appropriate 
medical 
therapy may include but is not limited 
to:

IV fluids

Antihistamines

NSAIDS

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids

Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the 
 
 
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Dose Modification Guidelines
Supportive Care Guidelines
Toxicity
Hold 
Treatment 
for Grade
Timing for 
Restarting 
Treatment
Treatment 
Discontinuation
CTCAE 
v4.0 
Grade
Action / Supportive Care Guidelines
opinion of the investigator.
Hospitalization may be indicated.
Subject 
is 
permanently 
discontinued from further trial 
treatment administration.
Pneumonitis
2
Toxicity resolves to 
Grade 0-1
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose or inability 
to reduce corticosteroid 
to 10 mg or less of 
prednisone or equivalent 
per day within 12 weeks
2
Treat with systemic corticosteroids. 
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks.
3-4 or 
Recurrent 
2
Permanently 
discontinue
Permanently discontinue
3-4 or 
Recurrent 
2
Immediately treat with IV steroids. 
Administer additional anti-
inflammatory measures, as needed.
Add prophylactic antibiotics for 
opportunistic infections in the case of 
prolonged steroid administration.
Renal 
Failure or 
Nephritis
2 
Toxicity resolves to 
Grade 0-1
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose or inability 
to reduce corticosteroid 
to 10 mg or less of 
prednisone or equivalent 
per day within 12 weeks
2
Treatment with corticosteroids.
When symptoms improve to Grade 1 
or less, steroid taper should be started 
and continued over no less than 4 
weeks.
3-4 
Permanently 
discontinue
Permanently discontinue
3-4

Treat with systemic 
corticosteroids.

When symptoms improve to Grade 
1 or less, steroid taper should be 
started and continued over no less 
than 4 weeks.
All Other 
Drug-
Related 
Toxicityc
3 or Severe
Toxicity resolves to 
Grade 0-1
Toxicity 
does 
not 
resolve within 12 weeks 
of last dose or inability 
to reduce corticosteroid 
to 10 mg or less of 
prednisone or equivalent 
per day within 12 weeks
4
Permanently 
discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for 
pneumonitis) drug-related AE that recurs, or any life-threatening event.
a For 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 subject should be discontinued.
b 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.
c Subjects with intolerable or persistent Grade 2 drug-related AE may hold study 
medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has 
been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
d Mild reaction; infusion interruption not indicated; 
intervention not indicated
e Requires infusion interruption but responds promptly 
to symptomatic treatment (e.g., antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications indicated for < =24 hrs.
f Prolonged (ie, 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)
g Life-threatening; pressor or ventilatory support 
indicated
 
 
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Timing of Dose Administration
5.2.4
All trial treatments will be administered on an outpatient basis.  
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed on the Trial Flow Chart (Section 6.0).   
Table 9
Treatment Schedule for Preladenant Monotherapy in each Arm for each 
Treatment Cycle
Treatment Arm 1 (Part 1)
Day 1
Days 2 – 21
am
pm
am
pm
Preladenant
X*
X
X
X
* The AM dose of preladenant on Day 1 of each cycle is witnessed at the site.
Table 10
Treatment Schedule for Preladenant and Pembrolizumab in each Arm for each 
Treatment Cycle
Treatment Arm 2 (Part 1 
and Part 2)
Day 1
Days 2 – 21
am
pm
am
pm
Preladenant
X*
X
X
X
Pembrolizumab
X
* The AM dose of preladenant on Day 1 of each cycle is witnessed at the site.
During the study (in Part 1 and Part 2, and in Arm 1 and Arm 2), starting on Day 1 of Cycle 
1, preladenant will be administered orally BID (twice a day) approximately every 12 hours 
on each day of a 21-day treatment cycle.  Preladenant may be administered up to 4 hours 
before or after the scheduled time for preladenant oral intake.  All capsules comprising a dose 
should be taken within approximately 15 minutes (See Pharmacy Manual).
In Arm 2 (Part 1 and Part 2), on Day 1 of each 21-day cycle, after preladenant administration 
in the morning, pembrolizumab will be administered at a fixed dose of 200 mg as a 
30-minute IV infusion.
Sites should make every effort to target the pembrolizumab 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) (See Pharmacy Manual).  
Trial treatment of pembrolizumab may be administered up to three days before or after the 
scheduled Day 1 of each cycle due to administrative reasons (up to three days after treatment 
allocation is permitted).
The Pharmacy Manual contains specific instructions for the handling of preladenant and for 
the preparation of the pembrolizumab infusion fluid and administration of infusion solution.
Trial Blinding 
5.2.5
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
 
 
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Randomization or Treatment Allocation
5.3
Treatment allocation will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS). There are 2 treatment arms. Subjects will be 
allocated to 1 of 2 treatment arms: preladenant monotherapy (Arm 1) or preladenant in 
combination with pembrolizumab (Arm 2) using an IVRS/IWRS in Part 1. 
In Part 1 of the study, treatment will be allocated by non-random assignment. Enrollment into 
the preladenant + pembrolizumab combination treatment arm (Arm 2) will begin once all 
subjects complete 1 cycle of preladenant monotherapy in Arm 1 and complete the DLT 
evaluation, and a dose finding decision has been made. This ensures that the starting dose of 
preladenant in the combination arm will be at least 1 level below the dose being tested in the 
preladenant monotherapy arm. When both treatment arms are open for enrollment, 
IVRS/IWRS will alternate subject assignment between Arm 1 and Arm 2 starting with Arm 
1. For example, once the 50 mg BID dose cohort of Arm 1 (preladenant monotherapy) and 
the 25 mg BID dose cohort of Arm 2 (preladenant + pembrolizumab) are open for 
enrollment, the first subject will be allocated to Arm 1, the second subject will be allocated to 
Arm 2, the third subject will be allocated to Arm 1, etc. Each new dose cohort will open for 
enrollment without delay once the 21-day DLT observation period of the previous dose 
cohort is completed and a dose escalation decision is made. When Part 2 is open for 
enrollment, IVRS/IWRS will assign subjects to one of two cohorts by tumor type. 
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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.   If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
 
 
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All concomitant medications taken by the subject from the date of first dose of trial treatment 
through 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.
Bisphosphonate or denosumab therapy is allowed as long as it is begun at least 2 weeks prior 
to treatment allocation.  
Prohibited Concomitant Medications 
5.5.2
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol (with the exception of denosumab as 
noted above in Section 5.5.1)

Chemotherapy not specified in this protocol

Investigational agents other than preladenant and pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the Investigator’s discretion.

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, chickenpox, yellow fever, rabies, 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.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology (see Section 5.5.2.2).   
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.
o
Note:  Inhaled steroids are allowed for management of asthma.
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.  Section 5.1.3 - Subject Exclusion Criteria describes other medications that are 
prohibited in this trial.
Prohibited Concomitant Medications for Preladenant
5.5.2.1
Specific restrictions for preladenant administration (Arm 1 and Arm 2) during the course of 
the trial are listed. These are based on the current known metabolism of the drugs as 
described. Restrictions may be removed if indicated by emergent data from drug-drug 
interaction trials. Any medications/therapies no longer contraindicated will be communicated 
 
 
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to the site by an administrative letter. The following medications/therapies are not permitted 
from 2 weeks prior to Day 1 through 2 weeks after the study treatment period.
For subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued. Subjects may 
receive other medications that the investigator deems to be medically necessary.

Inhibitors/inducers/substrates of CYP3A4 and substrates for CYP2C8 enzymes.
Preladenant is a competitive and irreversible metabolism-dependent inhibitor of cytochrome 
P450 (CYP) 3A4, a substrate of CYP3A4, and a direct competitive inhibitor of CYP2C8.   
As such, concomitant use of other drugs that are identified in Table 11 as strong inducers, 
strong or moderate inhibitors, or substrates (characterized with a narrow therapeutic range) of 
CYP3A4 or CYP2C8, is prohibited while the subject is enrolled in this study.  
If the use of a CYP3A4 or CYP2C8 medication listed in Table 11 is medically necessary, and 
an alternate therapeutic agent is not available, then the subject must discontinue treatment 
with preladenant.
Preladenant may potentially inhibit the activity of other CYP3A4 or CYP2C8 substrates that 
are not identified as prohibited in Table 11.  Caution and close drug monitoring is strongly 
advised when preladenant is administered concomitantly with other CYP3A4 or CYP2C8 
substrates.  See Table 11 for more detailed information regarding adverse effects of CYP3A4 
substrates with a narrow therapeutic range.   
Investigators should check an actively updated list of drugs that are clinically relevant 
substrates, 
inducers 
or 
inhibitors 
of 
cytochrome 
P450, 
including 
CYP3A4 
(http://medicine.iupui.edu/clinpharm/ddis/table.asp) as well as the product labeling of these 
compounds for reference.
CYP3A4 inhibitors/inducers/substrates are listed below.  The subject must not take the 
treatments listed in Table 11 during the trial after the start of the study treatment.  Since this 
list is not comprehensive, the investigator should use his/her medical judgment when a 
subject presents with a medication not on the list or call the Sponsor Clinical Director for 
clarification.
 
 
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Table 11
Medications, Supplements, and Other Substances Prohibited During the Trial
Strong 3A4
Inducersa,d
Strong CYP3A4
Inhibitorsb,d
Moderate CYP3A4 
Inhibitorsb,d
CYP3A4 or CYP2C8
Substrates With 
Narrow Therapeutic 
Rangec,d
Other
carbamazepine
phenobarbital
phenytoin
rifabutin
rifampin
troglitazone
indinavir
nelfinavir
ritonavir
clarithromycin
itraconazole
ketoconazole
nefazodone
atazanavir
saquinavir
telithromycin
cannabis (oral; IV)
amprenavir
aprepitant
dilitiazem
erythromycin
fluconazole
fosamprenavir
verapamil
grapefruit, starfruit
juices
alfentanilc
ergotaminec
diergotaminec
cyclosporine c
fentanylc
pimozidec
quinidinec
sirolimusc
tacrolimusc
astemizolec,e
terfenadinec,e
cisapridec,e
paclitaxelc
repaglinidec
lurasidonec
Any chemotherapy
Any biologic therapy
Any hormonal therapy
Investigational drugs
Radiation therapy 
(except palliative 
radiation to isolated 
lesions after 
discussion with the 
Sponsor)
Proton-pump inhibitors
CYP = cytochrome P450.
a
Strong 3A4 inducers listed are those that decrease plasma AUC values of 3A4 substrates by 30% or higher.
b
Moderate inhibitors are defined as causing a ≥2- but <5-fold increase in the AUC values or 50-80% decrease in 
clearance of sensitive CYP3A substrates when the inhibitors were given at the highest approved dose and the shortest 
dosing interval in clinical evaluations.   Strong inhibitors are defined as causing a >5-fold increase in the plasma AUC 
values or more than 80% decrease in clearance.
c
CYP3A4 and CYP2C8 substrates with narrow therapeutic range refers to drugs whose exposure-response indicates 
that increases in their exposure levels by the concomitant use of CYP3A4 or CYP2C8 inhibitors may lead to serious 
safety concerns.  
For specific information, see the Classification of Substrates tables available at:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/  (then 
click “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”)
d
Compiled from the in vivo inhibitors and inducers, inhibitor classification, and substrate classification tables available 
at:  http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
(then click “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”) and from the 
CYP450 
drug 
interaction 
table 
(accessed 
June 
2012) 
available 
at: 
http://medicine.iupui.edu/clinpharm/DDIs/table.aspx .
e
Not available in the United States, and limited availability in the European Union.

Proton-pump inhibitors
The subject must not take proton-pump inhibitors (PPI) during the trial from 5 days before 
the start of the study treatment to 5 days following the last administration of preladenant.  
The investigator should use his/her medical judgment when a subject presents with a PPI
treatment or call the Sponsor Clinical Director for clarification.
Of note, antacids, such as calcium carbonate or aluminum hydroxide-based product, will be 
allowed during the study, and are recommended to be taken either 4 hours before or after 
dosing of preladenant. 
 
 
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Prohibited Concomitant Medications for Pembrolizumab
5.5.2.2
Systemic glucocorticoids > 10 mg for any purpose other than to modulate symptoms from an 
adverse event are not allowed. However, the use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor:

Inhaled steroids as part of a stable regimen for the treatment of asthma/chronic 
obstructive pulmonary disease [COPD] are permitted.

Use of physiologic doses of corticosteroids (≤10 mg daily of prednisone equivalent)
as replacement therapy for endocrinopathies may be approved after consultation with 
the Sponsor.  

Non-immune suppressing doses of steroids in patients with stable CNS metastases
may be approved after consultation with the Sponsor.

Additionally, a short limited course of steroids may be used to treat medical 
conditions and/or adverse events during the study after sponsor notification and 
consultation.

Use of prophylactic corticosteroids to avoid allergic reactions (e.g.  IV contrast dye) 
is permitted.

Use of non-systemic steroids is permitted.
Section 5.1.3 Subject Exclusion Criteria describes other medications that 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 for Preladenant
5.6.1
Medications required to treat AEs or concurrent illnesses other than those prohibited in Table 
11 are allowed during the study. Contraceptive medications as described in Section 5.1 are 
allowed.
Bisphosphonates are allowed for subjects with lytic bone metastases.  
Antiemetics, including serotonin-receptor antagonists, metoclopramide, prochlorperazine, or 
thiethylperazine are allowed.  Aprepitant is a CYP3A4 inhibitor and should not be used in the 
study.
Asymptomatic increases in liver enzymes have been noted in human subjects receiving 
preladenant. Liver function will be monitored throughout the clinical study as recommended 
by the FDA Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation [21].
 
 
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Administration of preladenant to healthy volunteers and subjects with Parkinson’s disease
have been associated with transient non-dose-related increases in systolic and diastolic BP.
Blood Pressure monitoring will be conducted during the clinical study as appropriate to
further evaluate these changes and to support subject safety. Acute and symptomatic rises in 
BP should be treated according to the standard of care. 
Every medication taken by the subject during the trial and the reason for use must be 
recorded in the eCRF.  Note that the use of any concomitant medication must relate to the 
documented medical history, prophylaxis, or an adverse event of the subject. Subjects will be 
permitted to receive appropriate supportive care measures as deemed necessary by the 
treating physician.
Please refer to preladenant investigator brochure (IB) for detailed information.
Supportive Care Guidelines for Pembrolizumab
5.6.2
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.3.2, Table 8. Where appropriate, these guidelines include the use of 
oral or intravenous treatment with corticosteroids, as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.   Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
is decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab. 
Note: If after the evaluation the event, it is determined not to be related, the Investigator does 
not need to follow the treatment guidance. Refer to Table 8, Section 5.2.3.2 for guidelines 
regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Please refer to pembrolizumab IB for detailed information.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Foods that are CYP3A inhibitors must not be consumed during the study.  Grapefruit and star 
fruit are known to be CYP3A inhibitors, and should not be consumed for 2 weeks before the 
first dose of preladenant and for the entire duration of the study.  Consumption of CYP3A4 
inhibitors, such as grapefruit juice, may significantly increase the levels of preladenant and 
cause increased toxicity.  St. John's Wort is a CYP3A inducer, and the consumption of St. 
John's Wort or products containing St. John's Wort may reduce the levels of preladenant. A 
partial list of CYP3A inhibitors is provided in Section 5.5.2.1.
 
 
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Contraception
5.7.2
Preladenant and/or pembrolizumab may have adverse effects on a fetus in utero.   
Furthermore, it is not known if preladenant and/or pembrolizumab have transient adverse 
effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either: 

postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 

have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 

has a congenital or 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 study treatment and for 120 days 
after the last dose.   Subjects must comply with one 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)/Institutional Review Boards (IRBs).  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
OR 

use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡:

Single method (one 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
 
 
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
Combination method (requires use of two 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) 
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, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up through 
120 days after the last dose of trial medication.   If there is any question that a subject of 
childbearing potential will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study.
Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with preladenant and/or 
pembrolizumab, the subject will be immediately discontinued from study 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 reaction
(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 must be reported to 
the Sponsor and followed as described in Section 7.2.
Use in Nursing Women
5.7.4
It is unknown whether preladenant and/or pembrolizumab are excreted in human milk.   
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment.
 
 
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Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.5. – Visit Requirements .
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Non-compliance with trial treatment or procedure requirements.
o
A confirmed positive serum pregnancy test.
o
Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if the 
Sponsor approves treatment continuation).

A subject with confirmed radiologic progression may continue to receive study 
treatment, after consultation with the Sponsor, if the investigator deems the 
subject is receiving clinical benefit or value from treatment.
o
Unacceptable adverse experiences as described in Section 7.2.
o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
o
Investigator’s decision to discontinue treatment.
o
Recurrent Grade 2 pneumonitis.
o
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
o
Completion of 35 treatments with preladenant and/or pembrolizumab.
Note: 35 cycles (approximately. 2 years) are calculated from the first dose
o
Administrative reasons.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed. 
 
 
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Subjects who discontinue preladenant in the monotherapy arm due to disease progression 
may at the Investigator’s discretion and after consultation with the Sponsor, cross-over to 
combination treatment. The subject will receive the dose of preladenant that has been 
determined to be safe in the combination arm (e.g., 1 dose level below the dose being tested) 
at the time of treatment cross-over. The preladenant dose will not exceed the dose the subject 
received in the monotherapy arm. The first dose of combination treatment will not occur until 
the 21-day Cycle 1 of preladenant monotherapy treatment finishes. 
Specific details regarding procedures to be performed are provided in the Arm 2 Study
Flowchart in Section 6.0.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Withdrawal from the Trial
5.8.2
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
5.9
In order to adequately evaluate the safety of the doses administered in this study, all subjects 
enrolled must meet the criteria for evaluability for Cycle 1. Subjects are considered non-
evaluable and will be replaced if:

They are allocated but not treated

They discontinue from the trial prior to completing all the safety evaluations for 
reasons other than treatment-related adverse events

They receive less than 90% of the total pembrolizumab infusion in Cycle 1 (e.g., if 
the infusion had to be discontinued due to an infusion reaction) and did not 
experience a DLT
Subjects who are not evaluable will be replaced unless accrual to the cohort has stopped.  
Non-evaluable subjects will not be counted toward the total number of subjects in the cohort 
for DLT evaluation.   
If a subject experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion between the sponsor and Investigator. However, if the subject is deriving clinical 
benefit from the trial treatment, the subject may be allowed to continue after discussion 
between the sponsor and the Investigator.
 
 
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A subject who discontinues from trial treatment or withdraws from the trial during or after 
Cycle 2 (See Section 5.2.2.1 for subject replacement during Cycle 1) will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects
4. Plans to modify or discontinue the development of the study drug. 
In the event of the Sponsor decision to no longer supply study drug, ample notification will 
be provided to the sites so that appropriate adjustments to subject treatment can be made. 
 
 
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6.0 TRIAL FLOW CHART
Flowchart
6.1
Preladenant in Monotherapy (Arm 1 ; Part 1)
Screening
Treatment Phase
Tumor 
Assessment
End of 
Treatment
Post-treatment Follow-Up Phase
Cycle 1
Cycle 2-4
Cycles 5 
and all
Subsequent 
Cycles
Every 
9 weeks
Discontinuation
Safety Follow-up
Survival 
Follow-Up11
Up to 
28 days
Prior to 
Day 1 
Cycle 1
Day 1
Day 8
Day 15
Day 1
Day 
15
Day 1
At Treatment 
Discontinuation
30 days
after the last 
dose
90 days
after the 
last dose
Every 
12 weeks post 
discontinuation
Scheduling Window 
(Days) 1
-28 to -1
+3
±3
±3
±3
±3
±3
±7
+7
+7
±7
Administrative Procedures
Informed Consent 2
X
Informed Consent for 
Optional Future 
Biomedical Research 2, 24
X
Inclusion/Exclusion
Criteria2
X
Subject Identification Card 
3
X
Medical History 2
X
Prior Oncology Treatment 
History 2
X
Prior Medications 2, 4
X
Concomitant Medications 
2, 4
X
X
X
X
X
X
X
X
X
Clinic Procedures/Assessments
Physical Examination5
X
X
X
X
X5
X
12-Lead 
Electrocardiogram 5, 6
X
Vital Signs 5, 7
X
X
X
X
X
X
X
X
ECOG Performance Status 
5
X
X
X
X
X
X
Dispense preladenant 8
X
X
X
Adverse Events Reporting 
9
X
X
X
X
X
X
X
X
X
X
 
 
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Preladenant in Monotherapy (Arm 1 ; Part 1)
Screening
Treatment Phase
Tumor 
Assessment
End of 
Treatment
Post-treatment Follow-Up Phase
Cycle 1
Cycle 2-4
Cycles 5 
and all
Subsequent 
Cycles
Every 
9 weeks
Discontinuation
Safety Follow-up
Survival 
Follow-Up11
Up to 
28 days
Prior to 
Day 1 
Cycle 1
Day 1
Day 8
Day 15
Day 1
Day 
15
Day 1
At Treatment 
Discontinuation
30 days
after the last 
dose
90 days
after the 
last dose
Every 
12 weeks post 
discontinuation
Scheduling Window 
(Days) 1
-28 to -1
+3
±3
±3
±3
±3
±3
±7
+7
+7
±7
Tumor Imaging and 
RECIST 1.1 Response 
Assessment  10
X
X
X
Survival Status 11
X
Laboratory Procedures/Assessments
Archival or Newly 
Obtained Tumor Tissue 
Collection for  Biomarker 
Analysis and Molecular 
Profiling 12
X
Blood for Genetic 
Analyses 13
X
Hematology 5, 14
X
X
X
X
X
X
X
X
X
Blood for RNA Analyses15
X
X
X
X
Blood for Stimulation 
Assay16
X
X
PBMC for Biomarker 
Analysis17
X
X17
X17
Serum for Cytokine 
Analysis 18
X
X
X
Plasma Collection for 
Proteomic Analysis 19
X
X
X
X
X
Urinalysis 5, 20
X
Chemistry 5, 21
X
X
X
X
X
X
X
X
X
 
 
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Preladenant in Monotherapy (Arm 1 ; Part 1)
Screening
Treatment Phase
Tumor 
Assessment
End of 
Treatment
Post-treatment Follow-Up Phase
Cycle 1
Cycle 2-4
Cycles 5 
and all
Subsequent 
Cycles
Every 
9 weeks
Discontinuation
Safety Follow-up
Survival 
Follow-Up11
Up to 
28 days
Prior to 
Day 1 
Cycle 1
Day 1
Day 8
Day 15
Day 1
Day 
15
Day 1
At Treatment 
Discontinuation
30 days
after the last 
dose
90 days
after the 
last dose
Every 
12 weeks post 
discontinuation
Scheduling Window 
(Days) 1
-28 to -1
+3
±3
±3
±3
±3
±3
±7
+7
+7
±7
Prothrombin Time 
(PT)/International 
Normalized Ratio (INR) 
and Activated Partial 
Thromboplastin Time 
(aPTT)22
X
Serum or Urine Pregnancy 
Test – if applicable 23
X
X
On-treatment Tumor 
Biopsy 24
X
Pharmacokinetics Evaluations
Blood for preladenant          
PK assay 25
X
X
X
X
X
 
 
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AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CR = complete response; CT = computed tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; min = minute; PGt = pharmacogenetic; PK = pharmacokinetic; PR = interval between the P wave 
and the QRS wave; QRS = interval from onset of the Q wave to end of  the S wave; QT = interval from onset of the QRS complex to end of the T-wave; QTcF = QT interval 
corrected for heart rate; SAE = serious adverse event; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase.
1.
Visits should occur within the prespecified days window (e.g. +/- 3d). 
2.
Screening procedures to be performed within 28 days prior Cycle 1 Day1 (C1D1), unless otherwise noted.   Informed consent may be obtained more than 28 days prior to 
C1D1 to allow for tumor tissue collection pre-treatment.
3.
Subject Identification Card must be given to Subject at the start of study and must be collected when the Subject is no longer participating in any portion of the study.  
4.
Record medications taken 28 days prior to C1D1 and all medications taken up to and including 30 days after the last dose of study drug or the End-of-Treatment 
(whichever is later).  Refer to Inclusion/Exclusion criteria for prohibited medications and washout periods.
5.
Must be performed within 3 days prior to Day 1 of each cycle unless otherwise noted to coincide with the clinical and laboratory procedures.   Physical examination, 
ECOG Performance Status, ECG, Vital Signs must be performed within 3 days prior to C1D1.  It is not necessary to repeat C1D1 testing if the Screening testing was 
performed within 3 days prior to C1D1. Full Physical Examination will be performed at the Screening Visit and at the Treatment Discontinuation Visit. Directed Physical 
Examination will be done at all other visits.
6.
Perform standard 12-lead ECG reporting ventricular rate, PR and QRS duration and QT/QTcF intervals prior to any blood collections or other study procedures.   
7.
Vital signs include blood pressure, pulse rate, and respiratory rate while sitting; temperature, height (at screening only), and weight.  
8.
After Cycle 1, preladenant may be dispensed up to 3 days prior to the cycle start to coincide with the physical exam.   Study drug may only be dispensed after the treating 
physician has confirmed the subject will continue on to the next cycle.   Each cycle is 21 days.  Subjects may receive treatment for up to 35 cycles.
9.
Adverse events and serious adverse events will be recorded from the time of treatment allocation.  All adverse events and serious adverse events that occur after the 
consent form is signed but before treatment allocation must be reported by the Investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy or a study procedure.  After treatment discontinuation, each subject 
will be followed for 90 days for adverse event and serious adverse event monitoring, 30 days if the subject initiates new anticancer therapy less than 30 days after study 
treatment discontinuation, or the day new anticancer therapy is initiated if between 30 days and 90 days after study treatment discontinuation.  Subjects with an ongoing AE of 
Grade >1 at the time of treatment discontinuation will be followed until resolution of the AE to Grade 0-1, until considered stable by the treating physician, or until beginning 
a new anticancer therapy, whichever occurs first.
10. Baseline radiology images by CT (or MRI) of chest, abdomen, and pelvis, and all known tumor sites (if evaluable by imaging) must be obtained within 28 days prior to 
C1D1 and must be repeated every 9 weeks (±7 days) from C1D1 (See SIM).   Imaging must be obtained at the End of Treatment visit at discontinuation unless done within 
the previous 4 weeks. Images are to be submitted to the central imaging vendor for potential future central analysis.
11. After confirmed disease progression subjects will be contacted by telephone every 12 weeks for survival until withdrawal of consent to participate in the study, becoming 
lost to follow-up, death, or end of the study, whichever occurs first.
12. Tumor tissue (archival or newly obtained biopsy) will be required at Screening upon signing the informed consent for the study.    This sample will be assessed to collect 
information on biomarkers for all subjects enrolled in the study.  Tumor tissue will be sent to central laboratory for biomarker analysis and leftover tissue may be saved for 
future biomedical research (FBR) if the subject signs the FBR consent.
13. This blood sample will be drawn for planned analysis of the association between genetic variants in DNA and drug response.  If the IRB/IEC does not approve of the 
planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be limited.  
Leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. 
14. Hematology tests include complete blood count with 5-part differential and platelets.   Hematology does not need to be repeated on C1D1 if Screening samples were 
obtained within 3 days of C1D1.
15. Blood sample for RNA analysis should be obtained predose of administration of preladenant on Day 1 of Cycle 1, Cycle 2, Cycle 5 and at the Treatment Discontinuation 
Visit.  Leftover extracted RNA will be stored for future biomedical research if the subject signs the FBR consent. 
16. Procedures for collection of  PD samples and precise time points are described in the Procedures Manual. Blood sample for Stimulation Assay should be obtained 
predose, 2hr and 4hr post-dose of administration of preladenant on Day1 of Cycle 1 and Cycle 2. 
17. Procedures for collection of PD samples and precise time points are described in the Procedures Manual.  PBMC samples for Biomarker Analysis should be obtained at 
screening, and predose of administration of preladenant on Day 15 of Cycle 1, Cycle 2 and Cycle 3. 
 
 
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18. Procedures for collection of PD samples and precise time points are described in the Procedures Manual. Serum Sample for cytokine analysis should be obtained at 
predose of administration of preladenant  on Day 1 of each cycle for all treatment cycles. 
19. Procedures for collection of PD samples and precise time points are described in the Procedures Manual. Plasma Collection for Proteomic Analysis should be obtained at 
each time point when preladenant PK samples are collected. Samples need to be obtained at pre-dose, 1 hour, 2 hours, 4 hours and 8 hours after drug administration of 
preladenant (+/- 10 minutes) on Day 1 of Cycle 1 and Cycle 2; Prior to dosing on Cycle 1 Day 8; Prior to dosing on Cycle 1 Day 15; Prior to dosing on Cycle 4 Day 1; And, 
Prior to dosing on Cycle 8 Day 1.  If the sample day falls on a weekend or a holiday, please consult the Sponsor for alternate sample collection times.
20. Urine dipstick or microscopic urinalysis may be performed according to site SOP.  Urine dipstick includes pH, protein, glucose, leukocyte-esterase, ketones, and nitrite.   
Mandatory microscopic urinalysis will be performed if the dipstick results are abnormal.  Microscopic analysis includes white blood cell count, red blood cell count, epithelial 
cells and casts.
21. Serum Chemistry tests include sodium, potassium, calcium, phosphate, chloride, bicarbonate/CO2 (if performed in region), BUN or Urea , creatinine (Cystatin C if 
abnormal), SGOT (AST), SGPT (ALT), total proteins, total bilirubin (direct bilirubin if abnormal), albumin, alkaline phosphatase, glucose, uric acid, amylase, lipase, Lactate 
Dehydrogenase (LDH) and γ-glutamyltransferase (GGT).   Serum chemistry does not need to be repeated on C1D1 if screening samples were obtained within 3 days of C1D1.  
22. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Furthermore, any subject receiving anticoagulant therapy 
should have coagulation factors monitored closely throughout the trial.
23. For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours prior to the first dose of study treatment.  If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required and should be negative.  Additional pregnancy testing should be conducted as per local 
regulations where applicable.
24. On-treatment tumor biopsy will be performed on Day 15 of Cycle 2 (+/- 7 Days).  Tumor tissue will be sent to designated laboratory for biomarker analysis and leftover 
tissue may be saved for future biomedical research if the subject signs the FBR consent.
25. Procedures for collection of PK samples and precise time points are described in the Procedures Manual. Samples for preladenant and its metabolites pharmacokinetic 
(PK) testing should be collected prior to dosing, and 1 hour, 2 hours, 4 hours and 8 hours after drug administration of preladenant (+/- 10 minutes) on Cycle 1 Day 1 and 
Cycle 2 Day 1; Prior to dosing on Cycle 1 Day 8; Prior to dosing on Cycle 1 Day 15; Prior to dosing on Cycle 4 Day 1; And, Prior to dosing on Cycle 8 Day 1.  If the sample 
day falls on a weekend or a holiday, please consult the Sponsor for alternate sample collection times.
 
 
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Preladenant in Combination with Pembrolizumab  (Arm 2 ; Part 1 and Part 2) and (cross-over subjects)
Screening
Treatment Phase
Tumor 
Assessment
End of 
Treatment
Post-treatment Follow-Up Phase 9
Cycle 1
Cycle 2-4
Cycles 5 
and all 
Subsequent 
Cycles
Every 
9 weeks
Discontinuation
Safety Follow-up
Survival 
Follow-Up12
Up to 
28 days
Prior to 
Day 1 
Cycle 1
Day 1
Day 8
Day 15
Day 1
Day 
15
Day 1
At Treatment 
Discontinuation
30 days
after the last 
dose
90 days
after the 
last dose
Every 
12 weeks post 
discontinuation
Scheduling Window 
(Days) 1
-28 to -1
+3
±3
±3
±3
±3
±3
±7
+7
+7
±7
Administrative Procedures
Informed Consent 2
X 
Informed Consent for 
Optional Future 
Biomedical Research 2, 27
X
Inclusion/Exclusion 
Criteria2
X
Subject Identification Card 
3
X
Medical History 2
X
Prior Oncology Treatment 
History 2
X
Prior Medications 2, 4
X
Concomitant Medications 
2, 4
X
X
X
X
X
X
X
X
X
Clinic Procedures/Assessments
Physical Examination5
X
X
X
X
X5
X
12-Lead 
Electrocardiogram 5, 6
X
Vital Signs 5, 7
X
X 
X
X
X
X
X
X
ECOG Performance Status 
5
X
X 
X
X
X
X
Dispense Preladenant 8
X
X
X
Pembrolizumab infusion9
X
X
X
Adverse Events Reporting 
10
X
X
X
X
X
X
X
X
X
X
 
 
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Preladenant in Combination with Pembrolizumab  (Arm 2 ; Part 1 and Part 2) and (cross-over subjects)
Screening
Treatment Phase
Tumor 
Assessment
End of 
Treatment
Post-treatment Follow-Up Phase 9
Cycle 1
Cycle 2-4
Cycles 5 
and all 
Subsequent 
Cycles
Every 
9 weeks
Discontinuation
Safety Follow-up
Survival 
Follow-Up12
Up to 
28 days
Prior to 
Day 1 
Cycle 1
Day 1
Day 8
Day 15
Day 1
Day 
15
Day 1
At Treatment 
Discontinuation
30 days
after the last 
dose
90 days
after the 
last dose
Every 
12 weeks post 
discontinuation
Scheduling Window 
(Days) 1
-28 to -1
+3
±3
±3
±3
±3
±3
±7
+7
+7
±7
Tumor Imaging and 
RECIST 1.1 Response 
Assessment  11
X
X
X
Survival Status 12
X
Laboratory Procedures/Assessments
Archival or Newly 
Obtained Tumor Tissue 
Collection for Biomarker
Analysis and Molecular 
Profiling 13
X
Blood for Genetic 
Analyses 14
X
Hematology 5, 15
X
X
X
X
X
X
X
X
X
Blood for RNA Analyses16
X
X
X
X
Blood for Stimulation 
Assay17
X
X
PBMC for Biomarker 
Analysis18
X
X18
X18
Serum for Cytokine 
Analysis 19
X
X
X
Plasma Collection for 
Proteomic Analysis 20
X
X
X
X
X
Urinalysis 5, 21
X
Chemistry 5, 22
X
X
X
X
X
X
X
X
X
 
 
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Preladenant in Combination with Pembrolizumab  (Arm 2 ; Part 1 and Part 2) and (cross-over subjects)
Screening
Treatment Phase
Tumor 
Assessment
End of 
Treatment
Post-treatment Follow-Up Phase 9
Cycle 1
Cycle 2-4
Cycles 5 
and all 
Subsequent 
Cycles
Every 
9 weeks
Discontinuation
Safety Follow-up
Survival 
Follow-Up12
Up to 
28 days
Prior to 
Day 1 
Cycle 1
Day 1
Day 8
Day 15
Day 1
Day 
15
Day 1
At Treatment 
Discontinuation
30 days
after the last 
dose
90 days
after the 
last dose
Every 
12 weeks post 
discontinuation
Scheduling Window 
(Days) 1
-28 to -1
+3
±3
±3
±3
±3
±3
±7
+7
+7
±7
Prothrombin Time 
(PT)/International 
Normalized Ratio (INR) 
and Activated Partial 
Thromboplastin Time 
(aPTT)23
X
Serum or Urine Pregnancy 
Test – if applicable 24
X
X
Thyroid Function (T3 or 
FT3, FT4 and TSH)
25
X
X
X
X
X
X
Anti-pembrolizumab 
Antibodies 26
X
X
X
X
On-treatment Tumor 
Biopsy 27
X
Pharmacokinetics Evaluations
Blood for Preladenant          
PK assay 28
X
X
X
X
X
Blood for Pembrolizumab   
PK assay 29
X
X
X
X
 
 
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AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CR = complete response; CT = computed tomography; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; min = minute; PGt = pharmacogenetic; PK = pharmacokinetic; PR = interval between the P wave and 
the QRS wave; QRS = interval from onset of the Q wave to end of  the S wave; QT = interval from onset of the QRS complex to end of the T-wave; QTcF = QT interval 
corrected for heart rate; SAE = serious adverse event; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase.
1
Visits should occur within the prespecified days window (e.g. +/- 3d). 
2.
Screening procedures to be performed within 28 days prior Cycle 1 Day1 (C1D1), unless otherwise noted.   Informed consent may be obtained more than 28 days prior to 
C1D1 to allow for tumor tissue collection pre-treatment.
3.
Subject Identification Card must be given to Subject at the start of study and must be collected when the Subject is no longer participating in any portion of the study.  
4.
Record medications taken 28 days prior to C1D1 and all medications taken up to and including 30 days after the last dose of study drug or the End-of-Treatment (whichever 
is later).  Refer to Inclusion/Exclusion criteria for prohibited medications and washout periods.
5.
Must be performed within 3 days prior to Day 1 of each cycle unless otherwise noted to coincide with the clinical and laboratory procedures.   Physical examination, ECOG 
Performance Status, ECG, Vital Signs must be performed within 3 days prior to C1D1.  It is not necessary to repeat C1D1 testing if the Screening testing was performed within 3 
days prior to C1D1. Full Physical Examination will be performed at the Screening Visit and at the Treatment Discontinuation Visit. Directed Physical Examination will be done 
at all other visits..
6.
Perform standard 12-lead ECG reporting ventricular rate, PR and QRS duration and QT/QTcF intervals prior to any blood collections or other study procedures.   
7.
Vital signs include blood pressure, pulse rate, and respiratory rate while sitting; temperature, height (at screening only), and weight.  
8.
After Cycle 1, Preladenant may be dispensed up to 3 days prior to the cycle start to coincide with the physical exam.   Study drug may only be dispensed after the treating 
physician has confirmed the subject will continue on to the next cycle.   Each cycle is 21 days.  Subjects may receive treatment for up to 35 cycles.
9.
Pembrolizumab will be administered via IV infusion on Day 1 of each cycle.   See Table 6 for dosing instructions.   Each cycle is 21 days.  Subjects may receive treatment 
for up to 35 cycles.
10. Adverse events and serious adverse events will be recorded from the time of treatment allocation.  All adverse events and serious adverse events that occur after the consent 
form is signed but before treatment allocation must be reported by the Investigator if they cause the subject to be excluded from the trial, or are the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy or a study procedure.  After treatment discontinuation, each subject will be followed for 90 
days for adverse event and serious adverse event monitoring, 30 days if the subject initiates new anticancer therapy less than 30 days after study treatment discontinuation, or the 
day new anticancer therapy is initiated if between 30 days and 90 days after study treatment discontinuation. Subjects with an ongoing AE of Grade >1 at the time of treatment 
discontinuation will be followed until resolution of the AE to Grade 0-1, until considered stable by the treating physician, or until beginning a new anticancer therapy, whichever 
occurs first.
11. Baseline radiology images by CT (or MRI) of chest, abdomen, and pelvis, and all known tumor sites (if evaluable by imaging) must be obtained within 28 days prior to 
C1D1 and must be repeated every 9 weeks (±7 days) from C1D1.   Confirmatory imaging are required for all responses (CR and PR) seen by imaging at the study site should be 
obtained at least 4-5 weeks after the documented response.   Imaging must be obtained at the End of Treatment visit at discontinuation unless done within the previous 4 weeks. 
Images are to be submitted to the central imaging vendor for potential future central analysis.
12. After confirmed disease progression subjects will be contacted by telephone every 12 weeks for survival until withdrawal of consent to participate in the study, becoming 
lost to follow-up, death, or end of the study, whichever occurs first.
13. Tumor tissue (archival or newly obtained biopsy) will be required at Screening upon signing the informed consent for the study.    This sample will be assessed to collect 
information on biomarkers for all subjects enrolled in the study. Tumor tissue will be sent to central laboratory for biomarker analysis and leftover tissue may be saved for future 
biomedical research (FBR) if the subject signs the FBR consent.
14. This blood sample will be drawn for planned analysis of the association between genetic variants in DNA and drug response.  If the IRB/IEC does not approve of the 
planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data analysis will be limited.  Leftover 
extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.
15. Hematology tests include complete blood count with 5-part differential and platelets.   Hematology does not need to be repeated on C1D1 if Screening samples were 
obtained within 3 days of C1D1.
16. Blood sample for RNA analysis should be obtained predose of administration of preladenant on Day 1 of Cycle 1, Cycle 2, Cycle 5 and at the Treatment Discontinuation 
Visit.  Leftover extracted RNA will be stored for future biomedical research if the subject signs the FBR consent. 
 
 
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17. Procedures for collection of  PD samples and precise time points are described in the Procedures Manual. Blood sample for Stimulation Assay should be obtained predose, 
2hr and 4hr post-dose of administration of preladenant on Day1 of Cycle 1 and Cycle 2. 
18. Procedures for collection of PD samples and precise time points are described in the Procedures Manual.  PBMC samples for Biomarker Analysis should be obtained at 
screening, and predose of administration of preladenant  on Day 15 of Cycle 1, Cycle 2 and Cycle 3. 
19. Procedures for collection of PD samples and precise time points are described in the Procedures Manual. Serum Sample for cytokine analysis should be obtained at predose 
of administration of preladenant  on Day 1 of each cycle for all treatment cycles. 
20. Procedures for collection of PD samples and precise time points are described in the Procedures Manual. Plasma Collection for Proteomic Analysis should be obtained at 
each time point when preladenant PK samples are collected. Samples need to be obtained at pre-dose, 1 hour, 2 hours, 4 hours and 8 hours after drug administration of 
preladenant (+/- 10 minutes) on Day 1 of Cycle 1 and Cycle 2; Prior to dosing on Cycle 1 Day 8; Prior to dosing on Cycle 1 Day 15; Prior to dosing on Cycle 4 Day 1; And, Prior 
to dosing on Cycle 8 Day 1.  If the sample day falls on a weekend or a holiday, please consult the Sponsor for alternate sample collection times.
21. Urine dipstick or microscopic urinalysis may be performed according to site SOP.  Urine dipstick includes pH, protein, glucose, leukocyte-esterase, ketones, and nitrite.   
Mandatory microscopic urinalysis will be performed if the dipstick results are abnormal.  Microscopic analysis includes white blood cell count, red blood cell count, epithelial 
cells and casts.
22. Serum Chemistry tests include sodium, potassium, calcium, phosphate, chloride, bicarbonate/CO2 (if performed in region), BUN or Urea, creatinine (Cystatin C if 
abnormal), SGOT (AST), SGPT (ALT), total proteins, total bilirubin (direct bilirubin if abnormal), albumin, alkaline phosphatase, glucose, uric acid, amylase, lipase, Lactate 
Dehydrogenase (LDH) and γ-glutamyltransferase (GGT).   Serum chemistry does not need to be repeated on C1D1 if screening samples were obtained within 3 days of C1D1.  
23. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Furthermore, any subject receiving anticoagulant therapy 
should have coagulation factors monitored closely throughout the trial.
24. For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours prior to the first dose of study treatment.  If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required and should be negative.  Additional pregnancy testing should be conducted as per local 
regulations where applicable.
25. Samples for thyroid function testing should be collected at screening, on Day 1 of Cycle 1 and on Day 1 of Cycle 2.  Following Cycle 2, testing will be performed on Day 1 
of every other cycle (i.e.  Cycles 1, 2, 4, 6, etc.), at discontinuation, and at the 30 days Safety Follow-up Visit.  Analysis of T3 or FT3, FT4 and TSH will be performed by the 
local study site laboratory (or by central vendor if testing is not available at the local study site laboratory).
26. ADA samples for pembrolizumab will be collected within 24 hours before infusion in cycles 1, 2, 4, 8 and every 4 cycles thereafter, 30 days after discontinuation of study 
drug (or until the subject starts new anti-cancer therapy). Please refer to the procedure manual for detailed sampling timepoints.
27. On-treatment tumor biopsy will be performed on Day 15 of Cycle 2 (+/- 7 Days). Tumor tissue will be sent to designated l laboratory for biomarker analysis and leftover 
tissue may be saved for future biomedical research if the subject signs the FBR consent.
28. Procedures for collection of PK samples and precise time points are described in the Procedures Manual. Samples for preladenant and its metabolites pharmacokinetic (PK) 
testing should be collected prior to dosing, and 1 hour, 2 hours, 4 hours and 8 hours after drug administration of preladenant (+/- 10 minutes) on Cycle 1 Day 1 and Cycle 2 Day 
1; Prior to dosing on Cycle 1 Day 8; Prior to dosing on Cycle 1 Day 15; Prior to dosing on Cycle 4 Day 1; And, prior to dosing on Cycle 8 Day 1.  If the sample day falls on a 
weekend or a holiday, please consult the Sponsor for alternate sample collection times.
29. Procedures for collection of PK samples and precise time points are described in the Procedures Manual.    Pre-dose (trough) PK samples for pembrolizumab will be 
collected within 24 hours before infusion in cycles 1, 2, 4, 8 and every 4 cycles thereafter, 30 days after discontinuation of study drug (or until the subject starts new anti-cancer 
therapy). Post-dose (peak) PK samples will be drawn within 30 minutes after end of pembrolizumab infusion in cycles 1 and 8.
 
 
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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
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
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/IEC 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.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial as per Section 5.1.2 and 5.1.3.
Subject Identification Card
7.1.1.3
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. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the Investigator or qualified designee.  Medical history 
will collect all active conditions and any condition diagnosed within the prior 10 years that 
are considered clinically significant by the investigator. Details regarding the disease for 
which the subject has been enrolled in this trial will be recorded separately and should not be 
listed in medical history (see Section 7.1.1.5.1).
Disease Details and Treatments
7.1.1.5
7.1.1.5.1 Oncology Disease Details
Prior and current details regarding the disease for which the subject has been enrolled in the
trial will be obtained by the investigator or qualified designee.
7.1.1.5.2 Prior Oncology Treatment History
The investigator or qualified designee will record all prior cancer treatments including
systemic treatments, radiation, radiosurgeries, and surgeries regardless of time prior to first
dose of study treatment.
 
 
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Prior and Concomitant Medications Review
7.1.1.6
7.1.1.6.1 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 this trial will be recorded separately and not listed as a prior medication (see 
Section 7.1.1.5.2).
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Post-Treatment Safety Follow-Up visit, 30 days after the last dose 
of study drug. 
After the Safety Follow-Up visit, all medications related to reportable SAEs and ECIs as 
defined in Section 7.2, should be recorded.
All new anti-cancer therapy initiated after the study start must be recorded in the eCRF. If a
subject initiates another anti-cancer therapy other than the assigned study treatment(s), the
study treatment(s) should be discontinued and the subject will move into the survival follow-
up phase; if a subject initiates a new anti-cancer therapy within 30 days after the last dose of
the trial treatment, the 30 day Safety Follow-up visit should occur before the first dose of the
new therapy.
Assignment of Screening Number
7.1.1.7
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 treatment allocation.  Each subject will be 
assigned only one screening number.  Screening numbers must not be re-used for different 
subjects.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Treatment/Randomization Number
7.1.1.8
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation.  Although subjects are being allocated, 
and not randomized to treatment, this unique number is termed a randomization number 
throughout the protocol for operational purposes.  Allocation of subjects will be managed by 
the Sponsor through an IVRS/IWRS. Once a treatment/randomization number is assigned to 
a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
 
 
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Trial Compliance (Medication)
7.1.1.9
Preladenant will be taken orally twice a day by the subject at the dose allocated through an 
IVRS/IWRS for the currently enrolling cohort. During on-site visits, administration of 
preladenant will be witnessed by the investigator and/or trial staff.   The administration, the 
dose, the time of administration, as well as any immediate reactions at the time of intake will 
be documented in the eCRF.
For non-visit days, preladenant will be taken at home. When a subject attends a study visit, 
he/she will bring any unused capsules. Compliance will be assessed via tablet counts of 
returned medication and/or subject report, and will be reinforced at each visit. Subjects will 
be instructed to return preladenant containers with them at the time of clinic visits (See 
Pharmacy Manual).
Pembrolizumab will be administered at the fixed dose of 200 mg by IV infusion on Day 1 of 
each 21-day cycle.  The Pharmacy Manual contains specific instructions for the preparation 
and administration of the infusion solution. Administration of pembrolizumab will be 
witnessed by the investigator and/or trial staff. The total volume of pembrolizumab infused 
will be compared with the total volume prepared to determine compliance with each dose 
administered (See Pharmacy Manual).
Interruptions from the protocol specified treatment(s) for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
Clinical Procedures/Assessments
7.1.2
Adverse Event Monitoring  
7.1.2.1
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) and more frequently if 
clinically indicated.  Adverse events will be graded and recorded throughout the trial and 
during the follow-up period according to NCI CTCAE Version 4.0 (see Appendix 12.5).  
Toxicities will be characterized in terms including seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Examination
7.1.2.2
7.1.2.2.1 Full Physical Examination
The Investigator or qualified designee will perform a complete physical examination during 
the screening period.  Clinically significant findings from the screening examination should 
be recorded as medical history.  
A full physical examination should be repeated at the timepoints outlined in the Trial Flow 
Chart (Section 6.0).  After the first dose of study treatment, new clinically significant 
abnormal findings should be recorded as AEs.
 
 
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7.1.2.2.2 Directed Physical Examination
For visits that do not require a full physical examination (Section 6.0), the Investigator or 
qualified designee will perform a directed physical examination as clinically indicated prior 
to the administration of the trial treatment.  After the first dose of study treatment, new 
clinically significant abnormal findings should be recorded as AEs.
Height, Weight, and Vital Signs 
7.1.2.3
Height will be measured at screening only.
Weight will be measured at the timepoints outlined in the Trial Flow Chart (Section 6.0).  
The Investigator or qualified designee will measure vital signs at the time points outlined in 
the Trial Flow Chart (Section 6.0).  Vital signs include body temperature, pulse, respiratory 
rate, and blood pressure. Specifically, during on-site visits, blood pressure will be carefully 
monitored throughout the day.
Electrocardiogram 
7.1.2.4
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening.  Clinically significant abnormal findings should be recorded in 
the medical history. Additional ECGs may be performed as clinically necessary.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
7.1.2.5
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 administered at the 
clinic, and during the Follow-Up Period as specified in the Trial Flow Chart (Section 6.0).
Tumor Imaging and Assessment of Disease
7.1.2.6
Tumor imaging should be acquired by computed tomography (CT, strongly preferred).  
Magnetic resonance imaging (MRI) should be used when CT is contraindicated or for 
imaging of the brain.  The same imaging technique regarding modality and use of contrast 
should be used in a subject throughout the trial to optimize the visualization of existing and 
new tumor burden. The process for image collection and transmission to the central imaging 
vendor (CIV) can be found in the Site Imaging Manual (SIM).  
Although RECIST 1.1 references to maximum of 5 target lesions in total and 2 per organ, the 
Sponsor allows maximum of 10 target lesions in total and 5 per organ, if clinically relevant to 
enable a broader sampling of tumor burden. All scheduled images for all study subjects from 
the sites will be submitted to the CIV. In addition, additional imaging (including other 
modalities) that are obtained at an unscheduled time point to determine disease progression, 
as well as imaging obtained for other reasons but captures radiologic progression, should be 
submitted to the CIV as well.
7.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization.  The site trial team must review screening images to confirm the subject has 
measurable disease per RECIST 1.1. 
 
 
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Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e. without evidence of progression by imaging (confirmed by magnetic 
resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by computed 
tomography (CT) imaging if CT used at prior imaging) for at least 4 weeks prior to the first 
dose of trial treatment. Any neurologic symptoms must have returned to baseline and 
subjects must have no evidence of new or enlarging brain metastases, and have not used 
steroids for brain metastases for at least 7 days prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
7.1.2.6.2 Tumor Imaging During Trial 
The first on-trial imaging assessment should be performed at 9 weeks (63 days ±7 days]) 
from the date of randomization.  Subsequent tumor imaging should be repeated every 9
weeks or more frequently if clinically indicated.  Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression, the start of new anti-cancer treatment, withdrawal of 
consent, or death, whichever occurs first. 
Per RECIST 1.1, partial and complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented.  
The tumor imaging to confirm a response may be performed, at the earliest 4 weeks after the 
first indication of a response, or at the next scheduled scan (i.e., 9 weeks later), whichever is 
clinically indicated. Subjects will then return to regular scheduled imaging every 9 weeks, 
starting with the next scheduled imaging time point.  Subjects who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point.
Per irRECIST (Section 7.1.2.6.5), disease progression should be confirmed by the site at least 
4 weeks after site-assessed first radiologic evidence of PD in clinically stable subjects.  
Subjects who have unconfirmed disease progression may continue on treatment at the 
discretion of the site Investigator until progression is confirmed by the site provided they 
have met the conditions detailed in Section 7.1.2.6.5.  Subjects who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if clinically stable. 
Subjects who have confirmed disease progression as assessed by the site, will discontinue 
trial treatment.  Exceptions are detailed in Section 7.1.2.6.5.
7.1.2.6.3 End of Treatment and Follow-up Treatment 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 9 weeks) to monitor disease status 
 
 
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until the start of a new anticancer treatment, disease progression, death, or the end of the trial, 
whichever occurs first.
7.1.2.6.4 RECIST 1.1 Assessment of Disease
All images will be submitted to a central imaging vendor for potential analysis at the end of 
the study.   RECIST 1.1 will be only used by the central imaging vendor for potential 
retrospective analysis of the primary measure for assessment of tumor response and date of 
disease progression.
7.1.2.6.5 irRECIST Assessment of Disease 
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by the site 
Investigator/local radiology reviewers to assess tumor response and progression, and make 
treatment decisions.  This data will be collected in the clinical database. 
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site Investigator/radiology assessment.  This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some subjects can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response.  Subjects that are deemed clinically unstable are not 
required to have repeat tumor imaging for confirmation of PD.  Tumor flare includes any of 
the following scenarios:
•
Worsening of existing target lesion(s)
•
Worsening of existing nontarget lesion(s)
•
Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1, it is at the 
discretion of the Investigator whether to continue a subject on trial medication until repeat 
imaging is obtained (using irRECIST for subject management (see Table 12).  This clinical 
judgment decision by the site Investigator should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data.  Subjects 
may receive trial medication and the tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD by irRECIST per site assessment.  Clinical stability is defined as the 
following: 
•
Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values
•
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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Any subject deemed clinically unstable should be discontinued from trial treatment at site-
assessed first radiologic evidence of PD and is not required to have repeat imaging for PD 
confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site Investigator should consider all target and non-target lesions, as well as any 
incremental new lesion(s).
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the 
following occur (as assessed by irRECIST): 
•
Target lesion sum of diameters is <20% or <5 mm absolute increase compared to nadir
•
Non-target disease resulting in initial PD is stable or qualitatively improved
•
New lesion resulting in initial PD is stable or qualitatively improved 
•
No incremental new lesion(s) since last evaluation
•
No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
Investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule. 
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST):
•
Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir
•
Non-target disease resulting in initial PD is qualitatively worse
•
New lesion resulting in initial PD is qualitatively worse
•
Additional new lesion(s) since last evaluation
•
Additional new non-target lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor.  In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in Section 6.0 
and be submitted to the central imaging vendor.
 
 
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Additional details about irRECIST are provided in the Sponsor TIP Sheet for RECIST 1.1 
and irRECIST.
Table 12
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging 
at >4 weeks at 
site to confirm 
PD
May continue trial 
treatment at the local 
site Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
irRECIST.
Repeat imaging 
at >4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging confirms 
PD by irRECIST 
at the local site
No additional 
imaging required
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor)
No additional 
imaging required
Not applicable
Repeat tumor 
imaging shows 
SD, PR or CR by 
irRECIST at the 
local site
Continue 
regularly 
scheduled 
imaging 
assessments
Continue trial 
treatment at the local 
site investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments
May restart trial 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next tumor 
image should occur 
according to the regular 
imaging schedule
CR=complete response; irRECIST=immune-related response evaluation criteria in solid tumors; 
PD=progressive disease; PFS=progression-free survival; PR=partial response; SD=stable disease
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 Study Procedures 
Manual.  Refer to the Trial Flow Chart (Section 6.0) for the schedule of laboratory 
assessments.
 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 13.
Table 13
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT
WBC (total and 
differential)e
Aspartate aminotransferase
Specific gravity 
Total T3 or free T3, FT4, 
and TSHb,d
RBC
Bicarbonate/CO2c
Microscopic exam, if 
abnormal results are noted
Absolute 
lymphocyte count
Calcium
Chloride
Absolute neutrophil 
count
Creatinine (Cystatin C if 
abnormal)
Glucose
Phosphorus
Potassium
Sodium
Total bilirubin  
Direct bilirubin
Total protein
GGT
Blood urea nitrogen
Uric acid
Amylase
Lipase
LDH
a
Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1.  Pregnancy tests must 
be repeated prior to every cycle if required or as specified per local regulatory guidance.
b
T3 is preferred; if not available free T3 may be tested. 
c
If this test is not done as part of local standard of care, this test does not need to be performed.  
d
If the local laboratory is unable to perform these tests, the site should submit the sample to the central 
laboratory for testing. Details are provided in the Procedure Manual.
e
Report % or absolute results per standard of practice. Report the results in the same manner throughout the 
trial.
aPTT=activated partial thrombin time; FT4=free thyroxine; GGT=gamma-glutamyl transferace; INR=insulin 
receptor; PT=prothrombin time; RBC=red blood cells; T3=triothyronine; TSH=thyroid stimulating hormone 
(thyrotropin); WBC=white blood cells.
Laboratory tests for screening should be performed within 3 days prior to the first dose of 
trial treatment.  An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose.  After Cycle 1, pre-dose laboratory safety tests can be 
conducted up to 72 hours prior to dosing unless otherwise noted on the flow charts. 
Laboratory test results must be reviewed by the Investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment.  Unresolved abnormal 
laboratory values that are drug-related AEs should be followed until resolution.  Laboratory 
tests do not need to be repeated after the end of treatment if laboratory results are within the 
normal range.  
 
 
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Pregnancy Test 
7.1.3.2
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 of each cycle of 
trial treatment and 30 days post-treatment.  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. 
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.3
7.1.3.3.1 Blood Collection for PK Assessment for Preladenant
Samples for PK evaluations for preladenant will be collected at the timepoints outlined in 
Section 6.0 – Trial Flow Chart.  Sample collection, storage and shipment instructions for 
blood samples will be provided in the Procedures Manual.   
7.1.3.3.2 Blood Collection for PK and ADA Assessment for Pembrolizumab
To further evaluate pembrolizumab immunogenicity and exposure of the proposed dosing 
regimen, sample collections for analysis of antidrug antibodies (ADA) and PK are currently 
planned as shown in the Trial Flow Chart (Section 6.0).  Blood samples will be obtained to 
measure PK of serum pembrolizumab.  The pembrolizumab serum maximum concentration 
(Cmax) and minimum concentration (Ctrough) at planned visits and times will be 
summarized.  
If ongoing ADA and/or PK results continue to be consistent with existing ADA and/or PK 
data from other pembrolizumab clinical trials, it may be decided to discontinue or reduce 
further sample collection in this trial.  Should this occur, it will be communicated by an 
administrative memo. 
Pharmacokinetic data will also be analyzed using nonlinear mixed effects modeling.  Based 
on PK data obtained in this trial as well as PK data obtained from other studies, a population 
PK analysis will be performed to characterize PK parameters (clearance [CL], volume of 
distribution [V]) and evaluate the effect of extrinsic and intrinsic factors to support proposed 
dosing regimen.  Pharmacokinetic data will also be used to explore the exposure response 
relationships for pembrolizumab antitumor activity/efficacy as well as safety in the proposed 
patient population, if feasible.  The results of these analyses, if performed, will be reported 
separately.
7.1.3.3.3 Blood Collection for RNA, Plasma and Serum Biomarker Analysis
Blood should be collected pre-dose at the timepoints outlined in Section 6.0 – Trial Flow 
Chart. Leftover RNA, plasma, and serum will be stored at the end of the trial for FBR if the 
subject has consented (see Section 4.2.3.5).
Further details are provided in the Procedures Manual.
Planned Genetic Analysis Sample Collection (On-Treatment Tumor Biopsy)
7.1.3.4
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.  
 
 
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On-treatment tumor biopsy should be performed on Cycle 2 Day 15 (+/- 7 days).  Samples
will be collected for planned analysis of associations between genetic variants in
germline/tumor DNA and drug response.  
If a documented law or regulation prohibits (or local IRB/Independent Ethics Committee
[IEC] does not approve) sample collection for these purposes, then such samples should not
be collected at the corresponding sites.  
Leftover DNA extracted from planned genetic analysis samples will be stored for future
biomedical research only if subject signs the Future Biomedical Research consent.
Future Biomedical Research Samples 
7.1.3.5
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research.

Remaining RNA.

Remaining plasma and serum from biomarker analyses.

Remaining main study tumor.
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue treatment prior to completion of the treatment regimen should be 
encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the End of Treatment visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. .
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  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).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal 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 withdrawal cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.
Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines
Subject Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Domiciling
7.1.4.3
Subjects will report to the clinical research unit (CRU) prior to dosing on Day 1 of each 21-
day cycle to allow for completion of all pre-treatment procedures as outlined in the Trial 
Flow Chart (Section 6.0). 
Calibration of Critical Equipment
7.1.4.4
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment - as required for inclusion laboratory evaluations and trial 
assessments.  

Imaging equipment – calibration and maintenance of imaging equipment as required 
for study objectives per local regulations.  

ECG equipment – as required for study assessments.
 
 
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
Infusion equipment – as required for pembrolizumab administration.

Refrigerators and freezers – as required to store study treatments and laboratory 
samples.
Additional guidance regarding critical equipment is provided in the Procedures Manual, 
Pharmacy Manual, and Site Imaging Manual.  
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.
Screening Visit
7.1.5.1
Within 28 days prior to treatment randomization, 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 the Trial Flow Chart (Section 6.0).  Screening procedures may 
be repeated.
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.  Screening procedures are to be completed within 28 days prior to the first dose of 
trial treatment except for the following:
Use the bullets below that apply to the trial.

Laboratory tests are to be performed within 3 days prior to the first dose of trial 
treatment. An exception is hepatitis testing which may be done up to 28 days prior to 
the first dose of trial treatment.

Evaluation of ECOG is to be performed within 3 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine or serum 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 trial site laboratory).

Archival tumor sample collection is not required to be obtained within 28 days prior 
to the first dose of trial treatment.  Newly obtained tumor tissue may be obtained 
within 90 days of treatment initiation.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met.  Subjects who are rescreened will retain their original 
screening number.
 
 
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Treatment Period Visits
7.1.5.2
Visit requirements are outlined in the Trial Flow Chart (Section 6.0).  Specific procedure-
related details are provided in Section 7.1 – Trial Procedures.
Post-Treatment Visits
7.1.5.3
7.1.5.3.1 End of Treatment – Discontinuation Visit
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow up Visit, the Discontinuation visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 6.0- Trial Flow Chart. Additional details regarding subject withdrawal 
and discontinuation are presented in Section 5.7– Subject Withdrawal/Discontinuation.
7.1.5.3.2 Safety Follow-up Visit
When subjects discontinue study treatment, safety follow-up visit will be required. The Post-
Treatment Safety Follow-Up visit should occur approximately 30 days after the last dose of 
study treatment. If a subject initiates a new anticancer therapy within 30 days after the last 
dose of study treatment, the Post-Treatment Safety Follow-Up visit should occur before the 
first dose of the new therapy.
After treatment discontinuation, subjects will be monitored for AEs and SAEs for 90 days. 
Subjects who initiate new anticancer therapy less than 30 days after study treatment 
discontinuation will be monitored for AEs/SAEs for 30 days. Subjects who initiate new 
anticancer therapy between 30 days and 90 days after study treatment discontinuation will be 
monitored for AEs/SAEs until the day new anticancer therapy is initiated. 
Subjects who discontinue treatment for reasons other than confirmed disease progression will 
have post-treatment follow-up for disease status until disease progression, initiating a new 
anticancer therapy, withdrawing consent for trial participation, or becoming lost to follow-up, 
whichever occurs 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. 
7.1.5.3.3 Imaging Follow-up Visits
Subjects who discontinue treatment for reasons other than verified PD should continue with 
imaging assessments per the protocol defined schedule until: 1) PD is verified or further 
confirmed by the investigator, 2) initiation of a new anti-cancer treatment, 3) death, 4) 
withdrawal of consent or 5) study conclusion or early termination, whichever occurs first.
7.1.5.3.4 Survival Follow-up Visits
Subjects, who experience confirmed disease progression or start a new anti-cancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
 
 
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The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested prior to an 
efficacy interim analysis, and/or final analysis. All subjects who are not known to have died 
prior to the request for these additional survival status time points will be contacted at that 
time.
When a subject discontinues trial treatment in treatment period and/or retreatment period, 
procedures for discontinuation will be conducted.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of trial treatment if the subject initiates 
new anticancer therapy, whichever is earlier, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. The investigator will make every attempt to follow all 
subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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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 this trial, an overdose of preladenant will be defined as any dose exceeding the 
prescribed dose for preladenant by ≥20% of the indicated dose.  An overdose of 
pembrolizumab will be defined as any dose of 1000 mg or greater (≥5 times the indicated 
dose). 
No specific information is available on the treatment of overdose of preladenant or 
pembrolizumab.  In the event of overdose, the subject should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no othe r 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of trial treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies  must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
 
 
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(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 14 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 
24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.3.3 for additional details), whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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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 following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
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).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.  
 
 
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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 an 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.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse event to the single agent.
 
 
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Table 14
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and key 
secondary analyses of the study.  Exploratory and other non-confirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP). 
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9).  Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report (CSR) for the 
study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full details are
in the Statistical Analysis Plan (SAP), Section 8.2 through 8.12.
Trial Design Overview
Phase 1b/II trial of preladenant as monotherapy and preladenant in 
combination with pembrolizumab in subjects with advanced solid tumors. 
The trial applies an mTPI design for dose escalation and confirmation of 
RP2Ds, followed by an expansion phase to further examine safety and
exploratory efficacy in select tumor types.
Analysis Populations
Safety (Primary): All-Subjects-as-Treated (ASaT)
Efficacy (Secondary & Exploratory): Full Analysis Set (FAS)
Primary Endpoint(s)
Safety: Dose-limiting toxicities (DLTs)
Key Secondary Endpoints
ORR in subjects treated with preladenant as monotherapy and preladenant
in combination with pembrolizumab
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The point estimate and 95% confidence interval (CI) for ORR will be 
evaluated separately in subjects treated with preladenant as monotherapy 
and subjects treated with preladenant in combination with pembrolizumab, 
using exact binomial distribution. 
Treatment Assignment
Subjects will be allocated to receive single agent preladenant or 
preladenant co-administered with pembrolizumab centrally through an 
IVRS/IWRS. In Part 1, subjects will be allocated by non-random 
assignment. Allocation will alternate between the 2 arms when both arms 
are open for enrollment. In Part 2, subjects will be allocated to each cohort 
by tumor type. . The trial is open-label.
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentages, means, standard deviations, etc.) 
will be provided for the safety endpoints as appropriate. The pool-adjacent-
violators algorithm [22] that forces the DLT rate estimates to be non-
decreasing with dose levels and pools adjacent violators for weighted 
estimates by sample size will be used to estimate the DLT rates across 
doses. The estimates of the DLT rates among subjects treated at the RP2Ds
of preladenant when used as monotherapy and when used in combination 
with pembrolizumab and the 80% Bayesian credible intervals for the 
estimates will be provided.
 
 
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Interim Analyses
Data will be examined on a continuous basis to allow for dose escalation 
and confirmation decisions using the mTPI design in Part 1. An interim 
futility check will be performed for each of the select solid tumor cohorts
in Part 2.
Multiplicity
No multiplicity adjustment is planned for this Phase 1b/II trial.
Sample Size and Power 
The overall sample size for this trial depends on the observed DLT profiles 
of preladenant as monotherapy and preladenant in combination with 
pembrolizumab. A target sample size of 112 subjects will be used for trial
planning purposes.
Responsibility for Analyses/In-House Blinding
8.2
The statistical analyses of the data obtained from this trial will be the responsibility of th e 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, i.e., subjects, investigators, and Sponsor personnel will be aware of 
subject treatment assignment after each subject is enrolled and treatment is assigned.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are outlined in Section 3.0.
Analysis Endpoints
8.4
Efficacy/Immunogenicity/Pharmacokinetic Endpoints
8.4.1
Overall response rate is a secondary endpoint of the trial. Overall response rate is defined as 
the proportion of subjects in the analysis population who experience complete response (CR) 
or partial response (PR) using RECIST 1.1 criteria as assessed by investigator review. Other 
efficacy endpoints (e.g., DOR, PFS) are exploratory endpoints in this trial and will be defined 
in the sSAP.
Pharmacokinetic endpoints include serum concentrations of preladenant and pembrolizumab 
and derived PK parameters.
Safety Endpoints
8.4.2
The primary safety endpoint is the rate of DLTs. A description of safety measures is provided 
in Section 5.2.2 and Section 7.2. 
Analysis Populations
8.5
Safety Analysis Population
8.5.1
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 subjects who received at least one dose of 
study treatment.  In case of treatment administration errors, subjects will be analyzed 
according to the treatment they actually received.  For DLT evaluation, ASaT subjects that 
were observed for safety for 21 days after the first dose of assigned treatment or experienced 
a DLT prior to 21 days after the first dose of assigned treatment will be used. The 
replacement subjects will also be considered evaluable if the above specified criteria are met.  
 
 
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At least one 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.  Safety data from subjects 
who experienced disease progression in the monotherapy arm and crossed over into the 
combination arm will be presented separately.
Efficacy Analysis Populations
8.5.2
The Full Analysis Set (FAS) population will be used for the analysis of secondary and 
exploratory efficacy data in this trial. The FAS population consists of all subjects with a 
baseline scan with measurable disease by investigator assessment who were administered a 
dose of study treatment regardless of dose level. Data from subjects who experienced disease 
progression in the monotherapy arm and crossed over into the combination arm will be 
presented separately.
Statistical Methods
8.6
Statistical Methods for Efficacy Analyses
8.6.1
For the secondary endpoint of ORR, the point estimate and 95% CI will be evaluated 
separately in subjects treated with preladenant as monotherapy and subjects treated with 
preladenant in combination with pembrolizumab, using an exact method based on binomial 
distribution (Clopper-Pearson interval). 
Of note, patients enrolled in Part 1 in the 
combination arm (Arm 2) and treated at the same dose level as that selected for Part 2, will 
be pooled together with patients enrolled in Part 2 for efficacy analysis if they have the same 
tumor type. 
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
Adverse events will be summarized by counts and frequencies for each dose level and
treatment arm. Patients enrolled in Part 1 in the combination arm (Arm 2) and treated at the 
same dose level as that selected for Part 2, will also be pooled together with patients enrolled 
in Part 2 for safety analysis if they have the same tumor type. Laboratory tests, vital signs, 
and other safety endpoints will be summarized as appropriate.
Dose limiting toxicities will be listed, and further summarized by dose level and treatment 
arm.  The pool adjacent-violators-algorithm [22], which forces the DLT rate estimates to be 
non-decreasing with dose levels and pools adjacent violators for weighted estimates by 
sample size, will be used to estimate the DLT rates across doses in each treatment arm. The 
estimates of the DLT rates among subjects treated at the MTDs (or MADs) and the 80% 
Bayesian credible intervals based on a prior distribution of Beta (1,1) for the estimates will 
be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
 
 
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Interim Analyses
8.7
In this study there will be no hypothesis testing, although an interim analysis may be
conducted to enable future trial planning at the Sponsor’s discretion and data will be
examined on a continuous basis to allow for dose escalation and confirmation decisions.
An interim futility check will be performed for each of the select solid tumor cohorts in Part 
2. If there are no responders among approximately the first 15 evaluable patients that have at 
least 1 post-baseline scan assessment in a given cohort, that cohort may be stopped early for 
futility. If the true response rate is 10%, there is an 80% chance to observe at least one 
responder among 15 patients.
Multiplicity
8.8
There will be no multiplicity control in this trial.
Sample Size and Power Calculations
8.9
During Part 1 (dose escalation and confirmation), approximately 52 subjects (26 subjects in 
each treatment arm) are expected to be enrolled. 
For each testing dose level in each 
treatment arm, 3 to 6 subjects may be enrolled, however based on the occurrence of DLTs, 
up to 14 subjects may be enrolled. The actual sample size of Part 1 will depend on the safety 
profiles of preladenant in each treatment arm, and may be increased if the RP2D is not 
reached and additional dose levels are required.
In Part 2 (expansion phase) approximately 60 subjects (30 subjects in each cohort) are 
expected to be enrolled. The key efficacy endpoint will be the objective response rate based 
on the investigator assessment per RECIST 1.1. Table 15 shows the ORR estimate and at 
least 95% CI (Clopper-Pearson interval) in each cohort.  
Table 15
Estimate and 95% CI of ORR in Each Cohort
Sample Size
Number of 
Responses (PR/CR)
Observed ORR
95% CI of ORR
30
3
10%
(2.1%, 26.5%)
4
13.3%
(3.8%, 30.7%)
5
16.7%
(5.6%, 34.7%)
6
20%
(7.7%, 38.6%)
7
23.3%
(9.9%, 42.3%)
8
26.7%
(12.3%, 45.9%)
9
30%
(14.7%, 49.4%)
10
33.3%
(17.3%, 52.8%)
A target sample size of 112 subjects will be used for trial planning purposes.
Subgroup Analyses
8.10
Subgroup analyses of the efficacy endpoint ORR will be conducted by treatment arm, dose 
level, and tumor type.
Additional subgroup analyses for Part 2 may be conducted as needed, for example, age, race, 
 
 
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Compliance (Medication Adherence)
8.11
Drug accountability data for study treatment will be collected during the trial (see Section 
7.1.1.9).  Any deviation from protocol-directed administration will be reported.
Extent of Exposure
8.12
The extent of exposure will be summarized as duration of treatment in cycles.
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 16.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 16
Product Descriptions
Treatment 
Group
Product 
Name and 
Dosage Form
Dose
Potency
Total Dosage 
Forms
Additional 
Information
Part1
Arm 1
MK-3814 
capsule
Cohort DL-1 
10mg BID
5mg capsule
2 capsules 
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL1
25mg BID
25mg capsule
1 capsule
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL2
50mg BID
25mg capsule
2 capsules 
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL3
100mg BID
25mg capsule
4 capsules 
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL4
200mg BID
25mg capsule
8 capsules 
twice a day
Provided 
centrally by the 
Sponsor
 
 
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Treatment 
Group
Product 
Name and 
Dosage Form
Dose
Potency
Total Dosage 
Forms
Additional 
Information
Arm 2
MK-3814 
capsule
Cohort DL-1 
10mg BID
5mg capsule
2 capsules 
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL1
25mg BID
25mg capsule
1 capsule
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL2
50mg BID
25mg capsule
2 capsules 
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL3
100mg BID
25mg capsule
4 capsules 
twice a day
Provided 
centrally by the 
Sponsor
Cohort DL4
200mg BID
25mg capsule
8 capsules 
twice a day
Provided 
centrally by the 
Sponsor
MK-3475 vial
All cohorts
200mg/dose
100mg/4mL 
vial
2 vials
Provided 
centrally by the 
Sponsor
Part 2
Arm 2 only 
(cohort 1 and 
cohort 2)
MK-3814 
capsule
RP2D
TBD BID
TBD capsule
TBD
twice a day
Provided 
centrally by the 
Sponsor
MK-3475 vial
RP2D
200 mg/dose
100 mg/4mL 
vial
2 vials
Provided 
centrally by the 
Sponsor
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label supplies of MK-3814 and MK-3475 consistent with their
treatment arm and dose cohort.  
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.
 
 
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Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/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, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
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 that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
 
 
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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/IEC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
 
 
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approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The Sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
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 Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
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 
 
 
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to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
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]
Ji Y, Wang S-J. Modified toxicity probability interval design: a safer and more 
reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol 
2013;31:1-12.
[2]
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 
2011;480:480-9.
[3]
Leone RD, Lo YC, Powell JD. A2aR antagonists: Next generation checkpoint 
blockade for cancer immunotherapy. Comput Struct Biotechnol J. 2015 Apr 
8;13:265-72.
[4]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[5]
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.
[6]
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 Jun 19;358(25):2698-703.
[7]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[8]
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.
[9]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity 
2004;20:337-47.
[10]
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed death 1 
upon primary human T cell stimulation, but only receptor ligation prevents T cell 
activation. J Immunol 2004;173:945-54.
[11]
Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.
[12]
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
[13]
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25(21):9543-53.
[14]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
 
 
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[15]
Cekic C, Linden J. Purinergic regulation of the immune system. Nat Rev Immunol. 
2016 Mar;16(3):177-92.
[16]
Stagg J, Divisekera U, McLaughlin N, Sharkey J, Pommey S, Denoyer D, et al. 
Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl 
Acad Sci U S A. 2010 Jan 26;107(4):1547-52.
[17]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182:318-24.
[18]
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;59:909-19.
[19]
Beavis PA, Stagg J, Darcy PK, Smyth MJ. CD73: a potent suppressor of antitumor 
immune responses. Trends Immunol. 2012 May;33(5):231-7.
[20]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 2013 
Jul 15;19(14):3936-43.
[21]
FDA Guidance for industry drug-induced liver injury: Premarketing clinical 
evaluation.
[22]
Ji Y, Li Y, Bekele BN. Dose-finding in phase l clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law,
only the investigator, Sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.3 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology 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 the Sponsor or those working for 
or with the Sponsor.
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 the visit designated in the trial flow chart.  
If delayed, present consent at next possible Subject Visit.  Consent forms signed by the 
subject will be kept at the clinical trial site under secure storage for regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the Sponsor’s
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in the 
electronic Case Report Forms (eCRFs). Any specimens for which such an informed 
consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as outlined in 
the trial flow chart. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the subject is 
having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This 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 unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. 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 specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  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). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/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 withdrawal of consent and/or destruction cannot 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 the end of the main study. 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 Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-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 Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
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.
The Sponsor 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.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. 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
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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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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National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
12.5
Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  
(http://ctep.cancer.gov/reporting/ctc.html).  
 
 
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List of Abbreviations 
12.6
Abbreviation/Term 
Definition
A2AR
Adenosine Type 2a Receptor
ADA
Anti-Drug Antibody
ADP
Adenosine Diphosphate
AE
Adverse Event 
ALT
Alanine aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
AST
Aspartate aminotransferase
ATP
Adenosine Triphosphate
AUC
Area Under the Curve 
BCG
Bacille Calmette Guerin 
BID
Two times a day 
BUN
Blood Urea Nitrogen
CEA
Carcinoembryonic Antigen
CFR
Code of Federal Regulations
CI
Coordinating Investigator
Cmax
Maximum Concentration in blood
CNS
Central Nervous System
CO2
Carbon Dioxide
COPD
Chronic obstructive pulmonary disease 
CR
Complete Response
CRC
Colorectal Cancer
CRU
Clinical research unit
CrCl
Creatinine Clearance
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
Ctrough
Trough concentration in blood
DCs
Dendritic Cells
DCR
Drug Control Rate
DL
Dose Level 
DLT
Dose Limiting Toxicity
dMMR
deficient Mismatch Repair (MMR)
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
ERC
Ethics Review Committee
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin fixed paraffin embedded
 
 
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Abbreviation/Term 
Definition
FSH
Follicle Stimulating hormone
FT3
Triiodothyronine
FT4 
Free Thyroxine
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GGT
Gamma Glutamyl Transferase
GI
Gastrointestinal 
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HNSCC
Head and neck squamous cell cancer
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
Ig
Immunoglobulin
IHC
Immunohistochemistry 
INR
International Normalized Ratio
irAE
Immune-related Adverse Event
IRB
Institutional Review Board
irORR
Immune related Overall Response Rate 
irRECIST
Immune-related Response Evaluation Criteria in 
Solid Tumors
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Immunoglobulin Tail Tyrosine
IUD
IntraUterine Device
IV
IntraVenous 
IVD
InVitro Diagnostic
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
MDSCs
Myeloid Derived Suppressor Cells
mL
Milligram
MMR
Mismatch Repair
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MTD
Maximum Tolerated Dose 
mTPI
modified Toxicity Probability Interval
NK Cells
Natural Killer Cells
NSCLC
Non-Small Cell Lung Cancer 
ORR
Overall Response Rate
OS
Overall Survival 
PD
Progressive Disease
PD-L1
Programmed Cell Death-1
PFS
Progression Free Survival
PK/PD 
Pharmacokinetic/Pharmacodynamic
pMMR
Proficient Mismatch Repair
p.o
Administered orally 
PPI
Proton Pump Inhibitor
PR
Partial response
 
 
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Abbreviation/Term 
Definition
PT
Preferred Term 
Q2W
Once Every 2 weeks 
Q3W
Once Every 3 weeks 
RCC
Renal Cell Cancer 
RECIST
Response Evaluation Criteria in Solid Tumors 
RO
Receptor occupancy
RP2D
Recommended Phase II Dose
SAP
Statistical analysis plan 
SAE
Serious Adverse Event
SD
Stable disease
sSAP
Supplemental statistical analysis plan 
T3
Triiodothyronine
T4
Thyroxine
TAMs
Tumor-Associated Macrophages
TBNC
Triple negative breast cancer
TILs
Tumor-infiltrating T Lymphocytes
Tregs
Regulatory T cells
TSH
Thyroid Stimulating Hormone
TQT
Thorough QT/QTc
ULN
Upper Limit Of Normal 
VEGF
Vascular Endothelial Growth Factor
WBC
White Blood Cells 
ZAP70
Zeta-chain-associated protein kinase
β-hCG
Β-Human Chorionic Gonadotropin
 
 
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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 – TRIAL PROCEDURES (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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